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INSTIs and Metabolic Effects
Weight Gain Associated With INSTIs: What Are the Cardiovascular and Metabolic Implications?

Released: May 05, 2021

Expiration: May 04, 2022

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The association between weight gain and second-generation integrase strand inhibitors (INSTIs) is increasingly well recognized. What’s not as clear is how clinically significant this weight gain is (or isn’t). Recent updates from the Virtual 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021) help us start to dive beneath the surface to answer this question.

Data presented at CROI 2021 shed light but also raise some questions on cardiovascular and diabetes outcomes.

ADVANCE (Hindley et al)
The ADVANCE trial was a randomized, controlled trial of treatment-naive individuals in South Africa. Participants were randomized to receive dolutegravir (DTG) plus tenofovir alafenamide (TAF)/emtricitabine (FTC), DTG plus tenofovir disoproxil fumarate (TDF)/FTC, or efavirenz (EFV)/TDF/FTC. Those in the DTG plus TAF/FTC group had the most weight gain and had greater predicted 10-year risk of developing cardiovascular disease compared with EFV/TDF/FTC (P = .016). The DTG plus TAF/FTC group also had an increased risk of developing diabetes compared with DTG plus TDF/FTC (P = .024), and this risk was higher in women (9 additional cases of diabetes/1000 women).

REPRIEVE (Kileel et al)
In the REPRIEVE trial, a large international cohort of patients with HIV, patients receiving INSTIs had higher body mass index, odds of obesity, and waist circumference compared with patients receiving protease inhibitor or nonnucleoside reverse transcriptase–based therapies. However, fasting blood glucose and low-density lipoprotein levels were not significantly higher in the INSTI group.

IBM MarketScan (O’Halloran et al)
Data presented by O’Halloran and colleagues looked at incident diabetes associated with INSTI use in a large cohort of more than 100,000 patients with HIV between 2007 and 2018 using claims data. There was a significantly increased risk of developing either new-onset diabetes or hyperglycemia among those receiving an INSTI; this risk was largely driven by DTG compared with elvitegravir (EVG) and raltegravir (RAL).

HAILO (Masters et al)
The ACTG HAILO study also looked at risk factors for the progression from prediabetes to diabetes in a cohort of 1035 people with HIV. Unlike the IBM MarketScan study, the HAILO study found that taking an INSTI at or before a prediabetes diagnosis cut the risk of later progression to diabetes by nearly 80% (adjusted HR: 0.21; 95% CI: 0.07-0.67; P <.01). It is important to note that the majority of patients receiving INSTIs in this study were receiving either a RAL or EVG-containing regimen. This may account for the discrepant results between these data and those presented by O’Halloran, in which the use of DTG was much more prevalent.

RESPOND (Neesgaard et al)
Data from the RESPOND cohort of 21,267 patients with HIV looked at the association between cardiovascular events (myocardial infarction, stroke, or need of an invasive cardiovascular procedure) and initiation of an INSTI-containing regimen. Of patients receiving an INSTI, 6372 were receiving DTG and 2147 patients were receiving RAL (2147) or 2385 were receiving EVG. The investigators found that, even after controlling for baseline cardiovascular risk and a variety of other factors, the use of INSTIs was associated with increased cardiovascular events within the first 6 months following exposure.

Taken together, these data suggest that the weight gain associated with INSTIs, especially DTG, is linked to worse cardiovascular and metabolic outcomes. Of note, available data suggest that similar weight gain may occur with bictegravir (BIC)/FTC/TAF as with DTG-based regimens, but we currently lack data on metabolic outcomes associated with weight gain on BIC.

Regarding cardiovascular risk, the data presented from ADVANCE suggest that INSTIs are associated with higher predicted cardiovascular risk, and this is further supported by data from RESPOND. Although REPRIEVE did not demonstrate an increase in low-density lipoprotein levels in association with INSTIs, this was an observational study that was smaller than its counterparts and may not have been able to detect a difference. Regarding the impact of INSTIs on prediabetes and diabetes, the ADVANCE and IBM MarketScan studies both suggest that INSTI-associated weight gain does increase this risk. Although the risk of developing diabetes was actually lower among those receiving INSTIs in the HAILO study, the patients in this study were primarily receiving RAL, and therefore, we cannot conclude that second-generation INSTIs like DTG are also associated with this lowered risk.

What Are the Implications for My Patients?
At this time, benefits of second-generation INSTIs still far outweigh their risks in most patients regarding virologic suppression and tolerability. Moreover, the association between virologic control and improved morbidity and mortality is well documented. Antiretroviral therapy regimens containing a second-generation INSTI still remain the preferred therapy for most patients. That said, if additional data continue to emerge linking these types of poor cardiovascular and metabolic outcomes with the weight gain associated with second-generation INSTIs, the next important questions we will need to answer are (1) how can we prevent INSTI-associated weight gain and (2) how can we mitigate or decrease INSTI-associated weight gain once it takes place?

Your Thoughts?
What are your thoughts on the emerging data regarding potential cardiovascular and metabolic effects of weight gain associated with use of INSTIs? Answer the polling question and join the discussion by posting a comment.

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