Safety and Efficacy of Type 2 Diabetes Meds Compared in New Review

The analysis investigated 6 different therapies
The analysis investigated 6 different therapies

A review of the latest evidence regarding type 2 diabetes treatment, supports current guidelines which recommend metformin as a first-line therapy.  The study, published online in the Annals of Internal Medicine, looked at 179 trials and 25 observational studies to evaluate the comparative effectiveness and safety of the most common monotherapies and combination therapies used in the treatment of type 2 diabetes. Therapies included in this investigation included metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Treatments were assessed for both efficacy and safety outcomes.

All-Cause Mortality, Macrovascular and Microvascular Outcomes

  • Compared to sulfonylurea monotherapy, metformin monotherapy was associated with lower long-term cardiovascular mortality (Moderate strength)
  • Compared to sulfonylureas, metformin was associated with lower risk of all-cause mortality and cardiovascular morbidity (Low strength)
  • Insufficient or low strength evidence for all other drug comparisons

Hemoglobin A1C

  • In the short term, metformin, thiazolidinedione, and sulfonylurea monotherapy lowered HbA1C to a similar degree
  • DPP-4 inhibitors were less effective than metformin or sulfonylureas
  • Metformin + GLP-1 receptor agonist reduced HbA1C more than metformin + DPP-4 inhibitors, otherwise most combinations had no clinically meaningful between-group differences

Body Weight

  • Metformin decreased weight more than DPP-4 inhibitors
  • SGLT-2 inhibitors reduced weight more than metformin or DPP-4 inhibitors
  • Increases in weight were seen with sulfonylureas, thiazolidinediones, and insulin

Systolic Blood Pressure and Heart Rate

  • Compared with other monotherapy, SGLT-2 inhibitors reduced systolic BP by 3–5mmHg (Moderate strength)
  • Compared to metformin monotherapy, metformin + SGLT-2 inhibitor and metformin + GLP-1 receptor agonist reduced systolic BP by 3–5mmHg (Moderate to high strength)
  • Metformin + SGLT-2 inhibitor decreased heart rate more than metformin + sulfonylurea


  • Increased risk of severe hypoglycemia with sulfonylurea monotherapy and in combination with metformin
  • Increased risk with metformin + basal or premixed insulin over metformin + GLP-1 receptor agonist
  • Lower risk with metformin + basal insulin compared to metformin + premixed insulin

Gastrointestinal Side Effects

  • More GI side effects with metformin and GLP-1 receptor agonists (both as monotherapy or combination)
  • Nausea, vomiting more common with GLP-1 receptor agonists than with metformin

Congestive Heart Failure

  • Risk of CHF 1.2–1.6 times greater with thiazolidinediones than with sulfonylyreas (Low strength)
  • Insufficient or low evidence on comparative safety of DPP-4 inhibitors regarding CHF

Other Safety Outcomes

  • Insufficient or low strength evidence on outcomes of liver injury, pancreatitis, lactic acidosis, cancer, severe allergic reactrion, or macular edema
  • Increased risk of genital mycotic infections with SGLT-2 inhibitors, alone or in combination with metformin (Moderate to high strength)
  • Insufficient or low strength evidence on comparative safety of SGLT-2 inhibitors regarding renal impairment, UTI, and volume depletion

Given its beneficial effects on HbA1C, weight, cardiovascular mortality (vs. sulfonylurea), and safety profile, the evidence continues to support the use of metformin as first-line therapy to treat type 2 diabetes. “Metformin looks like a clear winner,” said Nisa Maruthur, MD, MHS, assistant professor of medicine at the Johns Hopkins University School of Medicine. Though she noted how, “The medications all have different benefits and side effects, so the choice of second-line medications must be based on an individual patient's preferences.”

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