Incident Type 2 Diabetes Mellitus After Initiation of Common HIV Antiretroviral Drugs

Ricky Hsu; Laurence Brunet; Jennifer S. Fusco; Karam Mounzer; Vani Vannappagari; Cassidy E. Henegare, Jean Van Wyk; Lloyd Curtis; Janet Lo; Gregory P. Fusco


AIDS. 2021;35(1):81-90. 

In This Article

Abstract and Introduction


Objectives: To describe the prevalence and incidence of prediabetes and type 2 diabetes mellitus (T2DM) among people living with HIV (PLHIV) and evaluate the association between antiretroviral therapy (ART) initiation with dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), or boosted darunavir (bDRV) and incident T2DM.

Design: Longitudinal study based on electronic health records of 29 674 PLHIV from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort.

Methods: Calculate prevalence of prediabetes and T2DM at regimen initiation. Among PLHIV without prevalent disease, estimate prediabetes and T2DM incidence (Poisson regression) and association between regimen and incident T2DM (multivariate Cox proportional hazards regression). Analyses stratified by ART experience.

Results: Among ART-naive and ART-experienced/suppressed PLHIV, the estimated prevalence of prediabetes was 8 and 11%; that of T2DM was 4 and 10%, respectively. The T2DM incidence rate was 9 per 1000 person-years [95% confidence interval (CI): 8–11] among ART-naive and 13 per 1000 person-years (95% CI: 12–15) among ART-experienced/suppressed PLHIV, with no statistically significant differences between regimens. Compared with DTG, no statistically significant association between T2DM risk and regimen was observed among ART-naive on EVG/c [adjusted hazard ratios: 0.70 (95% CI: 0.47–1.05)] or bDRV [0.53 (0.26–1.04)] and ART-experienced/suppressed on EVG/c [0.96 (0.70–1.33)], RAL [1.17 (0.70–1.96)] or bDRV [0.90 (0.57–1.42)].

Conclusion: No increased risk of T2DM was observed with EVG/c, RAL or bDRV compared with DTG in ART-naive and experienced PLHIV. However, despite a large cohort, there was a small number of events and differential risk cannot be excluded.


Long-term use of antiretroviral therapy (ART) has increased life expectancy[1] and affected patterns of morbidity over time for people living with HIV (PLHIV), with an increased burden of comorbidities.[2] The prevalence of prediabetes appears comparable among PLHIV (30% in a survey of predominantly African-American PLHIV on ART)[3] and the overall US population [34% among US adults in the National Health and Nutrition Examination Survey (NHANES)].[4] The prevalence of type 2 diabetes mellitus (T2DM) among PLHIV has been estimated to be between 3 and 15% in the United States, Europe and Australia.[5–14] When directly compared, PLHIV on ART may have a higher prevalence of T2DM than HIV-negative individuals. In a study of over one million individuals in tertiary care hospitals in the United States, the prevalence was higher among PLHIV (12%) than HIV-negative people (7%).[7] In 2009–2010, data from the Medical Monitoring Project and NHANES, the prevalence was also higher among PLHIV (10%) than HIV-negative people (8%).[8] However, in the Veterans Aging Cohort Study (VACS) of mostly men, the prevalence of T2DM was lower among PLHIV (12%) than HIV-negative individuals (23%).[9]

PLHIV may be at a greater risk of developing T2DM than HIV-negative individuals. In a systematic review of 44 studies of PLHIV receiving ART, the pooled T2DM incidence rate was 19 per 1000 person-years in the Americas (range: 8–47 per 1000 person-years) and 8 per 1000 person-years in seven European countries (range: 3–29 per 1000 person-years).[15] These estimates are higher than the incidence rates among all US adults (7 per 1000 person-years), according to 2013–2015 data from the National Health Interview Survey (NHIS).[4] In the VACS of mostly men, the cumulative incidence of T2DM was lower among PLHIV (5%) than HIV-negative individuals (11%) for an adjusted hazard ratio (aHR) of 0.56 [95% confidence interval (CI): 0.47–0.66].[9]

A variety of ART agents have been associated with an increased risk of incident T2DM in PLHIV, including nucleoside reverse transcriptase inhibitors (NRTI),[6,10,11,16,17] nonnucleoside reverse transcriptase inhibitors (NNRTI),[10] and protease inhibitors.[18] There is evidence of weight gain with use of integrase strand transfer inhibitors (INSTI), which likely impacts risk of T2DM.[19–23] However, far less research has been done evaluating the association between current standard-of-care regimens utilizing INSTIs and clinical health outcomes, such as T2DM, which may have a bigger impact on long-term health than weight gain. In the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), PLHIV who initiated treatment with an INSTI were more likely to develop diabetes (aHR: 1.22, 95% CI: 0.95–1.57) than PLHIV who initiated treatment with NNRTIs; results were similar to those for protease inhibitors. Among specific INSTIs, compared with NNRTI-based ART, raltegravir (RAL) was associated with an increased risk of diabetes (aHR: 1.50, 95% CI: 1.11–2.03) whereas dolutegravir (DTG) and elvitegravir (EVG) were not (aHR: 1.14 and 0.96, respectively).[24]

Using data from a large, real-world population of PLHIV receiving care in the United States who were new users of DTG, elvitegravir with cobicistat (EVG/c), RAL, or boosted darunavir (bDRV), we sought to first describe prevalence of prediabetes and T2DM. Among the PLHIV who did not have prediabetes or T2DM prior to or at core agent initiation, we then assessed the incidence rates of prediabetes and T2DM and estimated the association between the core agents of interest and development of T2DM during follow-up in both ART-naive as well as experienced patient populations.