Efficacy of Diabetes Treatments Varies by Age and Sex: SGLT2 Inhibitors More Effective in Older Adults, Study Reveals

The study, published in the Journal of the American Medical Association (JAMA), found that SGLT2 inhibitors and GLP-1 receptor agonists were linked to a reduced risk of major adverse cardiovascular events (MACEs). An analysis of age-treatment interactions indicated that SGLT2 inhibitors provided greater cardiovascular protection in older individuals than in younger ones, even though the reductions in HbA1c were smaller. On the other hand, GLP-1 receptor agonists offered more significant cardioprotective benefits in younger individuals.

The researchers note that the efficacy of treatments for type 2 diabetes, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors, in improving hyperglycemia and reducing the risk of major adverse cardiovascular events (MACEs) has been well-established. However, it remained unclear whether the effectiveness of these treatments varies with age or sex. In a recent study, Peter Hanlon, School of Health and Wellbeing, University of Glasgow, Glasgow, Scotland, and colleagues aimed to evaluate whether age or sex influences the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors.

For this purpose, the researchers comprehensively searched the MEDLINE and Embase databases, along with US and Chinese clinical trial registries, for articles published from inception to November 2022. The search was updated in August 2024 to capture the latest trial results. Two reviewers carefully screened randomized clinical trials comparing SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors against a placebo or active comparator in adults with type 2 diabetes. Using multilevel network meta-regression models, they extracted individual participants and aggregated data to assess age-treatment and sex-treatment interactions. The study's primary outcomes were hemoglobin A1c (HbA1c) levels and major adverse cardiovascular events.

Key Findings:

• Of the 601 eligible trials identified, 592 trials with 309,503 participants reported HbA1c data and 23 trials with 168,489 participants reported major adverse cardiovascular events (MACEs).

• Individual participant data were obtained for 103 trials, including 103 reporting HbA1c and six reporting MACEs.

• SGLT2 inhibitors (versus placebo) showed less HbA1c lowering with increasing age for all therapy types:

• Monotherapy: Absolute reduction (AR) of 0.24% per 30-year increment in age.

• Dual therapy: AR of 0.17% per 30-year increment in age.

• Triple therapy: AR of 0.25% per 30-year increment in age.

• GLP-1 receptor agonists were associated with greater HbA1c lowering with increasing age for monotherapy and dual therapy, but not for triple therapy:

• Monotherapy: AR of -0.18% per 30-year increment in age.

• Dual therapy: AR of -0.24% per 30-year increment in age.

• Triple therapy: AR of 0.04% per 30-year increment in age.

• DPP4 inhibitors showed slightly better HbA1c lowering with increasing age for dual therapy but no significant effect for monotherapy or triple therapy:

• Dual therapy: AR of -0.09% per 30-year increment in age.

• Monotherapy: AR of -0.08% per 30-year increment in age.

• Triple therapy: AR of -0.01% per 30-year increment in age.

• The relative reduction in MACEs with SGLT2 inhibitors was greater in older participants than younger ones (hazard ratio of 0.76 per 30-year increment in age).

• The relative reduction in MACEs with GLP-1 receptor agonists was less in older participants than younger ones (hazard ratio of 1.47 per 30-year increment in age).

• There was no consistent evidence for sex × treatment interactions using SGLT2 inhibitors and GLP-1 receptor agonists.

"The findings showed that recent glucose-lowering medications proved effective across various age and sex groups. Specifically, sodium-glucose cotransporter 2 inhibitors offered greater cardiovascular protection in older individuals than younger ones," the researchers concluded.

Reference:

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