Weight gain on antiretroviral treatment raises risk of diabetes

Weight gain after starting antiretroviral treatment is likely to raise the risk of diabetes but does not push up cardiovascular disease risk, two large analyses presented to the Conference on Retroviruses and Opportunistic Infections (CROI 2020) yesterday show.

Several randomised clinical trials carried out in sub-Saharan Africa have shown substantial weight gain occurs after starting antiretroviral treatment. Weight gain is greater in black women and in people exposed to both dolutegravir and tenofovir alafenamide (TAF), the newer formulation of tenofovir.

Cohort studies in North America and Europe have also shown that women and black people gain more weight after starting treatment and have raised questions about whether all integrase inhibitors, not just dolutegravir, might be associated with weight gain.

The implications of weight gain are unclear. Higher body mass index (BMI) has been associated with an increased risk of diabetes and cardiovascular disease in some, but not all, studies in the general population and among people living with HIV. Higher BMI may also be associated with earlier onset of cardiovascular disease and more years lived with cardiovascular disease.

Investigators calculated the impact of weight gain while on antiretroviral treatment on the risk of cardiovascular events or diabetes in the ADVANCE randomised clinical trial and the D:A:D observational cohort, which was set up to monitor adverse events associated with antiretroviral treatment.

Risks of cardiovascular disease and diabetes in the ADVANCE study

The ADVANCE study randomised adults who had not previously taken HIV treatment to one of three regimens:

• dolutegravir, tenofovir alafenamide (TAF) and emtricitabine,
• dolutegravir, tenofovir disoproxil fumarate (TDF) and emtricitabine, or
• efavirenz, tenofovir disoproxil fumarate (TDF) and emtricitabine.

Baseline characteristics and treatment outcomes of the study population have been reported previously.

In the ADVANCE study, women gained an average of 8kg over 96 weeks of treatment if they were taking dolutegravir/TAF/emtricitabine, 5.5kg in the dolutegravir/TDF/emtricitabine arm and 3kg in the efavirenz/TDF/emtricitabine arm. Men gained an average of 5kg, 4kg and 1kg in the three study arms respectively.

Twenty-eight per cent of women taking dolutegravir/TAF/emtricitabine gained enough weight over 96 weeks to be classed as clinically obese by the study’s end, compared to 7% of men taking the same regimen.

Changes in cholesterol were smaller in the dolutegravir/TDF/emtricitabine arm than in the other study arms, consistent with the minimal effects of dolutegravir and TDF on lipids. In comparison to this group, total cholesterol and LDL cholesterol levels rose significantly in people receiving dolutegravir/TAF/emtricitabine. Fasting glucose levels rose in all groups, but the increase was significantly greater in the efavirenz arm (p<0.001) than in the dolutegravir/TDF/emtricitabine arm.

Metabolic syndrome (clinical obesity plus at least two of: raised triglycerides; reduced HDL cholesterol; raised blood pressure; or raised fasting glucose) emerged in 8% of people in the dolutegravir/TAF/emtricitabine arm compared to 6% of people in the dolutegravir/TDF/emtricitabine arm and 3% of people in the efavirenz/TDF/emtricitabine arm after 96 weeks.

The study investigators used three risk equations to calculate the risk of cardiovascular events or diabetes in study participants.

The Framingham risk equation estimates the 10-year risk of heart attack or coronary death. Using the Framingham equation, the investigators calculated that the baseline risk score in the ADVANCE study ranged from 2.24% in the efavirenz arm to 2.53% in the dolutegravir/TDF/emtricitabine arm – a low risk. Over 96 weeks, the risk increased marginally and there was no significant difference between study arms.

The QRISK equation estimates the 10-year risk of heart attack or stroke using a larger number of variables than Framingham. Black African ethnicity is included in this risk equation.

Using QRISK, the investigators found that the baseline 10-year risk of heart attack or stroke was very low (0.5 or 0.6% in all study arms) and increased by only 0.1 or 0.2% over 96 weeks. However, the difference between the dolutegravir/TAF/emtricitabine arm and the efavirenz arm, favouring the latter, was of borderline statistical significance (p = 0.027).

"The investigators used three risk equations to calculate the risk of cardiovascular events or diabetes in study participants."

The QDiabetes score estimates the 10-year risk of diabetes. Black African ethnicity is included in this risk equation. The baseline risk score was 0.40% in the dolutegravir/TDF/emtricitabine arm and 0.30% in the other study arms. The risk of diabetes rose to 0.90% in the TAF arm, 0.70% in the efavirenz arm and 0.50% in the dolutegravir/TDF/emtricitabine arm. The risk of diabetes onset was significantly higher at week 96 in both the dolutegravir/TAF/emtricitabine arm and the efavirenz arm than the dolutegravir/TDF/emtricitabine (p = 0.004, p = 0.005 respectively).

This translates into an extra four cases of diabetes for every thousand people treated with TAF rather than TDF in combination with dolutegravir, the investigators concluded.

They say their findings have several limitations. Weight gain in women in the ADVANCE study did not plateau prior to week 96 and longer-term follow-up is needed to determine whether it does so eventually. None of the equations used takes into account ongoing changes in weight.

Risks of cardiovascular disease and diabetes in the D:A:D study

Investigators from the D:A:D study reported on the impact of early weight changes after starting treatment. The study cohort has well-validated information on cardiovascular disease and diabetes, collected on 43,011 people living in Europe, the US and Australia over the past 20 years.

The study population was 74% male, with a median age of 39 years at baseline, 37% were current smokers, had a median baseline body mass index of 23, and a quarter had a baseline BMI above 25, indicating that they were overweight or obese.

The investigators looked at risks of cardiovascular disease according to baseline BMI and change in BMI during the follow-up period. The analysis did not include details of the antiretroviral medications taken by participants, 63% of whom had already started treatment at the time of their first weight assessment in the study.

Find out more: Diabetes and HIV

They found that the risk of cardiovascular disease did not increase in people who gained weight, regardless of baseline BMI or the amount of weight gained. However, there was some evidence that weight loss in people with lower baseline BMI was associated with a higher risk of cardiovascular disease.

The risk of diabetes consistently rose 1.5 to 2-fold across all baseline weight categories when body mass increased by at least 2kg/m² (compared to weight remaining stable).

The investigators say that it is unclear if these results apply to people taking modern antiretroviral regimens containing integrase inhibitors or TAF. They also lack information about diet and exercise and observed very few clinical events at high and very low body weights or in women or non-whites.