Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations

Abstract

Background: Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.

Purpose: 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.

Data sources: 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.

Study selection: 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.

Data extraction: Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.

Data synthesis: 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 A(1c) 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.

Limitations: 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.

Conclusion: Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events.

Primary funding source: Agency for Healthcare Research and Quality.

Conflict of interest statement

Potential Conflicts of Interest: Drs. Bennett, Singh, Segal, Marinopoulos, Bass, and Bolen: Grant (money to institution): AHRQ. Dr. Maruthur: Grant: AHRQ. Dr. Singh: Grant: NIH/NCRR KL2 Johns Hopkins Clinical Research Scholars Program; Payment for development of educational presentations: American College of Physicians, Endocrine Society. Dr. Hutfless: Stock/stock options: Pfizer, GlaxoSmithKline (both inactive). Dr. Ranasinghe and Ms. Wilson: Other (money to institution): AHRQ. Dr. Nicholson: Grant (money to institution): Johns Hopkins University. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2867.

Figures

Appendix Figure 1. Summary of evidence search and selection

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.

Appendix Figure 2. Summary of evidence search and selection for systematic reviews

RCT = randomized, controlled trial. *Total may exceed the number in the corresponding box because articles could be excluded for more than 1 reason at this level.

Appendix Figure 3. Odds of fatal and nonfatal ischemic heart disease with metformin monotherapy and metformin plus rosiglitazone

Error bars represent 95% CIs. Met = metformin; Rosi = rosiglitazone.

Appendix Figure 4. Pooled between-group differences in HDL-C levels with monotherapy and combination therapies

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.

Appendix Figure 5. Pooled between-group differences in triglyceride levels with monotherapy and combination therapies

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.

Appendix Figure 6. Odds of congestive heart failure with thiazolidinediones and sulfonylureas

Error bars represent 95% CIs. SU = sulfonylurea; TZD = thiazolidinedione.

Figure 1. Pooled between-group differences in HbA1c level with monotherapy and combination therapies

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.

Figure 2. Pooled between-group differences in body weight with monotherapy and combination therapies

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.

Figure 3. Pooled between-group differences in LDL-C levels with monotherapy and combination therapies

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.

Figure 4. Pooled odds of mild or moderate hypoglycemia with monotherapy and combination therapies

Error bars represent 95% CIs. DPP-4 = dipeptidyl peptidase-4 inhibitor; Meg = meglitinide; Met = metformin; SU = sulfonylurea; TZD = thiazolidinedione.