GLP-1 agonists are recommended as second-line antihyperglycaemic agentfor obese persons with type 2 diabetes without cardiovascular or renal disease if metformin is not sufficient for obtaining glycaemic target or not suitable because of adverse effects. GLP-1 agonists are recommended as first-line drugs in combination with metformin in obese patients with type 2 diabetes and cardiovascular disease including stroke, and as an alternative to SGLT-2 inhibitors also in patients with renal disease if they cause adverse effects.
The recommendation is strong, because the effect size is moderate or large for patient important outcomes (cardiovascular events) compared to DPP-4 inhibitors, sulphonylureas, glitazones, or insulin for which cardiovascular benefits have not been shown. The recommendation attaches a relative high value for weight reduction in significant obesity and a relatively low value on cost. Because of lower price, SGLT-2 inhibitors appear more cost-effective compared with GLP-1 agonists. Some patients may prefer SGLT inhibitors over GLP-1 agonists because they want to avoid injections. Other patients may prefer GLP-1 agonists because of once-a-week dosing.
A systematic review and network-meta-analysis 4 included 816 RCTs with a total of 471 038 patients. SGLT-2 inhibitors (SGLT-2i) (odds ratio 0.88, 95% Cl 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (GLP-1a) (OR 0.88, 95% CI 0.82 to 0.93; high certainty) reduced all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduced mortality (OR 0.89, 95% CI 0.79 to 1.00; moderate certainty); other drugs did not. The study confirmed the benefits of SGLT-2i and GLP-1a in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Only GLP-1a reduced non-fatal stroke; SGLT-2i were superior to other drugs in reducing end stage kidney disease. GLP-1a and SGLT-2i and tirzepatide improved quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2i, severe gastrointestinal adverse events with tirzepatide and GLP-1a, hyperkalaemia leading to admission to hospital with finerenone).
A network-meta-analysis 3 including 764 RCTs with a total of 421 346 patients assessed addition of SGLT-2 inhibitors (SGLT-2i) or GLP-1 receptor agonists (GLP-1a) to existing type 2 diabetes treatment. Results included estimated absolute effects of treatment per 1000 patients treated for 5 years for patients at very low risk (no cardiovascular risk factors), low risk (3 or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular and kidney disease). Both SGLT-2i and GLP-1a lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). SGLT-2i reduced mortality and admission to hospital for heart failure. GLP-1a reduced non-fatal stroke. Main side-effects with SGLT-2i were genital infections and with GLP-1a severe gastrointestinal events. SGLT-2i and GLP-1a lowered body weight. The absolute benefits were seen in all patient groups, greatly more in the higher risk groups.
A Cochrane review [Abstract] 1 included 17 RCTs with a total of 6899 subjects to assess the effectiveness of glucagon-like peptide analogues (GLP-1 analogues) compared to placebo or other antihyperglycaemic agents in improving glycaemic control in type 2 diabetes mellitus (T2DM). Most of the studies evaluated exenatide (5 studies) or liraglutide (8 studies). All studies were of relatively short duration, minimum 8 weeks, usually 26 weeks.
In comparison with placebo, all GLP-1 agonists reduced HbA1c levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 μg twice daily, sitagliptin or pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 μg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin or rosiglitazone.
A systematic review 2 included 29 studies on incretin-based drug therapy for T2DM, with a total of 12 996 subjects. The drugs studied were either glucagonlike peptide 1 (GLP-1) analogues (exenatide 7 studies, n=2 781; liraglutide 2 studies, n=403) or dipeptidyl peptidase 4 (DPP4) inhibitors. GLP-1 analogues were mostly studied as add-ons to existing oral hypoglycemic therapy and compared with a double-blind injectable placebo, metformin, or subcutaneous insulin. GLP-1 analogues lowered hemoglobin A1c compared with placebo (weighted mean difference -0.97%, 95% CI -1.13% to -0.81%) and resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively). Adverse effects included gastrointestinal side effects, nausea and vomiting with GLP-1 analogues.
Clinical comments: Choose a GLP-1 agonist with a proven beneficial effect for cardiovascular events (all agents do not have the body of evidence for a beneficial effect).
Date of latest search: 2024-01-03
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