Frailty in randomized controlled trials of glucose-lowering therapies for type 2 diabetes: An individual participant data meta-analysis of frailty prevalence, treatment efficacy, and adverse events
Authors: Heather Wightman, Elaine Butterly, Lili Wei, Ryan McChrystal, Naveed Sattar, Amanda Adler, David Phillippo, Sofia Dias, Nicky Welton, Andrew Clegg, Miles Witham, Kenneth Rockwood, David A McAllister, Peter Hanlon
Journal: PLoS Medicine (2025)

Background The representation of frailty in type 2 diabetes trials is unclear. This study used individual participant data from trials of newer glucose-lowering therapies to quantify frailty and assess the association between frailty and efficacy and adverse events. Methods and findings We analysed IPD from 34 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DDP4) inhibitors. Frailty was quantified using a cumulative deficit frailty index (FI). For each trial, we quantified the distribution of frailty; assessed interactions between frailty and treatment efficacy (HbA1c and major adverse cardiovascular events [MACE], pooled using random-effects network meta-analysis); and associations between frailty and withdrawal, adverse events, and hypoglycaemic episodes. Trial participants numbered 25,208. Mean age across the included trials ranged from 53.8 to 74.2 years. Using a cut-off of FI &gt; 0.2 to indicate frailty, median prevalence was 9.5% (IQR 2.4%–15.4%). Applying a higher threshold of FI &gt; 0.3, median prevalence was 0.5% (IQR 0.1%–1.5%). Prevalence was higher in trials of older people and people with renal impairment however, even in these higher risk populations, people with FI &gt; 0.4 were generally absent. For SGLT2 inhibitors and GLP1 receptor agonists, there was a small attenuation in efficacy on HbA1c with increasing frailty (0.08%-point and 0.14%-point smaller reduction, respectively, per 0.1-point increase in FI), below the level of clinical significance. Findings for the effect of treatment on MACE (and whether this varied by frailty) had high uncertainty, with few events occurring in trial follow-up. A 0.1-point increase in the FI was associated with more all-cause adverse events regardless of treatment allocation (incidence rate ratio, IRR 1.44, 95% CI 1.35–1.54, p &lt; 0.0001), adverse events judged to the possibly or probably related to treatment (1.36, 1.23, to 1.49, p &lt; 0.0001), serious adverse events (2.09, 1.85, to 2.36, p &lt; 0.0001), hypoglycaemia (1.21, 1.06, to 1.38, p = 0.012), baseline risk of MACE (hazard ratio 3.01, 2.48, to 3.67, p &lt; 0.0001) and with withdrawal from the trial (odds ratio 1.41, 1.27, to 1.57, p &lt; 0.0001). The main limitation was that the large cardiovascular outcome trials did not include data on functional status and so we were unable to assess frailty in these larger trials. Conclusions Frailty was uncommon in these trials, and participants with a high degree of frailty were rarely included. Frailty is associated very modest attenuation of treatment efficacy for glycaemic outcomes and with greater incidence of both adverse events and MACE independent of treatment allocation. While these findings are compatible with calls to relax HbA1c-based targets in people living with frailty, they also highlight the need for inclusion of people living with frailty in trials. This would require changes to trial processes to facilitate the explicit assessment of frailty and support the participation of people living with frailty. Such changes are important as the absolute balance of risks and benefits remains uncertain among those with higher degrees of frailty, who are largely excluded from trials.