Wendy L. Bennett, MD, MPH; Nisa M. Maruthur, MD, MHS; Sonal Singh, MD, MPH; Jodi B. Segal, MD, MPH; Lisa M. Wilson, ScM; Ranee Chatterjee, MD, MPH; Spyridon S. Marinopoulos, MD, MBA; Milo A. Puhan, MD, PhD; Padmini Ranasinghe, MD, MPH; Lauren Block, MD; Wanda K. Nicholson, MD, MPH; Susan Hutfless, MPH, PhD; Eric B. Bass, MD, MPH; Shari Bolen, MD, MPH
Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.
To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.
Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.
Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.
Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A1c level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about −2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.
Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.
Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A1c levels, but some increased risk for hypoglycemia and other adverse events.
Agency for Healthcare Research and Quality.
There are numerous treatment regimens for type 2 diabetes.
This review found little evidence about the relative effects of various antihyperglycemic therapies on long-term clinical outcomes. Most monotherapies reduced hemoglobin A1c levels by similar amounts. Metformin therapy reduced body weight compared with thiazolidinediones and sulfonylureas; decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors; caused less hypoglycemia than sulfonylureas; and caused more diarrhea than thiazolidinediones.
Evidence on the comparative effects of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and different drug combinations was scant.
Consider metformin the initial drug of choice for treating type 2 diabetes.
Searches were done through April 2010. CENTRAL = Cochrane Central Database of Controlled Trials.
* Total may exceed the number in the corresponding box because articles could be excluded for more than 1 reason at this level.
† 71 studies were included in the 2007 review.
RCT = randomized, controlled trial.
Error bars represent 95% CIs. Met = metformin; Rosi = rosiglitazone.
Error bars represent 95% CIs. basal = basal insulin; DPP-4 = dipeptidyl peptidase-4 inhibitor; HbA1c = hemoglobin A1c; Meg = meglitinide; Met = metformin; Pio = pioglitazone; premixed = premixed insulin; Rosi = rosiglitazone; SU = sulfonylurea; TZD = thiazolidinedione.
Error bars represent 95% CIs. basal = basal insulin; DPP-4 = dipeptidyl peptidase-4 inhibitor; GLP-1 = glucagon-like peptide-1; Meg = meglitinide; Met = metformin; Pio = pioglitazone; premixed = premixed insulin; Rosi = rosiglitazone; SU = sulfonylurea; TZD = thiazolidinedione.
Error bars represent 95% CIs. To convert LDL-C values to mmol/L, multiply by 0.0259. DPP-4 = dipeptidyl peptidase-4 inhibitor; LDL-C = low-density lipoprotein cholesterol; Met = metformin; Pio = pioglitazone; Rosi = rosiglitazone; SU = sulfonylurea.
Error bars represent 95% CIs. To convert HDL-C values to mmol/L, multiply by 0.0259. DPP-4 = dipeptidyl peptidase-4 inhibitor; HDL-C = high-density lipoprotein cholesterol; Meg = meglitinide; Met = metformin; Pio = pioglitazone; Rosi = rosiglitazone; SU = sulfonylurea.
Error bars represent 95% CIs. To convert triglyceride values to mmol/L, multiply by 0.0113. DPP-4 = dipeptidyl peptidase-4 inhibitor; Meg = meglitinide; Met = metformin; Pio = pioglitazone; Rosi = rosiglitazone; SU = sulfonylurea.
Error bars represent 95% CIs. DPP-4 = dipeptidyl peptidase-4 inhibitor; Meg = meglitinide; Met = metformin; SU = sulfonylurea; TZD = thiazolidinedione.
Error bars represent 95% CIs. SU = sulfonylurea; TZD = thiazolidinedione.
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Bennett WL, Maruthur NM, Singh S, 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;154:602–613. doi: https://doi.org/10.7326/0003-4819-154-9-201105030-00336
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Published: Ann Intern Med. 2011;154(9):602-613.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism, Healthcare Delivery and Policy.
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