Abstract

Integrase strand transfer inhibitors (INSTIs) represented the preferred first-line antiretroviral therapy for HIV 
infection due to superior virological efficacy and tolerability profiles. However, emerging evidence suggested that 
certain INSTIs, particularly dolutegravir and bolutegravir, may adversely affect glucose metabolism and interfere 
with metformin pharmacokinetics through inhibition of organic cation transporters. Metformin remains the 
cornerstone treatment for type 2 diabetes mellitus, with over 40 percent of HIV-infected individuals developing 
metabolic complications including diabetes. This review critically evaluated the pharmacological interactions 
between integrase inhibitors and metformin, examining mechanisms of drug-drug interactions, effects on glycemic 
control, clinical outcomes, and management strategies in patients with concurrent type 2 diabetes and HIV infection. 
A comprehensive literature search of PubMed, EMBASE, Cochrane Library, and clinical trial registries was 
conducted for peer-reviewed studies published between 2013 and 2025 examining INSTI-metformin interactions 
and glycemic outcomes. Dolutegravir significantly inhibited renal organic cation transporter-2 and multidrug and 
toxin extrusion proteins, reducing metformin renal clearance by 30-40 percent and increasing plasma concentrations 
by similar magnitudes. This pharmacokinetic interaction correlated with enhanced metformin-related adverse 
effects, including gastrointestinal symptoms and lactic acidosis risk but paradoxically may improve glycemic control 
in some patients. Clinical studies demonstrated heterogeneous glycemic outcomes, with some investigations 
reporting improved HbA1c reductions while others document attenuated metformin efficacy attributed to INSTI
induced insulin resistance. Bictegravir and cabotegravir exhibit minimal transporter inhibition and reduced 
interaction potential. INSTI-metformin interactions presented complex clinical implications requiring 
individualized management approaches, dose adjustments, and enhanced monitoring to optimize both HIV 
virological control and glycemic management while minimizing adverse effects.