EFFICACY AND SAFETY OF FIXED-DOSE COMBINATION (FDC) THERAPY IN GERIATRIC TYPE 2 DIABETES MELLITUS: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS AND PRIMARY OBSERVATIONAL STUDIES

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) in geriatric populations is characterized by multimorbidity, polypharmacy, heterogeneous functional reserve, and disproportionate vulnerability to iatrogenic hypoglycaemia. Fixed-dose combination (FDC) formulations—co-formulating two or more glucose-lowering agents—have been proposed to reduce pill burden and improve therapeutic adherence. However, evidence specific to patients aged ≥65 years remains fragmented and has not been consolidated within a single analytical framework.

Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. Eligible designs included randomized controlled trials, cohort studies, case-control, cross-sectional, and other observational designs. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment using Cochrane RoB 2 for randomised studies and Newcastle-Ottawa Scale for non-randomised studies. Due to substantial heterogeneity, findings were synthesised narratively with structured outcome-specific tables.

Results: Twenty-two primary studies were included (10 RCTs, 12 observational), encompassing >700,000 individuals with T2DM, with substantial proportions aged ≥65 years. FDC regimens produced significant HbA1c reductions versus comparators (between-group differences: −0.34% to −1.14%; all p<0.01). Adherence measured by proportion of days covered was markedly superior with FDC versus loose-dose combinations (68.6% versus 46.5%; p<0.001), with the advantage widening with advancing age: 92.3% versus 88.1% at ages 65–74 years and 89.3% versus 84.8% at ≥75 years. FDC use was associated with reduced heart failure in patients aged ≥65 years (HR 0.79; 95% CI 0.69–0.91), with adherence mediating approximately 47% of the association, and reduced composite cardiovascular events (HR 0.86; 95% CI 0.77–0.97). Incretin-based and SGLT2i-containing FDCs demonstrated no excess hypoglycaemia; sulfonylurea-containing FDCs carried a measurable hypoglycaemia signal. Deprescribing to a single fixed-ratio injectable in patients aged ≥75 years significantly improved treatment satisfaction, activities of daily living, cognitive score, and depression score, with no severe hypoglycaemia.

Discussion: The evidence supports a coherent mechanistic chain: regimen simplification improves adherence; improved adherence improves glycaemic control and mediates a measurable fraction of downstream cardiorenal benefit. The adherence advantage is amplified in subgroups defining the geriatric phenotype—advanced age, high pill burden, frailty, and prior non-adherence. The principal limitation is pharmaceutical: fixed stoichiometry constrains individual dose titration in older adults with fluctuating renal function or reduced oral intake.

Conclusion: In geriatric patients with T2DM, FDC therapy delivers glycaemic efficacy at least equivalent—and in most comparisons superior—to loose-dose regimens, with substantial, age-amplified improvement in adherence and associated reduction in heart failure and cerebrovascular events. FDCs containing metformin with DPP-4 inhibitor, SGLT2 inhibitor, or fixed-ratio basal insulin–GLP-1 receptor agonist represent rational, low-hypoglycaemia options. Sulfonylurea-containing FDCs require close monitoring. Adequately powered trials designed specifically in populations aged ≥75 years, incorporating frailty stratification and patient-reported outcomes, remain a priority.