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Clinical Guidelines |

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians FREE

Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Donna E. Sweet, MD; Melissa Starkey, PhD; Paul Shekelle, MD, PhD, for the Clinical Guidelines Committee of the American College of Physicians*
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* This paper, written by Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Donna E. Sweet, MD; Melissa Starkey, PhD; and Paul Shekelle, MD, PhD, was developed for the Clinical Guidelines Committee of the American College of Physicians: Paul Shekelle, MD, PhD (Chair); Roger Chou, MD; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Nick Fitterman, MD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; Linda L. Humphrey, MD, MPH; Tanveer P. Mir, MD; Holger J. Schünemann, MD, PhD; Donna E. Sweet, MD; and David S. Weinberg, MD, MSc. Approved by the ACP Board of Regents on 19 November 2011.


From the American College of Physicians, Philadelphia, Pennsylvania; Oregon Health & Science University, Portland, Oregon; University of Kansas School of Medicine, Wichita, Kansas; and West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.

Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.

Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Department of Veterans Affairs.

Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.

Potential Conflicts of Interest: Any financial and nonfinancial conflicts of interest of the group members were declared, discussed, and resolved. A record of conflicts of interest is kept for each Clinical Guidelines Committee meeting and conference call and can be viewed at www.acponline.org/clinical_information/guidelines/guidelines/conflicts_cgc.htm. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2857.

Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, aqaseem@acponline.org.

Current Author Addresses: Drs. Qaseem and Starkey: 190 N. Independence Mall West, Philadelphia, PA 19106.

Dr. Humphrey: 3710 SW U.S. Veterans Hospital Road, Portland, OR 97207.

Dr. Sweet: 1010 North Kansas, Wichita, KS 67214.

Dr. Shekelle: 11301 Wilshire Boulevard, Los Angeles, CA 90073.

Author Contributions: Conception and design: A. Qaseem, P. Shekelle.

Analysis and interpretation of the data: A. Qaseem, L.L. Humphrey.

Drafting of the article: A. Qaseem, M. Starkey.

Critical revision of the article for important intellectual content: A. Qaseem, L.L. Humphrey, P. Shekelle.

Final approval of the article: A. Qaseem, L.L. Humphrey, P. Shekelle.

Statistical expertise: A. Qaseem.

Administrative, technical, or logistic support: A. Qaseem, M. Starkey.

Collection and assembly of data: A. Qaseem, M. Starkey.


Ann Intern Med. 2012;156(3):218-231. doi:10.7326/0003-4819-156-3-201202070-00011
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This article has been corrected. The original version (PDF) is appended to this article as a supplement.

Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness and safety of type 2 diabetes medications.

Methods: This guideline is based on a systematic evidence review evaluating literature published on this topic from 1966 through April 2010 that was identified by using MEDLINE (updated through December 2010), EMBASE, and the Cochrane Central Register of Controlled Trials. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular morbidity and mortality, cerebrovascular morbidity, neuropathy, nephropathy, and retinopathy. This guideline grades the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system.

Recommendation 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence).

Recommendation 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence).

Recommendation 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence).


Diabetes mellitus is the seventh leading cause of death in the United States. In addition, it is a leading cause of morbidity and leads to microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery, cerebrovascular, and peripheral vascular disease) complications. Type 2 diabetes mellitus is the most common form of the disease (affecting 90% to 95% of persons with diabetes), with a prevalence of approximately 25.8 million people in the United States (1). Type 2 diabetes increases with age, and nearly 27% of people in the United States older than 65 years have diabetes (1). In addition, because of increasing rates of obesity in the United States, the incidence and prevalence of diabetes mellitus are increasing substantially (1). The costs associated with diabetes in the United States alone reached $174 billion in 2007 (2).

Good management of type 2 diabetes with pharmacologic and nonpharmacologic therapies is important and includes patient education, evaluation for microvascular and macrovascular complications, treatment of glycemia, and minimization of cardiovascular and other long-term risks. In the United States, 11 unique classes of drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of hyperglycemia in type 2 diabetes; all of these medications vary in cost and risk (3). Among people diagnosed with diabetes, most will receive more than 1 class of diabetes medication: 14% take both insulin and oral medication and 58% take oral medications only (2).

The purpose of this American College of Physicians (ACP) guideline is to address the pharmacologic management of type 2 diabetes by comparing the effectiveness and safety of currently available oral pharmacologic treatment for type 2 diabetes. The target audience for this guideline includes all clinicians, and the target patient population comprises all adults with type 2 diabetes. These recommendations are based on a systematic evidence review by Bennett and colleagues (4) and an evidence report sponsored by the Agency for Healthcare Research and Quality (AHRQ) (5). The 2011 review expands on a 2007 AHRQ evidence report (6), which discussed mortality, microvascular and macrovascular outcomes, intermediate outcomes, and adverse effects for drugs available until 2006. The 2011 report focuses on head-to-head comparisons and includes direct comparisons for monotherapy and dual-therapy regimens. Combination therapies with more than 2 agents were not included in the review. The 2011 report also includes evidence for more recently approved diabetes medications and excludes data on α-glucosidase inhibitors, such as acarbose (5).

The evidence report informing this guideline reviewed data for 11 FDA-approved, unique classes of drugs for the treatment of hyperglycemia in type 2 diabetes (Appendix Table 1). This guideline is based on a systematic evidence review that addressed the following key questions:

Table Jump PlaceholderAppendix Table 1. Type 2 Diabetes Medications, Dosages, and Wholesale Price Range 

Key question 1: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative effectiveness of these treatment options for the intermediate outcomes of glycemic control (in terms of hemoglobin A1c [HbA1c]), weight, or lipids?

Key question 2: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative effectiveness of these treatment options in terms of the following long-term clinical outcomes: all-cause mortality, cardiovascular mortality, cardiovascular and cerebrovascular morbidity (for example, myocardial infarction and stroke), retinopathy, nephropathy, and neuropathy?

Key question 3: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative safety of these treatment options in terms of the following adverse events and side effects: hypoglycemia, liver injury, congestive heart failure, severe lactic acidosis, cancer, severe allergic reactions, hip and nonhip fractures, pancreatitis, cholecystitis, macular edema or decreased vision, and gastrointestinal side effects?

Key question 4: Do safety and effectiveness of these treatment options differ across subgroups of adults with type 2 diabetes, in particular for adults aged 65 years or older, in terms of mortality, hypoglycemia, and cardiovascular and cerebrovascular outcomes?

The systematic evidence review was conducted by the Johns Hopkins Evidence-based Practice Center. This review updates a 2007 systematic review on the same topic and focuses on head-to-head comparisons rather than placebo-controlled trials (67). The literature search included studies identified by using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. The studies that were selected included observational studies and trials published in the English language from 1966 through April 2010. In addition, the MEDLINE search was updated to December 2010 for long-term clinical outcomes (all-cause mortality, cardiovascular morbidity and mortality, nephropathy, neuropathy, and retinopathy). Reference lists, FDA medical reviews, European Public Assessment Reports, Health Canada Product Monographs, unpublished data from pharmaceutical companies, and public registries of clinical trials were also reviewed. Standardized forms were used for data abstraction, and each article underwent double review. Quality of randomized, controlled trials (RCTs) was assessed by using the Jadad criteria, and quality of observational studies was assessed as recommended in the Guide for Conducting Comparative Effectiveness Reviews (89). The I2 statistic was used to determine study heterogeneity (10). Further details about the methods and inclusion and exclusion criteria applied in the evidence review are available in the full AHRQ report (5).

This guideline rates the recommendations by using the American College of Physicians guideline grading system, which is based on the GRADE system (Table 1). Details of the ACP guideline development process can be found in ACP's methods paper (11). This guideline focuses on results that were statistically significant, and details on non–statistically significant results are available in the full AHRQ report (5).

Table Jump PlaceholderTable 1. The American College of Physicians Guideline Grading System 

Table 2 summarizes the key findings and strength of evidence for intermediate outcomes comparing various diabetes medications as monotherapy or as combination therapy.

Table Jump PlaceholderTable 2. Key Findings and Strength of Evidence for Intermediate Outcomes 
HbA1c Levels

Evidence was gathered from 104 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications (5).

Monotherapy vs. Monotherapy

Most diabetes medications had similar efficacy and reduced HbA1c levels by an average of 1 percentage point (4). However, pooled results from 3 studies (reported in 4 papers) showed that metformin decreased HbA1c levels more than did dipeptidyl peptidase-4 (DPP-4) inhibitors (mean difference, −0.37 percentage point [95% CI, −0.54 to −0.20 percentage point]; I2 = 0%; moderate-quality evidence) (1215).

Monotherapy vs. Combination Therapy

All dual-regimen combination therapies were more efficacious than monotherapy and reduced HbA1c levels by an average of 1 additional percentage point compared with monotherapy (4). Pooled data for the combination of metformin with another agent compared with metformin monotherapy showed a greater decrease in HbA1c levels: metformin plus a sulfonylurea (mean difference, 1.00 percentage point [CI, 0.75 to 1.25 percentage point]; I2 = 85%; high-quality evidence), metformin plus a DPP-4 inhibitor (mean difference, 0.69 percentage point [CI, 0.56 to 0.82 percentage point]; I2 = 97%; moderate-quality evidence), metformin plus a thiazolidinedione (mean difference, 0.66 percentage point [CI, 0.45 to 0.86 percentage point]; I2 = 84%; high-quality evidence). Comparisons between different combinations of drugs showed similar effects, although few trials were available. Evidence from trials that included glucagon-like peptide-1 (GLP-1) agonists was graded as insufficient or low.

Combination Therapy vs. Combination Therapy

One RCT showed that the combination of metformin plus a GLP-1 agonist (liraglutide) statistically significantly decreased HbA1c levels by 0.34 to 0.60 percentage points in low- and high-dose combinations compared with metformin plus a DPP-4 inhibitor (sitagliptin) (low-quality evidence) (16). A post hoc analysis of a small RCT showed that the combination of a thiazolidinedione plus a sulfonylurea decreased HbA1c levels by 0.03 percentage point (P = 0.04) more than did the combination of metformin plus a thiazolidinedione (low-quality evidence) (17). All other combinations had similar efficacy in reducing HbA1c levels (5).

Body Weight

Evidence was gathered from 79 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications (5).

Monotherapy vs. Monotherapy

Pooled results showed that monotherapy with metformin resulted in more weight loss compared with thiazolidinediones (mean difference, −2.6 kg [CI, −4.1 to −1.2 kg]; I2 = 85%; high-quality evidence) (1825), sulfonylureas (mean difference, −2.7 kg [CI, −3.5 to −1.9 kg]; I2 = 51%; high-quality evidence) (23, 2636), and DPP-4 inhibitors (mean difference, −1.4 kg [CI, −1.8 to −1.0; I2 = 5%; moderate-quality evidence) (12, 1415). Monotherapy with a thiazolidinedione compared with a sulfonylurea resulted in more weight loss (mean difference, 1.2 kg [CI, 0.6 to 1.9 kg]; I2 = 0%; low-quality evidence) (23, 3740). Compared with GLP-1 agonists, sulfonylureas showed more weight gain (mean difference, 2.5 kg [CI, 1.2 to 3.8 kg]; I2 = 93%; moderate-quality evidence), although the studies were very heterogeneous (4143).

Monotherapy vs. Combination Therapy

Pooled data showed that metformin monotherapy was more effective in decreasing body weight than metformin plus a thiazolidinedione (mean difference, −2.2 kg [CI, −2.6 to −1.9 kg]; I2 = 0%; high-quality evidence) (24, 4447) or metformin plus a sulfonylurea (mean difference, −2.3 kg [CI, −3.3 to −1.2 kg]; I2 = 83%; high-quality evidence) (2936, 4849). Metformin was also favored when compared with metformin plus meglitinides in 2 RCTs (5051).

Combination Therapy vs. Combination Therapy

Pooled data showed that the combination of metformin plus a sulfonylurea was favored for weight compared with metformin plus a thiazolidinedione (mean difference, 0.9 kg [CI, 0.4 to 1.3 kg]; I2 = 0%; moderate-quality evidence) (5256). Pooled data also showed that the combination of metformin plus a sulfonylurea is favored over the combination of a thiazolidinedione and sulfonylurea (mean difference, −3.17 [CI, −5.21 to −1.13 kg]; I2 = 83%; moderate-quality evidence). Compared with the combination of metformin plus a sulfonylurea (glipizide), metformin plus a DPP-4 inhibitor (sitagliptin) statistically significantly reduced weight in 1 RCT (mean difference, −2.5 kg [CI, −3.1 to −2.0 kg]) (57), and the trend continued when the study was extended for another year (mean difference, −2.3 kg [CI, −3.0 to −1.6 kg]) (low-quality evidence) (58). Combination of metformin plus a GLP-1 agonist also resulted in greater weight loss compared with the combination of metformin plus a sulfonylurea, as shown in 2 RCTs (low-quality evidence) (49, 59).

Plasma Lipid Levels

Evidence was gathered from 74 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications. Most diabetes medications had a small to moderate effect on lipid levels: 5 to 10 mg/dL for low-density lipoprotein (LDL) cholesterol, 3 to 5 mg/dL for high-density lipoprotein (HDL) cholesterol, and 10 to 30 mg/dL for triglycerides (5).

LDL Cholesterol Levels
Monotherapy vs. Monotherapy.

Monotherapy with metformin decreased LDL more than did thiazolidinedione monotherapy with pioglitazone (mean difference, −14.21 mg/dL [CI, −15.29 to −13.13 mg/dL]; I2 = 0%; high-quality evidence) (18, 22, 25, 6062) or rosiglitazone (mean difference, −12.76 mg/dL [CI, −23.96 to −1.56 mg/dL]; I2 = 56%; moderate-quality evidence) (2021, 24, 6365). Metformin was also favored over both sulfonylureas (mean difference, −10.1 mg/dL [CI, −13.3 to −7.0 mg/dL]; I2 = 85%; high-quality evidence) (28, 3031, 33, 3536, 6667) and DPP-4 inhibitors (mean difference, −5.9 mg/dL [CI, −9.7 to −2.0 mg/dL]; I2 = 28%; moderate-quality evidence) (12, 1415). Pooled data showed that monotherapy with sulfonylureas more effectively reduced LDL cholesterol than did pioglitazone (mean difference, 7.12 mg/dL [CI, 5.26 to 8.98 mg/dL]; I2 = 4%; low-quality evidence) (40, 6869), and 2 RCTs showed that rosiglitazone increased LDL cholesterol compared with sulfonylurea monotherapy (low-quality evidence) (37, 39).

Monotherapy vs. Combination Therapy.

Compared with metformin monotherapy, combination of metformin with other agents did not show any benefit (5).

Combination Therapy vs. Combination Therapy.

The combination of metformin plus a sulfonylurea was favored over metformin plus a thiazolidinedione, as pooled data showed for rosiglitazone (mean difference, 13.5 mg/dL [CI, 9.1 to 17.9 mg/dL]; I2 = 0%; moderate-quality evidence) (5455, 7071) and a single RCT showed for pioglitazone (mean difference, 8.5 mg/dL; P = 0.03; low-quality evidence) (56). The combination of metformin plus a sulfonylurea was also favored over the combination of pioglitazone plus a sulfonylurea, as reported in 2 RCTs (low-quality evidence) (7273).

HDL Cholesterol Levels
Monotherapy vs. Monotherapy.

Monotherapy with metformin was less effective than a thiazolidinedione (pioglitazone) at increasing HDL cholesterol levels (mean difference, −3.2 mg/dL [CI, −4.3 to −2.1 mg/dL]; I2 = 93%; high-quality evidence) (18, 2223, 25, 6062, 74). Monotherapy with a thiazolidinedione more effectively increased HDL cholesterol levels compared with a sulfonylurea, as shown by pooled data for pioglitazone (mean difference, 4.27 mg/dL [CI, 1.93 to 6.61 mg/dL]; I2 = 99%; moderate-quality evidence) (23, 40, 59, 68, 7475) and data from 2 RCTs for rosiglitazone (range in median between-group difference, 3.5 to 7.7 mg/dL; low-quality evidence) (37, 39). Two RCTs also showed that monotherapy with pioglitazone was favored over meglitinides (mean difference, 7 mg/dL; low-quality evidence) (7576). When thiazolidinediones were compared, pioglitazone increased HDL cholesterol levels more than did rosiglitazone (mean difference, −2.33 mg/dL [CI, −3.46 to −1.20 mg/dL]; I2 = 0%; moderate-quality evidence) (7779).

Monotherapy vs. Combination Therapy.

The combination of metformin with a thiazolidinedione was better than monotherapy with metformin, as shown by pooled data for rosiglitazone (mean difference, −2.8 mg/dL [CI, −3.5 to −2.2 mg/dL]; I2 = 83%; high-quality evidence) (24, 4445, 47, 8082), and 2 RCTs favored the combination of metformin plus pioglitazone over metformin monotherapy (46, 83).

Combination Therapy vs. Combination Therapy.

The combination of metformin plus a thiazolidinedione was favored over the combination of metformin and a sulfonylurea, as shown by pooled data for rosiglitazone (mean difference, 2.7 mg/dL [CI, 1.4 to 4.1 mg/dL]; I2 = 0%; moderate-quality evidence) (5455, 7071), data from 2 RCTs for pioglitazone (between-group differences ranged from 5.1 mg/dL [P < 0.001] to 5.8 mg/dL [P < 0.001]; low-quality evidence) (56, 84). Post hoc analysis in 1 RCT showed that the combination of metformin plus pioglitazone increased HDL cholesterol levels (2.3 mg/dL; P = 0.009) compared with pioglitazone plus sulfonylurea (0.4 mg/dL; P = 0.62) (low-quality evidence) (84). Three RCTs found an increase in HDL cholesterol levels with the combination of pioglitazone plus a sulfonylurea compared with metformin plus a sulfonylurea (low-quality evidence) (7273, 84).

Triglyceride Levels
Monotherapy vs. Monotherapy.

Metformin monotherapy decreased triglyceride levels compared with sulfonylureas (mean difference, −8.6 mg/dL [CI, −15.6 to −1.6 mg/dL]; I2 = 92%; moderate-quality evidence) (23, 26, 2831, 33, 3536, 66, 74) and rosiglitazone (mean difference, −26.86 mg/dL [CI, −49.26 to −4.47 mg/dL]; I2 = 70%; moderate-quality evidence) (2021, 24, 6365). However, pooled data from other studies showed that pioglitazone decreased triglyceride levels more than did metformin (mean difference, 27.2 mg/dL [CI, 24.4 to 30.0 mg/dL]; I2 = 0%; high-quality evidence) (18, 2223, 25, 6062, 74) and sulfonylureas (mean difference, −31.62 mg/dL [CI, −49.15 to −14.10 mg/dL]; I2 = 91%; low-quality evidence) (23, 40, 6869, 7475). Two RCTs also favor pioglitazone over meglitinides for reducing triglyceride levels (7576).

Monotherapy vs. Combination Therapy.

Metformin monotherapy decreased triglyceride levels more than metformin plus a thiazolidinedione (rosiglitazone) (mean difference, −14.5 mg/dL [CI, −15.8 to −13.3 mg/dL]; I2 = 0%; high-quality evidence) (24, 4445, 47, 8082). However, than with metformin monotherapy, combination therapy consisting of metformin plus a DPP-4 inhibitor (mean difference, 20.68 mg/dL [CI, −0.79 to 42.14 mg/dL]; low-quality evidence; P > 0.05) (1415, 47, 85) or metformin plus meglitinides (data from a single RCT: range of between-group differences, −17.8 to 8.9 mg/dL; P < 0.05 for the higher-dose nateglinide; low-quality evidence) (50) decreased triglyceride levels more than did metformin alone.

Combination Therapy vs. Combination Therapy.

Two RCTs showed that the combination of metformin plus pioglitazone decreased triglyceride levels more than did metformin plus a sulfonylurea (between-group differences ranged from −10 mg/dL [P = 0.30] to −24.9 mg/dL [P = 0.045]; moderate-quality evidence) (56, 84). One small RCT found that metformin plus a GLP-1 agonist fared better than the combination of metformin plus rosiglitazone (between-group mean difference in triglyceride levels, 36.3 mg/dL; significance not reported; low-quality evidence) (86). In addition, data from 4 RCTs showed that the combination of a thiazolidinedione (pioglitazone) plus a sulfonylurea decreased triglyceride levels more or increased triglyceride levels less than the combination of metformin plus a sulfonylurea (low-quality evidence) (7273, 84, 87).

A total of 66 studies (46 RCTs; duration, 12 weeks to 6 years) reported comparative effectiveness of oral diabetes medications on long-term outcomes. The mean age of participants ranged from 48 years to 75 years (5). It was difficult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes because of low quality or insufficient evidence (4). Appendix Table 2 summarizes the findings and strength of evidence for long-term outcomes comparing various diabetes medications as monotherapy or combination therapy.

Table Jump PlaceholderAppendix Table 2. Key Findings and Strength of Evidence for Long-Term Outcomes 
Mortality (All-Cause and Cardiovascular)

Five RCTs (3031, 33, 8889) and 11 observational studies (90100) were examined for all-cause mortality between metformin monotherapy and sulfonylurea monotherapy. These studies indicate that metformin was associated with lower all-cause mortality compared with sulfonylureas (low-quality evidence). Metformin was also favored over sulfonylureas for cardiovascular mortality (low-quality evidence), as evidenced by 4 cohort studies (92, 94, 96, 101), although 1 prospective cohort study (94) showed slightly higher cardiovascular mortality rates for metformin than for sulfonylurea monotherapy. Also, ADOPT (A Diabetes Outcome Progression Trial) (89) reported only 1 fatal CHF event in patients treated with either metformin or glyburide (nonstatistically significant difference), but patients treated with glyburide generally experienced fewer CHF as well as cardiovascular events.

Morbidity (Cardiovascular and Cerebrovascular)

Monotherapy with metformin was linked to lower cardiovascular morbidity than combination therapy for metformin plus sulfonylureas (low-quality evidence), as shown by 1 RCT (5% vs. 14% adverse cardiovascular events) (35) and 1 cohort study (adjusted incidence of hospitalization for myocardial infarction or coronary revascularization, 13.90 vs. 19.44 per 1000 person-years) (102). Evidence for all other comparisons was insufficient or unclear (Appendix Table 2) (5).

Retinopathy, Nephropathy, and Neuropathy

There was moderate-quality evidence for nephropathy only for the comparison between pioglitazone and metformin. In the 2 studies that addressed this comparison, pioglitazone significantly reduced the urinary albumin–creatinine ratio by 19% (25) and 15% (72), whereas the ratio was unchanged in patients treated with metformin.

Appendix Table 3 summarizes the findings and strength of evidence for adverse effects among various diabetes medications as monotherapy or combination therapy.

Table Jump PlaceholderAppendix Table 3. Key Findings and Strength of Evidence for Adverse Events 
Hypoglycemia

No particular monotherapy or combination therapy increased severe hypoglycemia (generally defined as hypoglycemia requiring assistance for resolution) compared with the other treatments (4).

Monotherapy vs. Monotherapy

Pooled results from monotherapy trials show that sulfonylureas increase the risk for mild to moderate hypoglycemia compared with metformin (odds ratio [OR], 4.60 [CI, 3.20 to 6.50]; I2 = 68%; high-quality evidence) (27, 2932, 36, 66, 74, 88), thiazolidinediones (OR, 3.88 [CI, 3.05 to 4.94]; I2 = 41%; high-quality evidence) (3740, 74, 89, 103105), and meglitinides (OR, 0.78 [CI, 0.55 to 1.12]; I2 = 18%; low-quality evidence) (106113). Data from RCTs also indicate that other agents were favored over sulfonylureas for hypoglycemia: DPP-4 inhibitors (data from 1 RCT showed that 21 of 123 patients treated with a sulfonylurea had mild or moderate hypoglycemia compared with no patients treated with a DPP-4 inhibitor; moderate-quality evidence) (114) and GLP-1 agonists (data from 3 RCTs; high-quality evidence) (4143). Monotherapy with meglitinides resulted in more hypoglycemia compared with metformin (OR, 3.00 [CI, 1.80 to 5.20]; I2 = 0%; moderate-quality evidence) (51, 115118) or thiazolidinediones (2 RCTs: relative risk [RR], 1.2 [CI, 0.8 to 1.8] [76]; RR, 1.6 [CI, 1.0 to 2.6] [119]; low-quality evidence).

Monotherapy vs. Combination Therapy

Compared with metformin monotherapy, the combination of metformin plus a thiazolidinedione (OR, 1.57 [CI, 1.01 to 2.43]; I2 = 0%; moderate-quality evidence) (24, 4447, 8183), metformin plus a sulfonylurea (RR, 1.6 to 25 in 9 RCTs; moderate-quality evidence) (27, 2931, 3536, 4849, 88), and metformin plus meglitinides (OR, 2.75 [CI, 0.98 to 7.71]; I2 = 21%; low-quality evidence; P > 0.05) (4951) resulted in an increase in hypoglycemia.

Combination Therapy vs. Combination Therapy

The combination of metformin plus a sulfonylurea increased the risk for hypoglycemia by about 6 times compared with the combination of metformin plus a thiazolidinedione (OR, 5.80 [CI, 4.30 to 7.70]; I2 = 0%; high-quality evidence) (17, 52, 54, 56, 71). One large RCT reported that metformin plus a thiazolidinedione resulted in fewer hypoglycemic events compared with a thiazolidinedione plus a sulfonylurea (0.05 vs. 0.47 event per 100 person-years of follow-up; low-quality evidence) (120). Another study found more hypoglycemic symptoms in patients treated with the combination of metformin plus a sulfonylurea than with the combination of a thiazolidinedione plus a sulfonylurea (RR, 1.3 [CI, 0.9 to 2]; low-quality evidence) (121).

Other Adverse Effects

Evidence was insufficient to show any difference among the various type 2 diabetes medications on liver injury.

Evidence from 51 studies was evaluated to determine gastrointestinal effects (5). Evidence examined from studies addressing these effects that compared metformin monotherapy with thiazolidinediones (high-quality evidence) (22, 2425, 89, 122), sulfonylureas (moderate-quality evidence) (2627, 2933, 35, 66, 8889), DPP-4 inhibitors (moderate-quality evidence) (12, 1415), or meglitinides (low-quality evidence) (115118) report more gastrointestinal adverse effects with metformin. Trials comparing metformin monotherapy with combination metformin plus thiazolidinedione therapy (moderate-quality evidence) (24, 4447, 8082) or metformin plus sulfonylurea therapy (moderate-quality evidence) (27, 2933, 35, 49, 66, 88, 123) generally favored the combination therapy, although the metformin dosage was typically lower in the combination group, possibly accounting for this difference. One RCT reported more dyspepsia with a combination of metformin plus a meglitinide than with metformin plus a sulfonylurea (13% vs. 3%; low-quality evidence) (124). Two RCTs reported more diarrhea in combination treatment with metformin plus a sulfonylurea than with a thiazolidinedione plus a sulfonylurea (moderate-quality evidence) (72, 121).

Although few studies reported on congestive heart failure, moderate-quality evidence from 5 observational studies favors metformin over sulfonylureas (98, 100, 125127), and moderate-quality evidence from 4 RCTs (39, 89, 103, 105) and 4 observational studies (98, 104, 125, 127128) favors sulfonylureas over thiazolidinediones. One 6-month observational study reported higher rates of heart failure with the combination of a thiazolidinedione plus a sulfonylurea (0.47 per 100 person-years) than with a thiazolidinedione plus metformin (0.13 per 100 person-years) (low-quality evidence) (120). One RCT reported that the combination of a thiazolidinedione plus a sulfonylurea or metformin doubled the risk for heart failure compared with a sulfonylurea plus metformin (RR, 2.1 [CI, 1.35 to 3.27]; low-quality evidence) (129).

Evidence was insufficient to show any difference among the various type 2 diabetes medications on macular edema.

One RCT identified 1 person with cholecystitis out of 105 patients treated with a thiazolidinedione compared with none of 100 patients treated with metformin (low-quality evidence) (22). Another RCT identified 1 person with cholecystitis (n = 280) treated with metformin monotherapy compared with no patients (n = 288) treated with a combination of metformin plus a thiazolidinedione (low-quality evidence) (44). Low-quality evidence for pancreatitis came from 1 trial that reported 1 patient (n = 242) with acute pancreatitis treated with a combination of metformin plus a sulfonylurea compared with no patients receiving metformin monotherapy (n = 121) (49). The evidence was insufficient to show any difference in cholecystitis or pancreatitis with other monotherapies or combination therapies.

For bone fractures, high-quality evidence from 1 RCT showed more bone fractures with thiazolidinedione monotherapy than with metformin monotherapy (hazard ratio [HR], 1.57 [CI, 1.13 to 2.17]), and subgroup analysis showed that the risk is higher for women (HR, 1.81 [CI, 1.17 to 2.80]; P = 0.008) (130). Data were assessed from 2 RCTs and 1 observational study, and results showed fewer fractures with sulfonylureas than with thiazolidinediones (high-quality evidence) (38, 130131). One RCT found an increase in fractures for patients treated with rosiglitazone compared with a sulfonylurea (HR, 2.13 [CI, 1.30 to 3.51]) (130), whereas another study reported 2 ankle fractures (n = 251) with pioglitazone monotherapy and no fractures with sulfonylurea monotherapy (n = 251) (38). The observational study found statistically significantly more fractures in women treated with pioglitazone (HR, 1.70 [CI, 1.30 to 2.23]; P < 0.001) and rosiglitazone (HR, 1.29 [CI, 1.04 to 1.59]; P = 0.02) than with sulfonylurea (131). The combination of metformin plus a sulfonylurea was favored over the combination of thiazolidinediones plus a sulfonylurea or thiazolidinediones plus metformin (RR, 1.57 [CI, 1.26 to 1.97]; P < 0.001; high-quality evidence), and the RR for fractures was higher for women than men (1.82 [CI, 1.37 to 2.41] vs. 1.23 [CI, 0.85 to 1.77]) (129).

Evidence was gathered from 28 studies (21 RCTs) that reported comparative effectiveness and safety data for subpopulations (defined by age, sex, or race; obesity, duration of diabetes, or geographic region; required medication dose; previous comorbid conditions) (5). The evidence favoring one medication over another across subgroups is not clear because of lack of sufficient power in the included studies.

The evidence shows that most diabetes medications reduced HbA1c levels to a similar degree. Metformin was more effective than other medications as monotherapy as well as when used in combination therapy with another agent for reducing HbA1c levels, body weight, and plasma lipid levels (in most cases). It was difficult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause and cardiovascular mortality, cardiovascular and cerebrovascular morbidity, and microvascular outcomes because of low-quality or insufficient evidence.

High-quality evidence shows that the risk for hypoglycemia with sulfonylureas exceeds the risk with metformin or thiazolidinediones and that the combination of metformin plus sulfonylureas is associated with 6 times more risk for hypoglycemia than the combination of metformin plus thiazolidinediones. Moderate-quality evidence shows that the risk for hypoglycemia with metformin and thiazolidinediones is similar. Metformin is associated with an increased risk for gastrointestinal side effects. Thiazolidinediones are associated with an increased risk for heart failure, and both rosiglitazone and pioglitazone are contraindicated in patients with serious heart failure (132133).

The current evidence was not sufficient to show any difference in effectiveness among various medications across subgroups of adults.

Recommendation 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence).

Initiation of oral pharmacologic therapy is an important approach to effective management of type 2 diabetes. There are no data on the best time to add oral therapies to lifestyle modifications; thus, to avoid an unacceptable burden on patients, other complicating factors should be considered, such as life expectancy of the patient, presence or absence of microvascular and macrovascular complications, risk for adverse events related to glucose control, and patient preferences (134). The goal for HbA1c should be based on individualized assessment of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences. An HbA1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.

Recommendation 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence).

The effectiveness, adverse effect profiles, and costs of various oral pharmacologic treatments vary. Metformin is more effective than other pharmacologic agents in reducing glycemic levels and is not associated with weight gain. In addition, metformin aids in decreasing weight and reduces LDL cholesterol and triglyceride levels. Metformin was also associated with slightly lower all-cause mortality and cardiovascular mortality compared with sulfonylureas. Finally, metformin is associated with fewer hypoglycemic episodes and is cheaper than most other pharmacologic agents. Therefore, unless contraindicated, metformin is the drug of choice for patients with type 2 diabetes, in addition to lifestyle modification. Metformin is contraindicated in patients with impaired kidney function, decreased tissue perfusion or hemodynamic instability, liver disease, alcohol abuse, heart failure, and any condition that might lead to lactic acidosis.

Physicians and patients should discuss adverse event profiles before selecting a medication. Compared with baseline values, most diabetes medications (metformin, thiazolidinediones, and sulfonylureas) reduced baseline HbA1c by about 1 percentage point 3 or more months after the initiation of treatment. For adverse effects, metformin is associated with an increased risk for gastrointestinal side effects, sulfonylureas and meglitinides are associated with an increased risk for hypoglycemia, and thiazolidinediones are associated with an increased risk for heart failure (with no conclusive evidence for an increase in ischemic cardiovascular risk). However, in comparing the effectiveness of various agents, the evidence shows that metformin is the most efficacious agent as monotherapy and in combination therapy.

Recommendation 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence).

All dual-therapy regimens were more efficacious than monotherapies in reducing the HbA1c level in patients with type 2 diabetes by about 1 additional percentage point. Combination therapies with more than 2 agents were not included in the evidence review. No good evidence supports one combination therapy over another, even though some evidence shows that the combination of metformin with another agent generally tends to have better efficacy than any other monotherapy or combination therapy. However, combination therapies are also associated with an increased risk for adverse effects compared with monotherapy. Generic sulfonylureas are the cheapest second-line therapy; however, adverse effects are generally worse with combination therapies that include a sulfonylurea.

Although this guideline addresses only oral pharmacological therapy, patients with persistent hyperglycemia despite oral agents and lifestyle interventions may need insulin therapy.

See Figure 1 for a summary of the recommendations and clinical considerations.

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Figure 1.

The American College of Physicians guideline on oral medications for type 2 diabetes.

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On the basis of the evidence reviewed in this paper, ACP has found strong evidence that in most patients with type 2 diabetes in whom lifestyle modifications have failed to adequately improve hyperglycemia, oral pharmacologic therapy with metformin (unless contraindicated) is an effective management strategy. It is cheaper than most other pharmacologic agents, has better effectiveness, and is associated with fewer adverse effects; of note, it does not result in weight gain (Figure 2).

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Figure 2.

The American College of Physicians best practice advice: oral medications for type 2 diabetes.

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National Diabetes Information Clearinghouse (NDIC).  Diabetes Overview. NIH Publication No. 09-3873. 2008, Accessed at diabetes.niddk.nih.gov/dm/pubs/overview/ on 2 August 2011.
 
Centers for Disease Control and Prevention.  National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.
 
Alexander GC, Sehgal NL, Moloney RM, Stafford RS. National trends in treatment of type 2 diabetes mellitus, 1994-2007. Arch Intern Med. 2008; 168:2088-94.
PubMed
CrossRef
 
Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011; 154:602-13.
PubMed
CrossRef
 
Bennett WL, Wilson L, Bolen S, Maruthur NM, Singh S, Chatterjee R, et al. Oral Diabetes Medications for Adults with Type 2 Diabetes: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Bolen S, Wilson L, Vassy J, Feldman L, Yeh H-C, Marinopoulos S. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes. Rockville, MD: Agency for Healthcare Research and Quality; 2007.
 
Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99.
PubMed
CrossRef
 
Agency for Healthcare Research and Quality. Guide for Conducting Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2007.
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12.
PubMed
CrossRef
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60.
PubMed
CrossRef
 
Qaseem A, Snow V, Owens DK, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010; 153:194-9.
PubMed
CrossRef
 
Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, et al, Sitagliptin Study 049 Group. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010; 12:252-61.
PubMed
CrossRef
 
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30:1979-87.
PubMed
CrossRef
 
Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009; 11:611-22.
PubMed
CrossRef
 
Williams-Herman D, Johnson J, Teng R, Luo E, Davies MJ, Kaufman KD, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009; 25:569-83.
PubMed
CrossRef
 
Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al, 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010; 375:1447-56.
PubMed
CrossRef
 
Comaschi M, Demicheli A, Di Pietro C, Bellatreccia A, Mariz S, COM06 Study Investigators. Effects of pioglitazone in combination with metformin or a sulfonylurea compared to a fixed-dose combination of metformin and glibenclamide in patients with type 2 diabetes. Diabetes Technol Ther. 2007; 9:387-98.
PubMed
CrossRef
 
Gupta AK, Smith SR, Greenway FL, Bray GA. Pioglitazone treatment in type 2 diabetes mellitus when combined with portion control diet modifies the metabolic syndrome. Diabetes Obes Metab. 2009; 11:330-7.
PubMed
CrossRef
 
Hällsten K, Virtanen KA, Lönnqvist F, Sipilä H, Oksanen A, Viljanen T, et al. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes. 2002; 51:3479-85.
PubMed
CrossRef
 
Iliadis F, Kadoglou NP, Hatzitolios A, Karamouzis M, Alevizos M, Karamitsos D. Metabolic effects of rosiglitazone and metformin in Greek patients with recently diagnosed type 2 diabetes. In Vivo. 2007; 21:1107-14.
PubMed
 
Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004; 27:1349-57.
PubMed
CrossRef
 
Pavo I, Jermendy G, Varkonyi TT, Kerenyi Z, Gyimesi A, Shoustov S, et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab. 2003; 88:1637-45.
PubMed
CrossRef
 
Ramachandran A, Snehalatha C, Salini J, Vijay V. Use of glimepiride and insulin sensitizers in the treatment of type 2 diabetes—a study in Indians. J Assoc Physicians India. 2004; 52:459-63.
PubMed
 
Rosenstock J, Rood J, Cobitz A, Biswas N, Chou H, Garber A. Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Diabetes Obes Metab. 2006; 8:650-60.
PubMed
 
Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P, Quartet Study Group. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004; 89:6068-76.
PubMed
CrossRef
 
Amador-Licona N, Guízar-Mendoza J, Vargas E, Sánchez-Camargo G, Zamora-Mata L. The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Arch Med Res. 2000; 31:571-5.
PubMed
CrossRef
 
Blonde L, Rosenstock J, Mooradian AD, Piper BA, Henry D. Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy. Diabetes Obes Metab. 2002; 4:368-75.
PubMed
CrossRef
 
Campbell IW, Menzies DG, Chalmers J, McBain AM, Brown IR. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabete Metab. 1994; 20:394-400.
PubMed
 
Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. Diabet Med. 2001; 18:828-34.
PubMed
CrossRef
 
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995; 333:541-9.
PubMed
CrossRef
 
Garber AJ, Donovan DS Jr, Dandona P, Bruce S, Park JS. Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes. J Clin Endocrinol Metab. 2003; 88:3598-604.
PubMed
CrossRef
 
Garber AJ, Larsen J, Schneider SH, Piper BA, Henry D, Glyburide/Metformin Initial Therapy Study Group. Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes. Diabetes Obes Metab. 2002; 4:201-8.
PubMed
 
Goldstein BJ, Pans M, Rubin CJ. Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea. Clin Ther. 2003; 25:890-903.
PubMed
CrossRef
 
Hermann LS, Bitzén PO, Kjellström T, Lindgärde F, Scherstén B. Comparative efficacy of metformin and glibenclamide in patients with non-insulin-dependent diabetes mellitus. Diabete Metab. 1991; 17:201-8.
PubMed
 
Hermann LS, Scherstén B, Bitzén PO, Kjellström T, Lindgärde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care. 1994; 17:1100-9.
PubMed
CrossRef
 
Marre M, Howlett H, Lehert P, Allavoine T. Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in type 2 diabetic patients inadequately controlled on metformin. Diabet Med. 2002; 19:673-80.
PubMed
CrossRef
 
Hanefeld M, Patwardhan R, Jones NP, Rosiglitazone Clinical Trials Study Group. A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes. Nutr Metab Cardiovasc Dis. 2007; 17:13-23.
PubMed
CrossRef
 
Jain R, Osei K, Kupfer S, Perez AT, Zhang J. Long-term safety of pioglitazone versus glyburide in patients with recently diagnosed type 2 diabetes mellitus. Pharmacotherapy. 2006; 26:1388-95.
PubMed
CrossRef
 
St John Sutton M, Rendell M, Dandona P, Dole JF, Murphy K, Patwardhan R, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care. 2002; 25:2058-64.
PubMed
CrossRef
 
Tan MH, Johns D, Strand J, Halse J, Madsbad S, Eriksson JW, et al, GLAC Study Group. Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with type 2 diabetes. Diabet Med. 2004; 21:859-66.
PubMed
CrossRef
 
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al, LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009; 373:473-81.
PubMed
CrossRef
 
Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR, NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004; 27:1335-42.
PubMed
CrossRef
 
Seino Y, Rasmussen MF, Nishida T, Kaku K. Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin. 2010; 26:1013-22.
PubMed
CrossRef
 
Bailey CJ, Bagdonas A, Rubes J, McMorn SO, Donaldson J, Biswas N, et al. Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, double-blind, parallel-group study. Clin Ther. 2005; 27:1548-61.
PubMed
CrossRef
 
Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000; 283:1695-702.
PubMed
CrossRef
 
Kaku K. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial. Curr Med Res Opin. 2009; 25:1111-9.
PubMed
 
Scott R, Loeys T, Davies MJ, Engel SS, Sitagliptin Study 801 Group. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10:959-69.
PubMed
CrossRef
 
Feinglos M, Dailey G, Cefalu W, Osei K, Tayek J, Canovatchel W, et al. Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. Diabetes Res Clin Pract. 2005; 68:167-75.
PubMed
CrossRef
 
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al, LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 32:84-90.
PubMed
 
Marre M, VanGaal L, Usadel KH, Ball M, Whatmough I, Guitard C. Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. Diabetes Obes Metab. 2002; 4:177-86.
PubMed
CrossRef
 
Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24.
PubMed
 
Bakris GL, Ruilope LM, McMorn SO, Weston WM, Heise MA, Freed MI, et al. Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J Hypertens. 2006; 24:2047-55.
PubMed
CrossRef
 
Derosa G, Cicero AF, Gaddi AV, Ciccarelli L, Piccinni MN, Salvadeo S, et al. Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trial. Clin Ther. 2005; 27:1383-91.
PubMed
CrossRef
 
Hamann A, Garcia-Puig J, Paul G, Donaldson J, Stewart M. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone. Exp Clin Endocrinol Diabetes. 2008; 116:6-13.
PubMed
CrossRef
 
Home PD, Jones NP, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, et al, RECORD Study Group. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007; 24:626-34.
PubMed
 
Umpierrez G, Issa M, Vlajnic A. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial. Curr Med Res Opin. 2006; 22:751-9.
PubMed
CrossRef
 
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007; 9:194-205.
PubMed
CrossRef
 
Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al, Sitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract. 2010; 64:562-76.
PubMed
CrossRef
 
Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Ragonesi PD, Querci F, et al. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther. 2010; 12:233-40.
PubMed
 
Erdem G, Dogru T, Tasci I, Bozoglu E, Muhsiroglu O, Tapan S, et al. The effects of pioglitazone and metformin on plasma visfatin levels in patients with treatment naive type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008; 82:214-8.
PubMed
CrossRef
 
Kato T, Sawai Y, Kanayama H, Taguchi H, Terabayashi T, Taki F, et al. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes. 2009; 117:593-9.
PubMed
CrossRef
 
Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care. 2004; 27:41-6.
PubMed
CrossRef
 
Hällsten K, Virtanen KA, Lönnqvist F, Janatuinen T, Turiceanu M, Rönnemaa T, et al. Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone. Diabet Med. 2004; 21:1280-7.
PubMed
CrossRef
 
Kiyici S, Ersoy C, Kaderli A, Fazlioglu M, Budak F, Duran C, et al. Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. Diabetes Res Clin Pract. 2009; 86:44-50.
PubMed
CrossRef
 
Virtanen KA, Hällsten K, Parkkola R, Janatuinen T, Lönnqvist F, Viljanen T, et al. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes. 2003; 52:283-90.
PubMed
 
Derosa G, Franzetti I, Gadaleta G, Ciccarelli L, Fogari R. Metabolic variations with oral antidiabetic drugs in patients with type 2 diabetes: comparison between glimepiride and metformin. Diabetes Nutr Metab. 2004; 17:143-50.
PubMed
 
Hermann LS, Kjellström T, Nilsson-Ehle P. Effects of metformin and glibenclamide alone and in combination on serum lipids and lipoproteins in patients with non-insulin-dependent diabetes mellitus. Diabete Metab. 1991; 17:174-9.
PubMed
 
Pfützner A, Marx N, Lübben G, Langenfeld M, Walcher D, Konrad T, et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol. 2005; 45:1925-31.
PubMed
CrossRef
 
Teramoto T, Yamada N, Shirai K, Saito Y. Effects of pioglitazone hydrochloride on Japanese patients with type 2 diabetes mellitus. J Atheroscler Thromb. 2007; 14:86-93.
PubMed
 
Derosa G, Gaddi AV, Piccinni MN, Salvadeo S, Ciccarelli L, Fogari E, et al. Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial. Diabetes Obes Metab. 2006; 8:197-205.
PubMed
CrossRef
 
Garber A, Klein E, Bruce S, Sankoh S, Mohideen P. Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2006; 8:156-63.
PubMed
 
Hanefeld M, Brunetti P, Schernthaner GH, Matthews DR, Charbonnel BH, QUARTET Study Group. One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004; 27:141-7.
PubMed
CrossRef
 
van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation. 2009; 119:2069-77.
PubMed
CrossRef
 
Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed type 2 diabetes. Diabet Med. 2005; 22:980-5.
PubMed
CrossRef
 
Nakamura T, Sugaya T, Kawagoe Y, Ueda Y, Koide H. Effect of pioglitazone on urinary liver-type fatty acid-binding protein concentrations in diabetes patients with microalbuminuria. Diabetes Metab Res Rev. 2006; 22:385-9.
PubMed
CrossRef
 
Jovanovic L, Hassman DR, Gooch B, Jain R, Greco S, Khutoryansky N, et al. Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. Diabetes Res Clin Pract. 2004; 63:127-34.
PubMed
CrossRef
 
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al, GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005; 28:1547-54.
PubMed
 
Khan MA, StPeter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care. 2002; 25:708-11.
PubMed
CrossRef
 
Vijay SK, Mishra M, Kumar H, Tripathi K. Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes. Acta Diabetol. 2009; 46:27-33.
PubMed
CrossRef
 
Gómez-Perez FJ, Fanghänel-Salmón G, Antonio Barbosa J, Montes-Villarreal J, Berry RA, Warsi G, et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev. 2002; 18:127-34.
PubMed
CrossRef
 
Stewart MW, Cirkel DT, Furuseth K, Donaldson J, Biswas N, Starkie MG, et al. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Diabet Med. 2006; 23:1069-78.
PubMed
CrossRef
 
Weissman P, Goldstein BJ, Rosenstock J, Waterhouse B, Cobitz AR, Wooddell MJ, et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin. 2005; 21:2029-35.
PubMed
CrossRef
 
Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther. 2000; 22:1395-409.
PubMed
CrossRef
 
Comaschi M, Corsi A, Di Pietro C, Bellatreccia A, Mariz S, COM06 Study Investigators. The effect of pioglitazone as add-on therapy to metformin or sulphonylurea compared to a fixed-dose combination of metformin and glibenclamide on diabetic dyslipidaemia. Nutr Metab Cardiovasc Dis. 2008; 18:373-9.
PubMed
CrossRef
 
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29:2638-43.
PubMed
CrossRef
 
DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010; 33:951-7.
PubMed
CrossRef
 
Jonker JT, Lamb HJ, van der Meer RW, Rijzewijk LJ, Menting LJ, Diamant M, et al. Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010; 95:456-60.
PubMed
CrossRef
 
Chien HH, Chang CT, Chu NF, Hsieh SH, Huang YY, Lee IT, et al. Effect of glyburide-metformin combination tablet in patients with type 2 diabetes. J Chin Med Assoc. 2007; 70:473-80.
PubMed
 
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al, ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355:2427-43.
PubMed
 
Azoulay L, Schneider-Lindner V, Dell'aniello S, Schiffrin A, Suissa S. Combination therapy with sulfonylureas and metformin and the prevention of death in type 2 diabetes: a nested case-control study. Pharmacoepidemiol Drug Saf. 2010; 19:335-42.
PubMed
 
Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005; 28:2345-51.
PubMed
CrossRef
 
Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia. 2006; 49:930-6.
PubMed
CrossRef
 
Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M. Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology. 1999; 91:195-202.
PubMed
CrossRef
 
Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, et al. Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. Clin Cardiol. 2001; 24:151-8.
PubMed
CrossRef
 
Gulliford M, Latinovic R. Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study. Diabetes Metab Res Rev. 2004; 20:239-45.
PubMed
CrossRef
 
Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002; 25:2244-8.
PubMed
CrossRef
 
Kahler KH, Rajan M, Rhoads GG, Safford MM, Demissie K, Lu SE, et al. Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration. Diabetes Care. 2007; 30:1689-93.
PubMed
CrossRef
 
Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009; 46:145-54.
PubMed
CrossRef
 
Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006; 174:169-74.
PubMed
 
Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009; 339:b4731.
PubMed
CrossRef
 
Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabet Med. 2005; 22:497-502.
PubMed
CrossRef
 
McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf. 2007; 16:711-25.
PubMed
CrossRef
 
Agarwal R, Saha C, Battiwala M, Vasavada N, Curley T, Chase SD, et al. A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidney Int. 2005; 68:285-92.
PubMed
 
Asche CV, McAdam-Marx C, Shane-McWhorter L, Sheng X, Plauschinat CA. Evaluation of adverse events of oral antihyperglycemic monotherapy experienced by a geriatric population in a real-world setting: a retrospective cohort analysis. Drugs Aging. 2008; 25:611-22.
PubMed
CrossRef
 
Tolman KG, Freston JW, Kupfer S, Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. Drug Saf. 2009; 32:787-800.
PubMed
CrossRef
 
Jibran R, Suliman MI, Qureshi F, Ahmed M. Safety and efficacy of repaglinide compared with glibenclamide in the management of type 2 diabetic Pakistani patients. Pak J Med Sci. 2006; 22:385-90.
 
Landgraf R, Bilo HJ, Müller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol. 1999; 55:165-71.
PubMed
CrossRef
 
Madsbad S, Kilhovd B, Lager I, Mustajoki P, Dejgaard A, Scandinavian Repaglinide Group. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabet Med. 2001; 18:395-401.
PubMed
CrossRef
 
Mafauzy M. Repaglinide versus glibenclamide treatment of type 2 diabetes during Ramadan fasting. Diabetes Res Clin Pract. 2002; 58:45-53.
PubMed
CrossRef
 
Marbury T, Huang WC, Strange P, Lebovitz H. Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract. 1999; 43:155-66.
PubMed
CrossRef
 
Vakkilainen J, Mero N, Schweizer A, Foley JE, Taskinen MR. Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes. Diabetes Metab Res Rev. 2002; 18:484-90.
PubMed
CrossRef
 
Wolffenbuttel BH, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care. 1999; 22:463-7.
PubMed
CrossRef
 
Wolffenbuttel BH, Nijst L, Sels JP, Menheere PP, Müller PG, Kruseman AC. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol. 1993; 45:113-6.
PubMed
CrossRef
 
Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007; 61:171-80.
PubMed
 
Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract. 2003; 60:161-9.
PubMed
CrossRef
 
Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-5.
PubMed
CrossRef
 
Horton ES, Foley JE, Shen SG, Baron MA. Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naíve patients with type 2 diabetes. Curr Med Res Opin. 2004; 20:883-9.
PubMed
CrossRef
 
Lund SS, Tarnow L, Stehouwer CD, Schalkwijk CG, Frandsen M, Smidt UM, et al. Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Diabetes Obes Metab. 2007; 9:394-407.
PubMed
CrossRef
 
Raskin P, McGill J, Saad MF, Cappleman JM, Kaye W, Khutoryansky N, et al, Repaglinide/Rosiglitazone Study Group. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabet Med. 2004; 21:329-35.
PubMed
CrossRef
 
Rosak C, Standl E, Reblin T, Stammer H, Seidel DK. Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes. Int J Clin Pract. 2006; 60:1040-7.
PubMed
CrossRef
 
Seufert J, Urquhart R. 2-year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with type 2 diabetes. Diabetes Res Clin Pract. 2008; 79:453-60.
PubMed
CrossRef
 
Perez A, Zhao Z, Jacks R, Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin. 2009; 25:2915-23.
PubMed
CrossRef
 
Tosi F, Muggeo M, Brun E, Spiazzi G, Perobelli L, Zanolin E, et al. Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study. Metabolism. 2003; 52:862-7.
PubMed
CrossRef
 
Schwarz SL, Gerich JE, Marcellari A, Jean-Louis L, Purkayastha D, Baron MA. Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment-naíve elderly patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10:652-60.
PubMed
 
Karter AJ, Ahmed AT, Liu J, Moffet HH, Parker MM. Pioglitazone initiation and subsequent hospitalization for congestive heart failure. Diabet Med. 2005; 22:986-93.
PubMed
CrossRef
 
Maru S, Koch GG, Stender M, Clark D, Gibowski L, Petri H, et al. Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting. Diabetes Care. 2005; 28:20-6.
PubMed
CrossRef
 
McAlister FA, Eurich DT, Majumdar SR, Johnson JA. The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur J Heart Fail. 2008; 10:703-8.
PubMed
CrossRef
 
Hsiao FY, Huang WF, Wen YW, Chen PF, Kuo KN, Tsai YW. Thiazolidinediones and cardiovascular events in patients with type 2 diabetes mellitus: a retrospective cohort study of over 473,000 patients using the National Health Insurance database in Taiwan. Drug Saf. 2009; 32:675-90.
PubMed
CrossRef
 
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al, RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009; 373:2125-35.
PubMed
CrossRef
 
Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, et al, Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008; 31:845-51.
PubMed
 
Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009; 169:1395-402.
PubMed
CrossRef
 
GlaxoSmithKline.  AVANDIA package insert. Accessed at us.gsk.com/products/assets/us_avandia.pdf on 28 July 2011.
 
Takeda Pharmaceutical America.  ACTOS package insert. Accessed at www.tpna.com/products/default.aspx on 28 July 2011.
 
Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK, Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med. 2007; 147:417-22.
PubMed
 

Figures

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Figure 1.

The American College of Physicians guideline on oral medications for type 2 diabetes.

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Grahic Jump Location
Figure 2.

The American College of Physicians best practice advice: oral medications for type 2 diabetes.

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Tables

Table Jump PlaceholderAppendix Table 1. Type 2 Diabetes Medications, Dosages, and Wholesale Price Range 
Table Jump PlaceholderTable 1. The American College of Physicians Guideline Grading System 
Table Jump PlaceholderTable 2. Key Findings and Strength of Evidence for Intermediate Outcomes 
Table Jump PlaceholderAppendix Table 2. Key Findings and Strength of Evidence for Long-Term Outcomes 
Table Jump PlaceholderAppendix Table 3. Key Findings and Strength of Evidence for Adverse Events 

References

National Diabetes Information Clearinghouse (NDIC).  Diabetes Overview. NIH Publication No. 09-3873. 2008, Accessed at diabetes.niddk.nih.gov/dm/pubs/overview/ on 2 August 2011.
 
Centers for Disease Control and Prevention.  National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.
 
Alexander GC, Sehgal NL, Moloney RM, Stafford RS. National trends in treatment of type 2 diabetes mellitus, 1994-2007. Arch Intern Med. 2008; 168:2088-94.
PubMed
CrossRef
 
Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011; 154:602-13.
PubMed
CrossRef
 
Bennett WL, Wilson L, Bolen S, Maruthur NM, Singh S, Chatterjee R, et al. Oral Diabetes Medications for Adults with Type 2 Diabetes: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Bolen S, Wilson L, Vassy J, Feldman L, Yeh H-C, Marinopoulos S. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes. Rockville, MD: Agency for Healthcare Research and Quality; 2007.
 
Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99.
PubMed
CrossRef
 
Agency for Healthcare Research and Quality. Guide for Conducting Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2007.
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12.
PubMed
CrossRef
 
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60.
PubMed
CrossRef
 
Qaseem A, Snow V, Owens DK, Shekelle P, Clinical Guidelines Committee of the American College of Physicians. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010; 153:194-9.
PubMed
CrossRef
 
Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, et al, Sitagliptin Study 049 Group. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010; 12:252-61.
PubMed
CrossRef
 
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30:1979-87.
PubMed
CrossRef
 
Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009; 11:611-22.
PubMed
CrossRef
 
Williams-Herman D, Johnson J, Teng R, Luo E, Davies MJ, Kaufman KD, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009; 25:569-83.
PubMed
CrossRef
 
Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al, 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010; 375:1447-56.
PubMed
CrossRef
 
Comaschi M, Demicheli A, Di Pietro C, Bellatreccia A, Mariz S, COM06 Study Investigators. Effects of pioglitazone in combination with metformin or a sulfonylurea compared to a fixed-dose combination of metformin and glibenclamide in patients with type 2 diabetes. Diabetes Technol Ther. 2007; 9:387-98.
PubMed
CrossRef
 
Gupta AK, Smith SR, Greenway FL, Bray GA. Pioglitazone treatment in type 2 diabetes mellitus when combined with portion control diet modifies the metabolic syndrome. Diabetes Obes Metab. 2009; 11:330-7.
PubMed
CrossRef
 
Hällsten K, Virtanen KA, Lönnqvist F, Sipilä H, Oksanen A, Viljanen T, et al. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes. 2002; 51:3479-85.
PubMed
CrossRef
 
Iliadis F, Kadoglou NP, Hatzitolios A, Karamouzis M, Alevizos M, Karamitsos D. Metabolic effects of rosiglitazone and metformin in Greek patients with recently diagnosed type 2 diabetes. In Vivo. 2007; 21:1107-14.
PubMed
 
Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004; 27:1349-57.
PubMed
CrossRef
 
Pavo I, Jermendy G, Varkonyi TT, Kerenyi Z, Gyimesi A, Shoustov S, et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab. 2003; 88:1637-45.
PubMed
CrossRef
 
Ramachandran A, Snehalatha C, Salini J, Vijay V. Use of glimepiride and insulin sensitizers in the treatment of type 2 diabetes—a study in Indians. J Assoc Physicians India. 2004; 52:459-63.
PubMed
 
Rosenstock J, Rood J, Cobitz A, Biswas N, Chou H, Garber A. Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Diabetes Obes Metab. 2006; 8:650-60.
PubMed
 
Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P, Quartet Study Group. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004; 89:6068-76.
PubMed
CrossRef
 
Amador-Licona N, Guízar-Mendoza J, Vargas E, Sánchez-Camargo G, Zamora-Mata L. The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Arch Med Res. 2000; 31:571-5.
PubMed
CrossRef
 
Blonde L, Rosenstock J, Mooradian AD, Piper BA, Henry D. Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy. Diabetes Obes Metab. 2002; 4:368-75.
PubMed
CrossRef
 
Campbell IW, Menzies DG, Chalmers J, McBain AM, Brown IR. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabete Metab. 1994; 20:394-400.
PubMed
 
Charpentier G, Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. Diabet Med. 2001; 18:828-34.
PubMed
CrossRef
 
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995; 333:541-9.
PubMed
CrossRef
 
Garber AJ, Donovan DS Jr, Dandona P, Bruce S, Park JS. Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes. J Clin Endocrinol Metab. 2003; 88:3598-604.
PubMed
CrossRef
 
Garber AJ, Larsen J, Schneider SH, Piper BA, Henry D, Glyburide/Metformin Initial Therapy Study Group. Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes. Diabetes Obes Metab. 2002; 4:201-8.
PubMed
 
Goldstein BJ, Pans M, Rubin CJ. Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea. Clin Ther. 2003; 25:890-903.
PubMed
CrossRef
 
Hermann LS, Bitzén PO, Kjellström T, Lindgärde F, Scherstén B. Comparative efficacy of metformin and glibenclamide in patients with non-insulin-dependent diabetes mellitus. Diabete Metab. 1991; 17:201-8.
PubMed
 
Hermann LS, Scherstén B, Bitzén PO, Kjellström T, Lindgärde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care. 1994; 17:1100-9.
PubMed
CrossRef
 
Marre M, Howlett H, Lehert P, Allavoine T. Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in type 2 diabetic patients inadequately controlled on metformin. Diabet Med. 2002; 19:673-80.
PubMed
CrossRef
 
Hanefeld M, Patwardhan R, Jones NP, Rosiglitazone Clinical Trials Study Group. A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes. Nutr Metab Cardiovasc Dis. 2007; 17:13-23.
PubMed
CrossRef
 
Jain R, Osei K, Kupfer S, Perez AT, Zhang J. Long-term safety of pioglitazone versus glyburide in patients with recently diagnosed type 2 diabetes mellitus. Pharmacotherapy. 2006; 26:1388-95.
PubMed
CrossRef
 
St John Sutton M, Rendell M, Dandona P, Dole JF, Murphy K, Patwardhan R, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care. 2002; 25:2058-64.
PubMed
CrossRef
 
Tan MH, Johns D, Strand J, Halse J, Madsbad S, Eriksson JW, et al, GLAC Study Group. Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with type 2 diabetes. Diabet Med. 2004; 21:859-66.
PubMed
CrossRef
 
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al, LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009; 373:473-81.
PubMed
CrossRef
 
Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR, NN2211-1310 International Study Group. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004; 27:1335-42.
PubMed
CrossRef
 
Seino Y, Rasmussen MF, Nishida T, Kaku K. Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin. 2010; 26:1013-22.
PubMed
CrossRef
 
Bailey CJ, Bagdonas A, Rubes J, McMorn SO, Donaldson J, Biswas N, et al. Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, double-blind, parallel-group study. Clin Ther. 2005; 27:1548-61.
PubMed
CrossRef
 
Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000; 283:1695-702.
PubMed
CrossRef
 
Kaku K. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial. Curr Med Res Opin. 2009; 25:1111-9.
PubMed
 
Scott R, Loeys T, Davies MJ, Engel SS, Sitagliptin Study 801 Group. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10:959-69.
PubMed
CrossRef
 
Feinglos M, Dailey G, Cefalu W, Osei K, Tayek J, Canovatchel W, et al. Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. Diabetes Res Clin Pract. 2005; 68:167-75.
PubMed
CrossRef
 
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al, LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 32:84-90.
PubMed
 
Marre M, VanGaal L, Usadel KH, Ball M, Whatmough I, Guitard C. Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. Diabetes Obes Metab. 2002; 4:177-86.
PubMed
CrossRef
 
Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24.
PubMed
 
Bakris GL, Ruilope LM, McMorn SO, Weston WM, Heise MA, Freed MI, et al. Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J Hypertens. 2006; 24:2047-55.
PubMed
CrossRef
 
Derosa G, Cicero AF, Gaddi AV, Ciccarelli L, Piccinni MN, Salvadeo S, et al. Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trial. Clin Ther. 2005; 27:1383-91.
PubMed
CrossRef
 
Hamann A, Garcia-Puig J, Paul G, Donaldson J, Stewart M. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone. Exp Clin Endocrinol Diabetes. 2008; 116:6-13.
PubMed
CrossRef
 
Home PD, Jones NP, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, et al, RECORD Study Group. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007; 24:626-34.
PubMed
 
Umpierrez G, Issa M, Vlajnic A. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial. Curr Med Res Opin. 2006; 22:751-9.
PubMed
CrossRef
 
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007; 9:194-205.
PubMed
CrossRef
 
Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al, Sitagliptin Study 024 Group. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract. 2010; 64:562-76.
PubMed
CrossRef
 
Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Ragonesi PD, Querci F, et al. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther. 2010; 12:233-40.
PubMed
 
Erdem G, Dogru T, Tasci I, Bozoglu E, Muhsiroglu O, Tapan S, et al. The effects of pioglitazone and metformin on plasma visfatin levels in patients with treatment naive type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008; 82:214-8.
PubMed
CrossRef
 
Kato T, Sawai Y, Kanayama H, Taguchi H, Terabayashi T, Taki F, et al. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes. 2009; 117:593-9.
PubMed
CrossRef
 
Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care. 2004; 27:41-6.
PubMed
CrossRef
 
Hällsten K, Virtanen KA, Lönnqvist F, Janatuinen T, Turiceanu M, Rönnemaa T, et al. Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone. Diabet Med. 2004; 21:1280-7.
PubMed
CrossRef
 
Kiyici S, Ersoy C, Kaderli A, Fazlioglu M, Budak F, Duran C, et al. Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. Diabetes Res Clin Pract. 2009; 86:44-50.
PubMed
CrossRef
 
Virtanen KA, Hällsten K, Parkkola R, Janatuinen T, Lönnqvist F, Viljanen T, et al. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes. 2003; 52:283-90.
PubMed
 
Derosa G, Franzetti I, Gadaleta G, Ciccarelli L, Fogari R. Metabolic variations with oral antidiabetic drugs in patients with type 2 diabetes: comparison between glimepiride and metformin. Diabetes Nutr Metab. 2004; 17:143-50.
PubMed
 
Hermann LS, Kjellström T, Nilsson-Ehle P. Effects of metformin and glibenclamide alone and in combination on serum lipids and lipoproteins in patients with non-insulin-dependent diabetes mellitus. Diabete Metab. 1991; 17:174-9.
PubMed
 
Pfützner A, Marx N, Lübben G, Langenfeld M, Walcher D, Konrad T, et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol. 2005; 45:1925-31.
PubMed
CrossRef
 
Teramoto T, Yamada N, Shirai K, Saito Y. Effects of pioglitazone hydrochloride on Japanese patients with type 2 diabetes mellitus. J Atheroscler Thromb. 2007; 14:86-93.
PubMed
 
Derosa G, Gaddi AV, Piccinni MN, Salvadeo S, Ciccarelli L, Fogari E, et al. Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial. Diabetes Obes Metab. 2006; 8:197-205.
PubMed
CrossRef
 
Garber A, Klein E, Bruce S, Sankoh S, Mohideen P. Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes Metab. 2006; 8:156-63.
PubMed
 
Hanefeld M, Brunetti P, Schernthaner GH, Matthews DR, Charbonnel BH, QUARTET Study Group. One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004; 27:141-7.
PubMed
CrossRef
 
van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation. 2009; 119:2069-77.
PubMed
CrossRef
 
Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed type 2 diabetes. Diabet Med. 2005; 22:980-5.
PubMed
CrossRef
 
Nakamura T, Sugaya T, Kawagoe Y, Ueda Y, Koide H. Effect of pioglitazone on urinary liver-type fatty acid-binding protein concentrations in diabetes patients with microalbuminuria. Diabetes Metab Res Rev. 2006; 22:385-9.
PubMed
CrossRef
 
Jovanovic L, Hassman DR, Gooch B, Jain R, Greco S, Khutoryansky N, et al. Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone. Diabetes Res Clin Pract. 2004; 63:127-34.
PubMed
CrossRef
 
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al, GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005; 28:1547-54.
PubMed
 
Khan MA, StPeter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care. 2002; 25:708-11.
PubMed
CrossRef
 
Vijay SK, Mishra M, Kumar H, Tripathi K. Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes. Acta Diabetol. 2009; 46:27-33.
PubMed
CrossRef
 
Gómez-Perez FJ, Fanghänel-Salmón G, Antonio Barbosa J, Montes-Villarreal J, Berry RA, Warsi G, et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev. 2002; 18:127-34.
PubMed
CrossRef
 
Stewart MW, Cirkel DT, Furuseth K, Donaldson J, Biswas N, Starkie MG, et al. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Diabet Med. 2006; 23:1069-78.
PubMed
CrossRef
 
Weissman P, Goldstein BJ, Rosenstock J, Waterhouse B, Cobitz AR, Wooddell MJ, et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin. 2005; 21:2029-35.
PubMed
CrossRef
 
Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther. 2000; 22:1395-409.
PubMed
CrossRef
 
Comaschi M, Corsi A, Di Pietro C, Bellatreccia A, Mariz S, COM06 Study Investigators. The effect of pioglitazone as add-on therapy to metformin or sulphonylurea compared to a fixed-dose combination of metformin and glibenclamide on diabetic dyslipidaemia. Nutr Metab Cardiovasc Dis. 2008; 18:373-9.
PubMed
CrossRef
 
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29:2638-43.
PubMed
CrossRef
 
DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010; 33:951-7.
PubMed
CrossRef
 
Jonker JT, Lamb HJ, van der Meer RW, Rijzewijk LJ, Menting LJ, Diamant M, et al. Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010; 95:456-60.
PubMed
CrossRef
 
Chien HH, Chang CT, Chu NF, Hsieh SH, Huang YY, Lee IT, et al. Effect of glyburide-metformin combination tablet in patients with type 2 diabetes. J Chin Med Assoc. 2007; 70:473-80.
PubMed
 
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al, ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355:2427-43.
PubMed
 
Azoulay L, Schneider-Lindner V, Dell'aniello S, Schiffrin A, Suissa S. Combination therapy with sulfonylureas and metformin and the prevention of death in type 2 diabetes: a nested case-control study. Pharmacoepidemiol Drug Saf. 2010; 19:335-42.
PubMed
 
Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005; 28:2345-51.
PubMed
CrossRef
 
Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia. 2006; 49:930-6.
PubMed
CrossRef
 
Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M. Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology. 1999; 91:195-202.
PubMed
CrossRef
 
Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, et al. Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. Clin Cardiol. 2001; 24:151-8.
PubMed
CrossRef
 
Gulliford M, Latinovic R. Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study. Diabetes Metab Res Rev. 2004; 20:239-45.
PubMed
CrossRef
 
Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002; 25:2244-8.
PubMed
CrossRef
 
Kahler KH, Rajan M, Rhoads GG, Safford MM, Demissie K, Lu SE, et al. Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration. Diabetes Care. 2007; 30:1689-93.
PubMed
CrossRef
 
Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009; 46:145-54.
PubMed
CrossRef
 
Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006; 174:169-74.
PubMed
 
Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009; 339:b4731.
PubMed
CrossRef
 
Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabet Med. 2005; 22:497-502.
PubMed
CrossRef
 
McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf. 2007; 16:711-25.
PubMed
CrossRef
 
Agarwal R, Saha C, Battiwala M, Vasavada N, Curley T, Chase SD, et al. A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidney Int. 2005; 68:285-92.
PubMed
 
Asche CV, McAdam-Marx C, Shane-McWhorter L, Sheng X, Plauschinat CA. Evaluation of adverse events of oral antihyperglycemic monotherapy experienced by a geriatric population in a real-world setting: a retrospective cohort analysis. Drugs Aging. 2008; 25:611-22.
PubMed
CrossRef
 
Tolman KG, Freston JW, Kupfer S, Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. Drug Saf. 2009; 32:787-800.
PubMed
CrossRef
 
Jibran R, Suliman MI, Qureshi F, Ahmed M. Safety and efficacy of repaglinide compared with glibenclamide in the management of type 2 diabetic Pakistani patients. Pak J Med Sci. 2006; 22:385-90.
 
Landgraf R, Bilo HJ, Müller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol. 1999; 55:165-71.
PubMed
CrossRef
 
Madsbad S, Kilhovd B, Lager I, Mustajoki P, Dejgaard A, Scandinavian Repaglinide Group. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabet Med. 2001; 18:395-401.
PubMed
CrossRef
 
Mafauzy M. Repaglinide versus glibenclamide treatment of type 2 diabetes during Ramadan fasting. Diabetes Res Clin Pract. 2002; 58:45-53.
PubMed
CrossRef
 
Marbury T, Huang WC, Strange P, Lebovitz H. Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res Clin Pract. 1999; 43:155-66.
PubMed
CrossRef
 
Vakkilainen J, Mero N, Schweizer A, Foley JE, Taskinen MR. Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes. Diabetes Metab Res Rev. 2002; 18:484-90.
PubMed
CrossRef
 
Wolffenbuttel BH, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care. 1999; 22:463-7.
PubMed
CrossRef
 
Wolffenbuttel BH, Nijst L, Sels JP, Menheere PP, Müller PG, Kruseman AC. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol. 1993; 45:113-6.
PubMed
CrossRef
 
Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007; 61:171-80.
PubMed
 
Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract. 2003; 60:161-9.
PubMed
CrossRef
 
Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-5.
PubMed
CrossRef
 
Horton ES, Foley JE, Shen SG, Baron MA. Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naíve patients with type 2 diabetes. Curr Med Res Opin. 2004; 20:883-9.
PubMed
CrossRef
 
Lund SS, Tarnow L, Stehouwer CD, Schalkwijk CG, Frandsen M, Smidt UM, et al. Targeting hyperglycaemia with either metformin or repaglinide in non-obese patients with type 2 diabetes: results from a randomized crossover trial. Diabetes Obes Metab. 2007; 9:394-407.
PubMed
CrossRef
 
Raskin P, McGill J, Saad MF, Cappleman JM, Kaye W, Khutoryansky N, et al, Repaglinide/Rosiglitazone Study Group. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabet Med. 2004; 21:329-35.
PubMed
CrossRef
 
Rosak C, Standl E, Reblin T, Stammer H, Seidel DK. Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes. Int J Clin Pract. 2006; 60:1040-7.
PubMed
CrossRef
 
Seufert J, Urquhart R. 2-year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with type 2 diabetes. Diabetes Res Clin Pract. 2008; 79:453-60.
PubMed
CrossRef
 
Perez A, Zhao Z, Jacks R, Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin. 2009; 25:2915-23.
PubMed
CrossRef
 
Tosi F, Muggeo M, Brun E, Spiazzi G, Perobelli L, Zanolin E, et al. Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study. Metabolism. 2003; 52:862-7.
PubMed
CrossRef
 
Schwarz SL, Gerich JE, Marcellari A, Jean-Louis L, Purkayastha D, Baron MA. Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment-naíve elderly patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10:652-60.
PubMed
 
Karter AJ, Ahmed AT, Liu J, Moffet HH, Parker MM. Pioglitazone initiation and subsequent hospitalization for congestive heart failure. Diabet Med. 2005; 22:986-93.
PubMed
CrossRef
 
Maru S, Koch GG, Stender M, Clark D, Gibowski L, Petri H, et al. Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting. Diabetes Care. 2005; 28:20-6.
PubMed
CrossRef
 
McAlister FA, Eurich DT, Majumdar SR, Johnson JA. The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur J Heart Fail. 2008; 10:703-8.
PubMed
CrossRef
 
Hsiao FY, Huang WF, Wen YW, Chen PF, Kuo KN, Tsai YW. Thiazolidinediones and cardiovascular events in patients with type 2 diabetes mellitus: a retrospective cohort study of over 473,000 patients using the National Health Insurance database in Taiwan. Drug Saf. 2009; 32:675-90.
PubMed
CrossRef
 
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al, RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009; 373:2125-35.
PubMed
CrossRef
 
Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, et al, Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008; 31:845-51.
PubMed
 
Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009; 169:1395-402.
PubMed
CrossRef
 
GlaxoSmithKline.  AVANDIA package insert. Accessed at us.gsk.com/products/assets/us_avandia.pdf on 28 July 2011.
 
Takeda Pharmaceutical America.  ACTOS package insert. Accessed at www.tpna.com/products/default.aspx on 28 July 2011.
 
Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK, Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med. 2007; 147:417-22.
PubMed
 

Letters

July 3, 2012
Robert S. Moskowitz, MD
AIM. 2012;157(1):75  doi:10.7326/0003-4819-157-1-201207030-00016



July 3, 2012
Helena W. Rodbard, MD; Paul S. Jellinger, MD
AIM. 2012;157(1):75-76  doi:10.7326/0003-4819-157-1-201207030-00017



July 3, 2012
Thibault Richard, MD; Dany Brohee, PhD; Alain Van Meerhaeghe, MD; Michel Vanhaeverbeek, MD
AIM. 2012;157(1):76  doi:10.7326/0003-4819-157-1-201207030-00018



July 3, 2012
Amir Qaseem, MD, PhD, MHA; Linda Humphrey, MD, MPH; Paul Shekelle, MD, PhD
AIM. 2012;157(1):76-77  doi:10.7326/0003-4819-157-1-201207030-00019



NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Metformin use for Diabetics
Posted on February 16, 2012
Robert S.Moskowitz, MD, FACP
Conflict of Interest: None Declared

To The Editor:

The Clinical Guideline for oral pharmacologic treatment of Type Two Diabetes Mellitus (1) touted metformin for its efficacy and benefits and then went on to say "metformin is contraindicated in patients with impaired kidney function...heart failure, and any condition that might lead to lactic acidosis." These contraindications leave out the majority of elderly patients who are the best candidates for metformin use (no hypoglycemia, positive cardiovascular effects, etc...).

Metformin has been shown to be safe except in those with severe renal impairment (2,3) and has been shown to cuase less lactic acidosis than other oral agents (4). Many diabetic experts have put forth their opinion that the contraindications to metformin be reformulated so that millions of diabetics can benefit from its use.

References

1. Ann Int Med 2012; 156: 218-231

2. Heaf;JG, Van Biesen, W: Metformin and Chronic Renal Impairment: A Sutdy of Choices and Ugly Ducklings. Clinical Diabetes Vol 29, Nov. 3, 2011.

3. Jones, CG, Macklin J.P., Alexander W.D.: Contraindications to the Use of Metformin. BMJ Vol 3, March 2003.

4. Bodmer M, Maier, C, Krahenbuhl, S. Metformin Sulfonylureas, or Other Antidiabetes Drugs and the Risk of Lactic Acidosis or Hypoglycemia, Diabetes Care Vol 31, Nov 2008.

Conflict of Interest:

None declared

Internists and Primary Care Physicians should become familiar with algorithms developed by physicians who specialize in management of patients with diabetes
Posted on February 27, 2012
Helena W.Rodbard, MD, FACP, MACE, Medical Director,, Paul S. Jellinger, MD, MACE, Professor of Clinical Medicine, University of Miami, The Center for Diabetes & Endocrine Care, Hollywood, FL
Endocrine and Metabolic Consultants, Rockville, MD
Conflict of Interest: None Declared

The recently published American College of Physicians guidelines for management of patients with diabetes (1) fail to consider algorithms developed by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE)(2), the American Diabetes Association (ADA)(3), the Canadian Diabetes Association (CDA) (4), and the Yale Diabetes Center (5). Although these algorithms (2- 5) were developed by specialists, they were specifically intended for use by the internists and primary care physicians who treat the vast majority of patients with type 2 diabetes. The AACE/ACE and ADA algorithms recommend a target level to be used for the majority of patients (A1C of 6.5% and 7.0%, respectively). The AACE/ACE algorithm stratifies treatment by A1c and elevated the priority for the newer incretin based therapies - DPP-4 inhibitors and GLP-1 receptor agonists - because of their safety, low risk of hypoglycemia, efficacy, and weight neutrality and weight loss, respectively (2). The AACE/ACE algorithm downgraded the role of sulfonylureas due to their consistently high risk of hypoglycemia (30% of patients in several series) (2), and downgraded thiazolidinediones due to associated risks of heart failure, weight gain, fractures, and possibly bladder cancer (2).

AACE/ACE recommends initiation of dual therapy when the presenting A1C is greater than 7.5, because it is very unlikely that monotherapy could be successful in achieving the desired goal. When the presenting A1C is above 9.0% and the patient is symptomatic or has failed previous oral therapy, AACE/ACE recommends initiation of insulin therapy. To reduce "clinical inertia," AACE/ACE and ADA recommend reevaluation and readjustment of therapy at 2-3 month intervals. These algorithms provide greater depth. detail and explanation than the one proposed by ACP (1). The ACP approach gives inappropriately favorable mention to sulfonylureas, presumably in deference to their low cost. However, the CDC has estimated that medication cost is only 10% of the long term costs for diabetes; 80% is devoted to hospitalizations and complications. A single hypoglycemic reaction with a visit to the Emergency Room will nullify savings associated with low cost medications such as sulfonylureas.

Algorithms for treatment are necessarily based on a combination of expert judgment and critical review of the literature. AACE/ACE, ADA, and the CDA have published detailed, evidence based guidelines. American College of Physicians, internists, and primary care physicians should carefully study and adopt the guidelines and algorithms as developed and published by specialists in endocrinology and diabetes and implement them with modifications if necessary - but not ignore them.

Helena W. Rodbard MD, FACP, MACE Medical Director Endocrine and Metabolic Consultants Rockville MD hrodbard@comcast.net

Paul S. Jellinger, MD, MACE Professor of Clinical Medicine University of Miami The Center for Diabetes & Endocrine Care Hollywood FL pjellinger@diabetes-endocare.com

References

1. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P; for the Clinical Guidelines Committee of the American College of Physicians. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2012 Feb 7;156(3):218-231. [PMID: 22312141]

2. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009 Sep-Oct;15(6):540-59. Updated in: Endocr Pract. 2009 Nov-Dec;15(7):768-70. [PMID: 19858063] https://www.aace.com/sites/default/files/GlycemicControlAlgorithm.pdf (Accessed 2/16/2012).

3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009 Jan;32(1):193- 203. [PMID: 18945920]

4. Woo V. Important differences: Canadian Diabetes Association 2008 clinical practice guidelines and the consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009 Mar;52(3):552-3 [PubMed PMID: 19107458]

5. Inzucchi SE. Diabetes Facts and Guidelines 2011-2012. pp 71-78. Type 2 DM Treatment Algorithms. http://endocrinology.yale.edu/patient/50135_Yale%20National%20F.pdf (Accessed February 15, 2012).

Conflict of Interest:

Dr. Rodbard conducts clinical research, serves on advisory panels, consults, and lectures with support of Amylin, BMS, Boehringer Ingelheim, Lilly, Merck, Novo Nordisk, Roche, and Sanofi. Dr. Jellinger serves on advisory panels, consults, and lectures with support of Amylin, , Boehringer Ingelheim, Lilly, Merck and Novo Nordisk .

HbA1c: a surrogate outcome
Posted on March 2, 2012
ThibaultRichard, MD, Dany Brohee, Alain Van Meerhaeghe, Michel Vanhaeverbeek
CHU de Charleroi-H?pital Andr? V?sale. Belgium
Conflict of Interest: None Declared

In the clinical guideline of the American College of Physician (ACP) for the oral pharmacologic treatment of type 2 diabetes mellitus, the ACP recommends the addition of a second agent in patients with persistent hyperglycemia despite metformin use and lifestyle modifications (strong recommendation, high quality evidence). We do not agree with this level of recommendation. Our main concern is that the superiority of bitherapy over metformin alone has been only validated using a surrogate outcome i.e. the level of glycosylated hemoglobin. There are many examples in recent years of an evidence founded on surrogate end-points which have been proved to provide no benefit (or even harm) patients when hard endpoints are considered. The effect of an intensive glycemic control on hard endpoint is doubtful in type 2 diabetes: indeed, several recent meta-analyses have shown no effect on mortality, and little effect on vascular complications1,2. Furthermore, two clinical studies3,4 have raised concerns about the safety of combination therapy in type 2 diabetes: in the United Kingdom Prospective Diabetes Study (UKPDS), the patients who had insufficient metabolic control despite the use of a sulfonylurea were rerandomized to either monotherapy continuation or the addition of metformin. The combination therapy was associated with a 60% raise of total mortality and a 97% of diabetes-related death3. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the intensification of the treatment targeting a lower HbA1c level (42 versus 58 mmol/mol) was associated with a relative excess mortality of 22%. In conclusion, in patients with type 2 diabetes and insufficient glycemic control despite metformin and lifestyle adjustment, the addition of a second agent can be considered, but the clinician should be aware that both the innocuity and the clinical benefit of this option are hypothetical, compared with the continuation of the metformin alone.

References

1. Victor M. Montori, MD, MSc, and Merce Fernandez-Balsells, MD. Glycemic Control in Type 2 Diabetes: Time for an Evidence-Based About-Face? Ann Intern Med. 2009;150:803-8. `

2. Bianca Hemmingsen dent , S?ren S Lund , Christian Gluud et al: BMJ 2011;343:d6898 doi: 10.1136/bmj.d6898

3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood- glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-65

4. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes.N Engl J Med 2008;358:2545-59.

Conflict of Interest:

None declared

Posted on March 14, 2012
Thomas E.Finucane, Professor of Medicine
Johns Hopkins University School of Medicine
Conflict of Interest: None Declared

To the Editor:

Qaseem and colleagues make a fairly standard Recommendation 1: For patients diagnosed with DM2 "clinicians (should) add oral medications" when lifestyle interventions, "have failed to adequately improve hyperglycemia". They grade this as "strong recommendation; high-quality evidence". I think this is conventional repetition of an unsupported dogma.

Shouldn't this strong, high-quality recommendation reference data from randomized trials of "tight control" showing that oral medications benefit patients more than placebo (or parenteral medications) in clinically meaningful ways? The authors could then proceed to comparisons. They provide no such data and refer to evidence from comparisons as "low- quality or insufficient."

They also leave the definition of "adequate" delicately unspoken, creating a comforting, irrefutable vagueness about the recommendation. There is no glycemic target whose use in clinical trials has been shown to lead to improved clinical outcomes.

Thomas E. Finucane, MD

Conflict of Interest:

None declared

Treatment of Type 2 Diabetes
Posted on April 3, 2012
AmirQaseem, MD, PhD, MHA, Linda Humphrey, MD; Paul Shekelle, MD, PhD
Conflict of Interest: None Declared

We thank Drs. Moskowitz, Rodbard, Jellinger, and Dr. Richard and colleagues for their comments regarding the American College of Physicians' recent clinical guideline on Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus (1).

In response to Dr. Moskowitz, based on the available evidence, we believe that it was important to mention the caveats of metformin being contraindicated for patients with conditions such as renal impairment and heart failure. Most current clinical guidelines identify very specific contraindications to the use of metformin. We disagree with Dr. Moskowitz that metformin is harmless in all patients except those with severe renal impairment, as the precise creatinine threshold for the safe use of metformin is not certain. Also, lactic acidosis is a major concern due to its association with high case-fatality. We agree with Dr. Moskowitz that many elderly patients with heart failure are prescribed metformin and it is possible that some of these patients benefit from treatment with metformin. However, as with all guidelines, clinical judgment must be exercised for individual circumstances and a physician must weigh the potential benefits and harms.

In response to Drs. Rodbard and Jellinger, ACP follows stringent standards when it comes to the development of clinical guidelines and the rigorous approach includes utilization of systematic reviews (2, 3). Although algorithms might be useful to clinicians for managing patients, the methods used to develop the referenced algorithms are either not described in detail or are informed, at least in part, by expert opinion and clinical judgment. We also disagree with using an HbA1c level of 6.5% as a primary target for treatment since there are not data from randomized trials supporting this HbA1c level. Furthermore, our evidence review (4) does not support starting combination therapy in patients with HbA1c less than 7.5%, and we believe that a second agent should only be added when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia.

Dr. Richard and colleagues raise important issues regarding the benefit of using combination therapy as well as concerns with using HbA1c as a surrogate outcome. We agree that using surrogate outcomes will result in less reliable evidence about efficacy and safety of various treatments. However, HbA1c levels provide a practical assessment of glycemic control in patients who are receiving pharmacological treatment and are associated with some relevant clinical outcomes. Also, the authors bring up concerns regarding the safety of combination therapy. We believe that the studies referenced by the authors targeted intensive glycemic control (HbA1c below 6% in some cases). The cause of the increase in mortality in the ACCORD trial has not been established; it is not attributable to any medication or combination of medications.

Authors: Amir Qaseem, MD, PhD, MHA American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106

Linda Humphrey, MD Oregon Health and Science University, 3710 SW US Veterans Hospital Road, Portland, OR 97201

Paul Shekelle, MD, PhD Greater Los Angeles VA Health Center/RAND, 1776 Main Street, Santa Monica, CA 90401

References:

1. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P. 2012. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine. 156(3):218-31.

2. Qaseem, A, Forland, F, Macbeth, F, Ollenschl?ger, G, Phillips, S, and van der Wees, P, for the Board of Trustees of the Guidelines International Network. 2012. Guidelines International Network: Toward International Standards for Clinical Practice Guidelines. Annals of Internal Medicine. 156: 525-531

3. Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Pr; 2011

4. Bennett WL, Wilson L, Bolen S, Maruthur NM, Singh S, Chatterjee R, et al. Oral Diabetes Medications for Adults with Type 2 Diabetes: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

Conflict of Interest:

None declared

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Oral Drug Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians

The full report is titled “Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians.” It is in the 7 February 2012 issue of Annals of Internal Medicine (volume 156, pages 218-231). The authors are A. Qaseem, L.L. Humphrey, D.E. Sweet, M. Starkey, and P. Shekelle, for the Clinical Guidelines Committee of the American College of Physicians.

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