Age May Modify Cardioprotective Effects of SGLT2 Inhibitors, GLP-1 RAs

A network meta-analysis linked treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to a lower risk of major adverse cardiovascular events (MACE) in people with type 2 diabetes (T2D), citing interactions by age and sex.1

This review of 601 trials, involving individual participant data from 103 trials, found the efficacy of SGLT2 inhibitor use modestly reduced with increasing age, but a greater MACE reduction in older cohorts. GLP-1 RA use showed some hemoglobin A1c (HbA1c) lowering in older participants, while the benefit for MACE was more identifiable in younger, female participants.

“Current clinical guidelines recommend less stringent glycemic targets in older people living with multiple long-term conditions or frailty due to greater risks of adverse events,” wrote the investigative team, led by Peter Hanlon, PhD, school of health and well-being, University of Glasgow. “The current findings highlight the need to consider the cardioprotective effects of therapies when treating older people in addition to safety, tolerability, and the priorities of patients.”

Advancements in glucose-lowering medications have transformed T2D management, with SGLT2 inhibitors and GLP-1 RAs proven to benefit cardiovascular and kidney outcomes.2 These data, however, have not yet confirmed this treatment effect by individual characteristics, including age and sex, with Hanlon and colleagues questioning the application of the findings to cohorts less represented in clinical trials, including older age and women.1

As a result, the team performed a systematic review and meta-analysis to estimate the differences in the efficacy of SGLT2 inhibitors, GLP-1 RAs, and dipeptidyl peptidase 4 (DPP4) inhibitors by age and sex. They searched the Medline and Embase databases and US and Chinese clinical trial registries from inception to November 2022, with an update in August 2024 to expand the search to capture trial results.

Eligible studies were randomized clinical trials enrolling adults aged ≥18 with T2D and measured the efficacy of the 3 drug classes on glycated HbA1c or MACE, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The analysis estimated age and sex treatment interactions using both individual participant and aggregate data in multi-level network meta-regression models.

Among the 601 trials that matched eligibility criteria, individual participant data was included from 103, with all reporting HbA1c and 6 reporting MACE outcomes. Primary treatment effects for HbA1c showed the 3 treatment classes reduced absolute HbA1c by −0.5% to −1.5% versus placebo. These treatment effects for MACE showed a reduced risk for SGLT2 inhibitors and GLP-1 RAs, compared with placebo, but null findings for DPP4 inhibitors.

Further analysis linked SGLT2 inhibitors to less HBA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% per 30-year increment in age), dual therapy (AR, 0.17%), and triple therapy (AR, 0.25%). GLP-1 RA use, on the other hand, was linked to greater HbA1c lowering with increasing age for monotherapy (AR, –0.18%) and dual therapy (AR, –0.24%), but not triple therapy (AR, 0.04%).

Hanlon and colleagues also found DPP4 inhibitor use correlated with slightly improved HbA1c lowering in older people for dual therapy (AR, –0.09% per 30-year increment in age), but not monotherapy (AR, –0.08%) nor triple therapy (AR, –0.01%).

Regarding age- and sex-specific effects for trials investigating MACE, SGLT2 inhibitors were associated with a reduction in MACE in older people, regardless of sex, versus younger individuals (hazard ratio [HR], 0.76 per 30-year increment in age). Meanwhile, in trials of GLP-1 RAs, older age was linked to a lower relative reduction in MACE versus younger age (HR, 1.47). Investigators indicated the estimates for DPP4 inhibitors included the null (HR, 0.73).

Otherwise, Hanlon and colleagues identified no consistent evidence of a sex-treatment interaction with the use of SGLT2 inhibitors (HR, 0.95 for males vs. females) or GLP-1 RAs (HR, 1.17 for males vs. females). They noted the effect of age on treatment efficacy could be due to other measurable age-related factors, including kidney function or the presence of comorbidities.

“Accounting for such characteristics in future work may allow a more nuanced understanding of the likely benefits of treatments according to more specific characteristics, determining not only the overall treatment efficacy in older people but in older people with different physiological and clinical characteristics,” they wrote.

References

1. Hanlon P, Butterly E, Wei L, et al. Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes: A Network Meta-Analysis. JAMA. Published online February 03, 2025. doi:10.1001/jama.2024.27402
2. Davies MJ, Aroda VR, Collins BS, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753-2786. doi:10.2337/dci22-0034