Heart Protection With SGLT2, GLP-1 Drugs for Diabetes Mediated by Age

The age of type 2 diabetes patients may alter the level of cardioprotection from two newer classes of anti-diabetic agents, a network meta-analysis suggested.

The relative reduction in major adverse cardiovascular events (MACE) with SGLT2 inhibitors was greater in older versus younger participants, but the relative reduction in MACE with GLP-1 receptor agonists was less, reported researchers led by Peter Hanlon, PhD, of the University of Glasgow in Scotland, in JAMA.

Among 601 trials, there was a 24% greater relative reduction in MACE with use of SGLT2 inhibitors per 30-year increment in age (HR 0.76, 95% credible interval [CrI] 0.62-0.93). This was despite SGLT2 inhibitors’ modestly reduced HbA1c-lowering efficacy with increasing age:

• Monotherapy: absolute reduction (AR) 0.24% per 30-year increment in age (95% CrI 0.10-0.38)
• Dual therapy: AR 0.17% (95% CrI 0.10-0.24)
• Triple therapy: AR 0.25% (95% CrI 0.20-0.30)

For GLP-1 receptor agonists, older age was tied with a lower relative reduction in MACE (HR 1.47 per 30-year increment in age, 95% CrI 1.07-2.02). GLP-1 agents also were associated with greater HbA1c-lowering at age 75 compared with age 45, except when used in triple therapy:

• Monotherapy: AR -0.18% per 30-year increment in age (95% CrI -0.31 to -0.05)
• Dual therapy: AR -0.24% (95% CrI -0.40 to -0.07)
• Triple therapy: AR 0.04% (95% CrI -0.02 to 0.11)

“[I]t is notable that the reductions in major adverse cardiovascular events with SGLT2 inhibitors were greater in older people, despite lower glycemic efficacy,” Hanlon’s group wrote. “This highlights the limitation of surrogate outcomes (such as hemoglobin A1c) in determining the risks of major adverse cardiovascular events, for which hyperglycemia is a less important risk factor than hypertension or dyslipidemia.”

The efficacy of SGLT2 inhibitors and GLP-1 receptor agonists didn’t vary between the sexes.

“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,” Hanlon and co-authors advised.

“The efficacy of SGLT2 inhibitors and GLP-1 receptor agonists in improving cardiovascular and kidney outcomes has been established, with widespread use in clinical practice and inclusion in clinical guidelines,” they wrote. “However, the possibility that treatment effects may differ depending on participant characteristics has led to questions about applying trial findings to individuals less represented in trials, such as older people and women.”

Currently, clinical guidelines do not recommend different diabetes therapies for male and female patients or across different age groups. But the researchers emphasized the importance of determining whether treatment effects differ by age and sex, given that an estimated one in five people older than 65 have diabetes globally and nearly half of people with type 2 diabetes are over age 65.

Of the data included in the network meta-analysis, 592 trials with 309,503 participants reported on HbA1c (mean age 58.9, 42.3% were female), 23 trials with 168,489 participants reported on MACE (mean age 64, 35.3% were female), and 14 trials reported both outcomes. Trials ranged from a median of 24 to 26 weeks.

For trials that reported MACE, GLP-1 receptor agonists included semaglutide (Ozempic), liraglutide (Victoza), exenatide (Byetta, Bydureon), lixisenatide (Adlyxin), dulaglutide (Trulicity), ITCA 650 (not approved in the U.S.), efpeglenatide (not approved in the U.S.), and albiglutide (discontinued). SGLT2 inhibitors included dapagliflozin (Farxiga), ertugliflozin (Steglatro), sotagliflozin (Inpefa), canagliflozin (Invokana), and empagliflozin (Jardiance).

Outcomes on DPP4 inhibitors were also assessed, but these cardioprotection effects didn’t interact with age. While the use of DPP4 inhibitors was associated with slightly better HbA1c-lowering in older people for dual therapy (AR -0.09% per 30-year increment in age, 95% CrI -0.15 to -0.03), there was no interaction for monotherapy or triple therapy.

DPP4 inhibitors included in the trials were sitagliptin (Januvia), saxagliptin (Onglyza), glimepiride (Amaryl), linagliptin (Tradjenta), omarigliptin (not approved in the U.S.), and alogliptin (Nesina).

Although Hanlon’s group examined a large number of trials, most had aggregate data; individual participant data were available for only 103 studies. Data on additional outcomes like end-stage kidney disease, heart failure, and medication-related harms weren’t assessed. Also, clinical trials rarely enroll patients older than 80, and the generalizability of the findings to people older than that may be limited.

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