SGLT-2 inhibitors are recommended as second-line antihyperglycaemic agent for 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. SGLT-2 inhibitors are recommended as first-line drugs with or without metformin in patients with type 2 diabetes and cardiovascular disease.
The recommendation is strong, because the the effect size is moderate or large for many patient important outcomes (progression of renal disease and cardiovascular events including heart failure) compared to DPP-4 inhibitors, sulfonylureas, glitazones or insulin for which cardiovascular benefits have not been shown. 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).
Another network-meta-analysis 3 including 764 RCTs with a total of 421 346 patients assessed addition of SGLT-2i or 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 systematic review and meta-analysis1 evaluating sodium-glucose co-transporter 2 inhibitors (SGLT2-i) for type 2 diabetes included 34 double-blinded RCTs with 9 154 patients. Canagliflozin was administered 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day for at least 12 weeks. SGLT2-i reduced HbA1c compared with placebo: mean difference (MD) -0.69%, 95CI -0.75 to -0.62%. In 12 RCTs, there was no difference in HbA1c-reduction between SGLT2-i and metformin (MD -0.05%, 95% CI 0.21 to 0.12%), but a larger HbA1c reducing effect of SGLT2-i compared with sulphonylureas (MD -0.15%, 95% CI -0.21 to -0.08%) and dipeptidyl peptidase 4 inhibitors (DPP-4-i) (MD -0.25%, 955 CI -0.36 to -0.14%). Beneficial effects was found on bodyweight, blood pressure, lipids and alanine aminotransferase. There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine.
Another systematic review and meta-analysis2 evaluatede SGLT2-i for type 2 diabetes. SGLT2-i were compared with placebo in 45 studies (n=11 232) and with active comparators in 13 studies (n=5 175). They had a favorable effect on HbA1c (mean difference vs. placebo, -0.66%, 95% CI -0.73% to -0.58%; mean difference vs. active comparators was non-significant, -0.06%, 95% CI -0.18% to 0.05%). Compared with other agents, SGLT2-i reduced body weight (MD -1.80 kg, 95% CI -3.50 to -0.11 kg) and systolic blood pressure (MD -4.45 mm Hg, 95% CI -5.73 to -3.18 mm Hg). Urinary and genital tract infections were more common with SGLT2-i (odds ratios 1.42, 95% CI 1.06 to 1.90 and 5.06, 95% CI 3.44 to 7.45, respectively).
Choose a SGLT-2 inhibitor with a proven beneficial effect for cardiovascular events (all agents do not have the body of evidence for a beneficial effect). GLP-1 agonists can be preferred in patients with significant obesity.
Date of latest search: 2021-02-17
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