Association between integrase strand transfer inhibitor use with insulin resistance and incident diabetes mellitus in persons living with HIV: a systematic review and meta-analysis

Abstract

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web of Science, and ClinicalTrials.gov registries were searched for studies published between 1 January 2000 and 15 June 2022. Eligible studies reported incident DM or mean changes in insulin resistance measured by Homeostatic Model for Insulin Resistance (HOMA-IR) in patients on INSTIs compared with other ARTs. We performed random-effects meta-analyses to obtain pooled relative risks (RRs) with 95% CIs.A total of 16 studies were pooled: 13 studies meta-analyzed for incident diabetes with a patient population of 72 404 and 3 for changes in HOMA-IR. INSTI therapy was associated with a lower risk of incident diabetes in 13 studies (RR 0.80, 95% CI 0.67 to 0.96, I2=29%), of which 8 randomized controlled trials demonstrated a 22% reduced risk (RR 0.88, 95% CI 0.81 to 0.96, I2=0%). INSTIs had a lower risk compared with non-nucleoside reverse transcriptase inhibitors (RR 0.75, 95% CI 0.63 to 0.89, I2=0%) but similar to protease inhibitor-based therapy (RR 0.78, 95% CI 0.61 to 1.01, I2=27%). The risk was lower in studies with longer follow-up (RR 0.70, 95% CI 0.53 to 0.94, I2=24%) and among ART-naïve patients (RR 0.78, 95% CI 0.65 to 0.94, I2=3%) but increased in African populations (RR 2.99, 95% CI 2.53 to 3.54, I2=0%).In conclusion, exposure to INSTIs was not associated with increased risk of DM, except in the African population. Stratified analyses suggested reduced risk among ART-naïve patients and studies with longer follow-up.International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42021273040.

Blood glucose outcomes of anti-retroviral therapy naïve Ugandan people with HIV with pre-diabetes mellitus initiated on dolutegravir for 48 weeks

“…In an earlier meta-analysis evaluating the association of INSTI use with incident diabetes mellitus, we demonstrated reduced risk in comparison to NNRTIs and protease inhibitors (PIs) apart from African populations where the risk was threefold increased [39]. These results have been replicated in another published meta-analysis [40].…”

Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? A case report

“…Review of current suggests that at population level, integrase inhibitors are associated with a reduced risk of incident diabetes mellitus compared to NNRTIs and PIs [1], [2]. There is also evidence to demonstrate insigni cant differences in effects on insulin resistance compared to other HIV drug classes [2].…”

“…Review of current suggests that at population level, integrase inhibitors are associated with a reduced risk of incident diabetes mellitus compared to NNRTIs and PIs [1], [2]. There is also evidence to demonstrate insigni cant differences in effects on insulin resistance compared to other HIV drug classes [2]. Additionally, there are published case reports documenting that a certain section of heavily ART experienced PWH, probably with a currently unclear predisposition develop accelerated hyperglycemia when exposed to integrase inhibitors[3]- [7].…”

“…Integrase strand transfer inhibitors (INSTIs) have been demonstrated to have reduced risk of incident type 2 diabetes mellitus (T2DM) compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in different sub-populations in two meta-analyses [1], [2]. The risk was heightened in African populations which were generally under-represented [2] and multiple case reports of patients presenting with accelerated hyperglycemia within weeks to a few months of starting INSTIs have been published [3]- [7]. Following these case reports, the Uganda Ministry of Health guidelines recommended dolutegravir substitution in all patients with incident diabetes mellitus (T2DM) [8].…”

Clinical consequences of weight gain during treatment for HIV infection

“…A systematic review and meta-analysis of 13 randomized controlled trials and six observational cohort studies has shown no significant increase in the risk of Type 2 diabetes for people taking integrase inhibitors [32]. The most commonly reported endpoint was fasting hyperglycemia of at least Grade 2, or HbA1C above 6.5%.…”