SGLT-2, GLP-1 effects on cardiovascular risk differ by age

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are more cardioprotective in older than younger people with type 2 diabetes, despite providing smaller reductions in HbA1c levels, while glucagon-like peptide-1 (GLP-1) receptor agonists are more cardioprotective in younger people, according to a meta-analysis.

To determine whether age or sex is associated with the efficacy of SGLT-2 inhibitors, GLP-1 receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors, researchers searched MEDLINE and Embase databases and U.S. and Chinese clinical trial registries for relevant studies. Of 601 eligible trials, 103 included individual participant data (92,182 participants) and 498 included aggregate data (303,311 participants). All trials with individual participant data reported HbA1c levels and six reported major adverse cardiovascular events (MACEs). Findings were published by JAMA on Feb. 3.

SGLT-2 inhibitors were associated with less lowering of HbA1c levels with increasing age as monotherapy, dual therapy, and triple therapy. GLP-1 receptor agonists were associated with more lowering of HbA1c levels with increasing age as monotherapy or dual therapy, but not as triple therapy. DPP-4 inhibitors were associated with slightly better lowering of HbA1c levels in older people as dual therapy, but not monotherapy or triple therapy. In addition, the relative reduction in MACEs with SGLT-2 inhibitor use was greater in older versus younger participants per 30-year increment in age (hazard ratio [HR], 0.76; 95% credible interval [Crl], 0.62 to 0.93).

The relative reduction in MACEs was less pronounced in older versus younger participants taking GLP-1 receptor agonists (HR, 1.47; 95% CrI, 1.07 to 2.02). For DPP-4 inhibitors, the estimate included the null (HR, 0.73; 95% CrI, 0.52 to 1.00). Researchers found no consistent evidence for sex and treatment interactions with use of SGLT-2 inhibitors and GLP-1 receptor agonists. There was also no age and treatment interaction or sex and treatment interaction for any class of medication on gastrointestinal adverse events, hypoglycemia, or urinary tract infections.

Individual participant data were not available for all trials, and a relatively small proportion of trials assessed cardiovascular outcomes, the authors cautioned.

Compared with previous studies, the current analysis “more clearly demonstrated that sex is not associated with any important difference in the efficacy of these medication classes for the treatment of type 2 diabetes,” the authors wrote. When it comes to age, the researchers hypothesized that its effect on treatment efficacy is likely moderated by characteristics like kidney function or the presence of comorbidities.