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 (*)
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 All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.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.
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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, email@example.com.
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.
This article has been corrected. The original version (PDF) is appended to this article as a supplement.
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.
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.
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).
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).
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).
Appendix Table 1. Type 2 Diabetes Medications, Dosages, and Wholesale Price Range
Table 1. The American College of Physicians Guideline Grading System
Table 2. Key Findings and Strength of Evidence for Intermediate Outcomes
Appendix Table 2. Key Findings and Strength of Evidence for Long-Term Outcomes
Appendix Table 3. Key Findings and Strength of Evidence for Adverse Events
The American College of Physicians guideline on oral medications for type 2 diabetes.
The American College of Physicians best practice advice: oral medications for type 2 diabetes.
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Robert S.Moskowitz, MD, FACP
February 16, 2012
Metformin use for Diabetics
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.
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.
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
February 27, 2012
Internists and Primary Care Physicians should become familiar with algorithms developed by physicians who specialize in management of patients with diabetes
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 firstname.lastname@example.org
Paul S. Jellinger, MD, MACE Professor of Clinical Medicine University of Miami The Center for Diabetes & Endocrine Care Hollywood FL email@example.com
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] <Medline: http://www.ncbi.nlm.nih.gov/pubmed/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] <Medline: http://www.ncbi.nlm.nih.gov/pubmed/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] <Medline: http://www.ncbi.nlm.nih.gov/pubmed/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] <Medline: http://www.ncbi.nlm.nih.gov/pubmed/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).
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 .
ThibaultRichard, MD, Dany Brohee, Alain Van Meerhaeghe, Michel Vanhaeverbeek
CHU de Charleroi-H?pital Andr? V?sale. Belgium
March 2, 2012
HbA1c: a surrogate outcome
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.
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.
Thomas E.Finucane, Professor of Medicine
Johns Hopkins University School of Medicine
March 14, 2012
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
AmirQaseem, MD, PhD, MHA, Linda Humphrey, MD; Paul Shekelle, MD, PhD
April 3, 2012
Treatment of Type 2 Diabetes
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
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.
Amir Qaseem, Linda L. Humphrey, Donna E. Sweet, Melissa Starkey, Paul Shekelle, . Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2012;156:218–231. doi: 10.7326/0003-4819-156-3-201202070-00011
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Published: Ann Intern Med. 2012;156(3):218-231.
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