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

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 > 0.2 to indicate frailty, median prevalence was 9.5% (IQR 2.4%–15.4%). Applying a higher threshold of FI > 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 > 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