HIV Protease Inhibitors and Insulin Sensitivity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Protease inhibitors (PIs) are believed to affect insulin sensitivity. We aimed to analyze the effect of PIs on insulin sensitivity and the onset of diabetes mellitus (DM) in patients with HIV. Methodology: We searched PubMed, Google Scholar, ClinicalTrals.gov, and the WHO International Clinical Trials Registry Platform till November 2020 for randomized controlled trials (RCTs) that studied the effects of PIs on insulin sensitivity and DM in patients with HIV. We followed the PRISMA and PICOS frameworks to develop the search strategy. We used the random-effects meta-analysis model to estimate the mean difference (MD), standardized mean difference (SMD), and risk ratios for our outcomes, using Stata 14 software. Results: We included nine RCTs that enrolled 1,000 participants, with their ages ranging from 18 to 69 years. The parameters and investigations used in the studies to determine insulin sensitivity were glucose disposal rates, hyperglycemia, and mean glucose uptake. The majority of results showed an association between PIs and insulin sensitivity. The pooled analysis showed no statistically significant difference in insulin sensitivity with atazanavir, whether the study was performed on healthy individuals for a short term or long term in combination with other drugs like tenofovir or emtricitabine [SMD = 0.375, 95% CI (0.035, 0.714)]. The analysis showed reduced glucose disposal rates and hence reduced insulin sensitivity with lopinavir (heterogeneity chi-squared = 0.68, I-squared [variation in SMD attributable to heterogeneity] = 0.0%, p = 0.031). The heterogeneity with chi-squared was substantial (61-80%), while with I-squared was not significant (0-40%), p = 0.031). Less adverse events were observed with atazanavir than with lopinavir [RR = 0.987, 95% CI (0.849, 1.124)]. Darunavir and indinavir did not demonstrate any significant changes in insulin sensitivity. Most of the studies were found to have a low risk of bias. Conclusions: There are significant variations in the effects of PIs on insulin sensitivity and onsets of DM. Atazanavir, fosamprenavir, and darunavir did not demonstrate any significant changes in insulin sensitivity, compared to the rest of the group. There is a need to assess the benefits of PIs against the long-term risk of impaired insulin sensitivity. All patients newly diagnosed with HIV should have DM investigations before the start of ARVs and routinely. RCTs should focus on sub-Saharan Africa as the region is worst affected by HIV, but limited studies have been documented.