Switching to an integrase inhibitor can raise diabetes risk in people with HIV

Two large studies have found that switching to an integrase inhibitor carries a moderately increased risk of developing type 2 diabetes for some groups of people with HIV.

In one study, which combined data from 27 cohorts of people receiving HIV care in North America, switching from a protease inhibitor to an integrase inhibitor increased the risk of developing type 2 diabetes within two years. Switching from a non-nucleoside reverse transcriptase inhibitor to an integrase inhibitor did not raise the risk of developing diabetes.

In a second study, of participants in the REPRIEVE trial of statin treatment for people with HIV at low-to-moderate risk of major cardiovascular events, switching to an integrase inhibitor raised the risk of developing type 2 diabetes within five years. The switch to an integrase inhibitor also raised the risk of developing obesity or high blood pressure, but was not associated with a raised risk of major cardiovascular events.

Integrase inhibitors – including dolutegravir and bictegravir – are recommended for first-line treatment of HIV or as a switch option for people already taking another type of HIV regimen. Some studies have shown that integrase inhibitors are associated with greater weight gain after starting treatment than other drug classes. Obesity can contribute to the development of diabetes and cardiovascular disease.

Several studies have also identified that integrase inhibitor treatment is associated with a higher risk of developing insulin resistance, a potential precursor to type 2 diabetes, and an international cohort study has reported a higher risk of developing diabetes among people taking integrase inhibitors, regardless of weight gain.

Two studies published in Lancet HIV in March 2026 reported a moderately increased risk of type 2 diabetes after switching to an integrase inhibitor.

Diabetes risk in a North American cohort study

The North American AIDS Cohort Collaboration on Research and Design reported on the incidence of diabetes in people who switched from a protease inhibitor (PI) (n = 1714) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) (n=2702) to an integrase inhibitor, compared to people who stayed on those drug classes (4459 continued a PI, 7895 continued an NNRTI). The study followed people from switching or the first clinic visit in 2016, for up to five years.

Integrase inhibitors may influence the development of diabetes and hypertension by mechanisms other than weight gain.

In the NNRTI group, the incidence of type 2 diabetes was 24.5 cases per 1000 person-years of follow up in those who continued an NNRTI and 27.7 cases per 1000 person-years in those who switched, a non-significant difference (hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.87-1.39).

In the PI group, the incidence of type 2 diabetes was 22.7 cases per 1000 person-years of follow up in those who continued a PI and 30.4 cases per 1000 person-years in those who switched, a 38% increase in the risk of developing diabetes (HR 1.38, 95% CI 1.06-1.80).

The risk of developing type 2 diabetes after switching from a PI to an integrase inhibitor was significantly higher in the first two years after switching, but not thereafter. Weight gain after switching from a PI did not explain the risk of developing diabetes; even when the analysis assumed that no one gained more than 5% in body weight in the first year after switching, the risk of developing diabetes was 37% higher for people who switched from a PI compared to non-switchers.

There were no differences between integrase inhibitors in the risk of new-onset diabetes, suggesting that the risk is associated with the drug class rather than specific agents. Long-acting cabotegravir was not included in this analysis.

As protease inhibitors are known to cause metabolic complications, one theory is that most people who switch from a protease inhibitor to an integrase inhibitor do so because they already have metabolic issues, and that any effects of an integrase inhibitor on insulin resistance provide a further nudge in the direction of developing type 2 diabetes. The study investigators tried to control for this by adjusting for known metabolic co-morbidities.

The study investigators say that screening for new-onset diabetes is especially important in the first two years after people switch to an integrase inhibitor.

Diabetes and obesity risk in the REPRIEVE trial

In the REPRIEVE study of pitavastatin for prevention of major cardiovascular events, study investigators compared the risks of developing obesity, diabetes, hypertension and major cardiovascular events in people who switched to an integrase inhibitor or stayed on a regimen that did not contain an integrase inhibitor.

The REPRIEVE study followed participants for five years. This analysis divided the five-year follow-up into sequential segments of 60 days. The study compared outcomes between switchers and non-switchers during each 60-day period. During the study, 2981 participants switched to an integrase inhibitor and 5059 participants did not during at least one 60-day period.

Although switching was at the discretion of participants and their doctors and non-randomised, the distribution of demographic characteristics and lifestyle and biological risk factors for cardiovascular disease was similar between switchers and non-switchers in all respects apart from race. A higher proportion of switchers were Black or African American compared to non-switchers (44% vs 37%).

As statin treatment at higher doses has been associated with insulin resistance in some studies, the analysis was adjusted for exposure to pitavastatin during the study, as well as demographic and HIV-related factors.

During a median follow up of 2.8 years, 9% of switchers developed obesity, 4.5% developed diabetes and 10% developed hypertension, indicating that the absolute risk of developing these conditions was relatively low. In addition, 1.7% experienced a major cardiovascular event.

Compared to non-switchers, people who switched to an integrase inhibitor had a significantly higher risk of developing obesity (HR 1.41, 95% CI 1.22-1.59), diabetes (HR 1.50, 95% CI 1.24-1.81) and hypertension (HR 1.45, 95% CI 1.26-1.67). There was no significant difference between switchers and non-switchers in the risk of experiencing a major cardiovascular event such as stroke or heart attack during the median follow-up period of 2.8 years.

The elevated risk in people who switched to an integrase inhibitor remained significant in analyses restricted to people who were taking efavirenz at study entry and after adjustment for exposure to tenofovir disoproxil or tenofovir alafenamide. Each of these agents has been shown to affect the extent of weight gain after switching to an integrase inhibitor.

The study found that adjusting for changes in body mass index over time did not affect the risk of experiencing a major cardiovascular event or developing diabetes or hypertension, suggesting that integrase inhibitors influence the development of diabetes and hypertension by mechanisms other than weight gain.

In an accompanying comment article, two French HIV specialists say that given the metabolic risks shown in both studies, screening early for diabetes and hypertension, together with proactive management of cardiovascular risk factors, could avert long-term harm. They note that in REPRIEVE, participants had low-to-moderate risk of cardiovascular disease at study entry and half received statin treatment, which reduced their risk during the follow-up period.