Dolutegravir-associated hyperglycemia: a narrative review.

Allan Buzibye, Barbara Castelnuovo, Robert C Bollinger, Joseph Ssebulime, Denis Omali, Daniel Muller, Frank Mulindwa, Eva Laker, Catriona Waitt, Irene Andia, Mohammed Lamorde, Ahmet Hoke, Bernard S Bagaya, Yukari C Manabe

Journal: AIDS research and therapy 2025;22(1):93

PMID: 41013560

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Abstract

Dolutegravir is a preferred antiretroviral drug given its high resistance barrier and efficacy; however, reports from sub-Saharan Africa indicate increased hyperglycemia rates among individuals living with HIV on dolutegravir. Potential mechanisms include mitochondrial dysfunction from previous exposure to NRTIs like stavudine and zidovudine, which causes mitochondrial toxicity and predisposes patients to hyperglycemia upon switching to dolutegravir; magnesium chelation, which is borrowed from dolutegravir's mode of action (dolutegravir inhibits the action of integrase by chelation of magnesium required as a cofactor by the HIV enzyme); and chronic inflammation, with elevated pro-inflammatory markers like IL-6, CRP, and TNF-α contributing to insulin resistance. The narrative review highlights variability in hyperglycemia among patients, influenced by genetics, lifestyle, and prior antiretroviral therapy. The exact nature of dolutegravir-associated hyperglycemia, whether due to insulin resistance or reduced insulin release, remains unclear, although insulin resistance is significant.

Address: Infectious Diseases Institute, Makerere University College of Health Sciences, P.O.BOX 22418, Kampala, Uganda. [email protected].; Infectious Diseases Institute, Makerere University College of Health Sciences, P.O.BOX 22418, Kampala, Uganda.; Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.; Infectious Diseases Institute, Makerere University College of Health Sciences, P.O.BOX 22418, Kampala, Uganda.; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.; Department of Internal Medicine, School of Medicine, College of Health Sciences Unit, Makerere University, Kampala, Uganda.; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.; Department of Immunology and Molecular Biology, College of Health Sciences, Makerere, Kampala, Uganda.; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

DOI: 10.1186/s12981-025-00800-1

MeSH Terms: Humans, Pyridones, Heterocyclic Compounds, 3-Ring, Hyperglycemia, Piperazines, HIV Infections, Oxazines, HIV Integrase Inhibitors, Insulin Resistance