Large review compares benefits, harms of drugs to treat type 2 diabetes

High-certainty evidence indicated that sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists reduce all-cause death, while finerenone probably also reduced mortality based on moderate-certainty evidence.

A large review recently compared the benefits and harms of drugs for type 2 diabetes, finding mortality benefits for certain drug classes and raising concerns about the harms of others.

Researchers conducted a systematic review and network meta-analysis of 816 randomized controlled trials comparing the benefits and harms of drug treatments for adults with type 2 diabetes. They compared treatment estimates of the drugs versus the control arms, which typically received standard treatment at the time the trials were conducted. Eligible trials had a follow-up of 24 weeks or longer. Results were published April 6 by The BMJ.

The included trials totaled 471,038 patients and evaluated a total of 13 drug classes. There was a high certainty of evidence that sodium-glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio [OR], 0.88 [95% CI, 0.83 to 0.94]) and glucagon-like peptide-1 (GLP-1) receptor agonists (OR, 0.88 [95% CI, 0.82 to 0.93]) reduce all-cause death. There was moderate certainty that nonsteroidal mineralocorticoid receptor antagonists (so far tested only with finerenone in patients with chronic kidney disease) probably reduce mortality (OR, 0.89; 95% CI, 0.79 to 1.00). Other drugs may not have such a mortality benefit, the review found.

The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, nonfatal myocardial infarction, heart failure hospitalization, and end-stage kidney disease. Finerenone probably reduces heart failure hospitalizations and end-stage kidney disease and possibly reduces cardiovascular death, the review found. Only GLP-1 receptor agonists reduced nonfatal stroke, while SGLT-2 inhibitors were superior to other drugs in reducing end-stage kidney disease. GLP-1 receptor agonists, and probably SGLT-2 inhibitors and tirzepatide, improved quality of life, the review found. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in patients with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes.

Reported harms were largely specific to drug class (e.g., genital infections with SGLT-2 inhibitors, severe GI adverse events with tirzepatide and GLP-1 receptor agonists, and hyperkalemia leading to hospitalization with finerenone). Sulfonylureas may increase all-cause mortality (low certainty of evidence), and thiazolidinediones probably increase heart failure hospitalization (moderate certainty of evidence). Dipeptidyl peptidase-4 inhibitors, in addition to sulfonylurea and insulin, showed a probably intermediate increased risk of severe hypoglycemia (moderate certainty of evidence). Tirzepatide probably results in the largest reduction in body weight (mean difference, −8.57 kg; moderate certainty of evidence), and basal insulin and thiazolidinediones probably result in the largest weight increases (mean differences, 2.15 kg and 2.81 kg, respectively; moderate certainty of evidence for both).

For many outcomes that are important to patients, the researchers found low- to very low-certainty evidence for the oldest as well as the newest classes of drugs, they noted. They added that their analysis could not ascertain the benefits and harms of coadministration of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone, among other limitations.

“Our results raise concerns about the use of some well established drugs for glucose lowering in adults with type 2 diabetes. In particular, sulfonylureas may increase all cause mortality (low certainty), and thiazolidinediones probably increase admission to hospital due to heart failure (moderate certainty),” the study authors wrote. “Clinicians should be cautious in prescribing these drugs, especially to those at higher baseline risks for such outcomes.”