No association between weight gain with integrase inhibitors and diabetes

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A large Italian study demonstrated that integrase inhibitor-based antiretroviral therapy was not associated with the risk of developing type 2 diabetes. We also found that baseline weight, rather than weight gain while taking these drugs, was the main factor associated with the development of diabetes. Another study, synthesizing previously published studies on this issue, concluded that these drugs did not increase the risk of diabetes compared with other antiretroviral drugs, except in African populations.

Multiple reports of weight gain with integrase inhibitors have raised concerns among HIV-infected individuals, who are already at higher risk of developing diabetes than the general population. The question of which studies have produced intriguing but so far inconclusive results about the potential association between weight gain and increased diabetes risk in HIV-infected people recurs. floating.

Dr. Antonio Di Bajo of the University of Genoa and colleagues analyzed data on the incidence of diabetes during antiretroviral treatment with SCOLTA (surveillance cohort long-term toxicity antiretrovirals) collected between 2003 and 2021. bottom.

Glossary

Diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body no longer produces insulin, the hormone that regulates blood sugar. Type 2 diabetes occurs when the body does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, excessive thirst, and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

integrase inhibitors (INI, INSTI)

A type of antiretroviral drug. Integrase strand transfer inhibitor (INSTI) blocks integrase, the HIV enzyme that the virus uses to insert genetic material into infected cells. Blocking integrase prevents HIV replication.

Nucleoside

Precursor of the building blocks of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA.

glucose

A simple form of sugar present in the bloodstream. All sugars and starches are converted to glucose before being absorbed. Cells use glucose as an energy source. People who have consistently high blood sugar levels may have a disease called diabetes.

reverse transcriptase

A retroviral enzyme that converts genetic material from RNA to DNA and is an essential step in the HIV life cycle. Several classes of anti-HIV drugs, including nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs), interfere with this stage of the HIV life cycle. .

SCOLTA is an observational study involving 25 Italian infectious disease centers. It follows HIV-infected individuals starting antiretroviral therapy, including newly approved agents, to identify drug toxicity in real-world settings rather than clinical trials. Her SCOLTA is open to people who have never been treated for HIV or who have changed their treatment.

In this analysis, the researchers defined diabetes as having the lowest confirmed fasting blood glucose level of 125 mg/dL or higher (normal is less than 100 mg/dL, 100–125 mg/dL indicates prediabetes, indicating diabetes) or a single blood glucose level. A blood glucose level of 200 mg/dl or more (normal is less than 180 mg/dl when measured after a meal). Diabetes was also demonstrated when antidiabetic medication was initiated during follow-up.

Of the 4,597 HIV-infected individuals enrolled in SCOLTA during the study period, 231 (5%) were excluded because they already had diabetes. Of the remaining 4,366 participants, 3,170 (73%) were male, with a mean age of 46 years and a median CD4 count of 460. At baseline, 356 (8%) participants were on statin therapy and 587 (13%) were on statin therapy. Hypertension (512 treated, 75 untreated). The average weight was 71 kg and the average body mass index (BMI) was 24, within the normal range of 18.5 to 24.9. Regarding antiretroviral drugs, 2,627 participants started an integrase inhibitor-based regimen, 1,288 started a protease inhibitor-based regimen, and 451 started a non-nucleoside reverse transcriptase inhibitor-based regimen.

Mean weight gain in the study was moderate, 0.7 kg (95% CI 0.5-0.8) at 1 year and 1.3 kg (95% CI 1.1-1.5) at 2 years of follow-up. Of note, male participants taking dolutegravir (2.3 kg over 2 years) and victegravir (2.7 kg) had the next highest increase (1.2 kg each over 2 years for elvitegravir, raltegravir and darunavir). ) was more significant when compared to

There were 120 new cases of diabetes, with an estimated incidence of 1.26 per 100 person-years of follow-up (95% CI 1.05 to 1.50). Baseline weight, but not weight gain, was found to be significantly associated with incidence of diabetes (adjusted hazard ratio per kilogram added 1.03, 95% CI 1.01 to 1.04). This was defined as older age (aHR 1.03, 95% CI 1.01-1.06 by 1 year), untreated hypertension (aHR 2.90, 95% 1.30-6.45), or fasting blood glucose >100 mg/dl. (aHR 5.47, 95) was also true. % CI 3.82-7.85 at baseline): These are all risk factors associated with diabetes in the general population.

Participants who were on antiretroviral therapy and who had not fully suppressed viral disease at study entry had more than twice the risk of diabetes compared with participants who had undetectable viral loads (aHR 2.27, 95% CI 1.48-3.49). No significant association was found between antiretroviral drugs and diabetes risk, whether the analysis focused on individual drugs or drug classes. Only raltegravir seemed to keep a distance compared to others, with a 70% increase in risk for him compared to dolutegravir. However, this was borderline statistically significant.

After emphasizing that neither integrase inhibitor-based regimens nor weight gain were associated with the development of diabetes, Di Bagio et al. emphasized that it is consistent with previous studies. . However, they also say that a possible explanation for the lack of association between weight gain and increased risk of diabetes may lie in the moderate weight gain seen in the SCOLTA cohort.

The other study was a systematic review and meta-analysis conducted by Dr. Frank Murindwa and colleagues at Makerere University, Kampala, Uganda. To establish whether integrase inhibitors have a higher risk of developing new type 2 diabetes than other antiretroviral agents, we pooled the results of previous studies. To be eligible for this analysis, these previous studies had to have HIV infection taking an integrase inhibitor for at least 12 weeks compared to either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. A cohort of patients had to have reported onset of diabetes.

Thirteen such studies were identified between 2000 and 2022 and pooled their results, representing more than 72,000 participants.

Integrase inhibitor-based treatment was associated with a 20% reduction in the risk of developing diabetes (risk ratio 0.80, 95% CI 0.67 to 0.96), including a 12% reduction in risk in eight randomized controlled trials was demonstrated (RR 0.88, 95% CI 0.81 to 0.96). Overall, integrase inhibitors were associated with lower risk than non-nucleoside reverse transcriptase inhibitors (RR 0.75, 95% CI 0.63 to 0.89), although the risk reduction was borderline significant compared to protease inhibitors (RR 0.78, 95% CI 0.61 to 1.01). ). The researchers also found that in studies with long-term follow-up (RR 0.70, 95% CI 0.53 to 0.94) and in antiretroviral drug-naive patients (RR 0.78, 95% CI 0.65 to 0.94) They also found the risk to be low.

However, integrase inhibitors were associated with a threefold risk in the African population (RR 2.99, 95% CI 2.53 to 3.54). This discovery builds on two of his studies. The majority of participants in other studies lived in high-income countries.

Mulindwa et al. therefore conclude that integrase inhibitor-based regimens do not carry a higher risk of diabetes than other antiretroviral regimens. Nonetheless, they argue that more targeted research is needed on Africans living with HIV, and that clinicians should monitor diabetes in “specific high-risk groups.”

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