Greater weight gain and changes in body composition in the first year after starting antiretroviral treatment were associated with an increased risk of developing diabetes and metabolic syndrome over nine years of follow-up among participants in several large clinical trials, study investigators report in Clinical Infectious Diseases.
The study also found that greater weight gain was associated with a higher risk of developing potential precursors of heart disease in the form of high blood pressure (hypertension) and coronary artery disease (atherosclerosis). However, the study found no association between early weight gain and the subsequent risk of heart attack, stroke or a clinical intervention for heart disease such as stenting or angioplasty.
The large US study also highlighted differences in risk by race and sex. Whereas substantial weight gain in men was associated with a higher incidence of diabetes, the same association was not observed in women. Also, White and Black non-Hispanic participants experienced a higher incidence of cardiometabolic events including hypertension and coronary artery disease after substantial weight gain than other racial groups.
Weight gain after starting antiretroviral treatment is common. Recent studies have shown that one in six people gain at least 10% in body weight over one to two years. But the long-term consequences of weight gain have been uncertain until now.
To investigate these questions, researchers associated with the US AIDS Clinical Trials Group looked at the long-term outcomes of participants in a series of ACTG randomised studies of antiretroviral treatment in previously untreated people. Participants in these studies were recruited into the A5001 and A5322 cohort studies for long-term follow-up after the trials had been completed.
The analysis included all cohort participants who had been exposed to tenofovir disoproxil (TDF), emtricitabine, lamivudine, abacavir, efavirenz, atazanavir, darunavir or raltegravir during the randomised studies.
Total weight and waist circumference were measured at least annually in all cohort participants. Lipid levels and glucose were measured two to three times a year.
The analysis evaluated the relationship between weight changes in the first year of treatment and the following outcomes during long-term follow-up:
- Cardiovascular events: stroke, heart attack or clinical cardiac procedure
- Cardiometabolic events: diagnosis of hypertension, initiation of antihypertensive medication, coronary artery disease or any cardiovascular event as above
- Type 2 diabetes
- Metabolic syndrome, defined as three or more of the following: waist circumference >102cm in men or > 88cm in women; blood pressure >130/85; diagnosis of or drug treatment for hypertension; fasting triglyceride >150mg/dL; fasting HDL < 40mg/dL (men) or 50mg/dL (women); fasting blood glucose > 100mg/dL or new diagnosis of diabetes.
The study participants (2624 people) were predominantly male (81%); 39% were white, 35% Black non-Hispanic and 22% Hispanic. The mean age at baseline was 38 years, 48% were either overweight or obese and 27% already had metabolic syndrome at baseline.
Study outcomes
Forty-eight weeks after starting treatment, men had gained an average of 3.5kg and women had gained 4.2 kg, and 22% of participants had gained at least 10% in body weight.
By week 480 (approximately nine years after study entry), participants had gained an average of 7.1 kg in weight and 45% of women and 38% of men had gained at least 10% in body weight compared to baseline. The study investigators note that this degree of weight gain is in line with the general population in the United States, where the NHANES study reported that 36% of a large, diverse cohort of US adults gained at least 10% in body weight over 10 years of follow-up.
In the ACTG study, weight gain of greater than 10% was associated with a baseline CD4 count below 200.
Each analysis of the association between weight gain and the outcomes of interest excluded people who already had the condition or who developed it in the first 48 weeks on treatment, in order to assess the impact of weight gain on new episodes of the condition.
Glucose and diabetes: After adjusting for baseline body mass index, history of diabetes and history of hypertension, every 1kg increase in weight up to week 48 was associated with a 1.13mg/dL increase in fasting glucose. During follow-up, 130 people developed diabetes. Those who experienced greater than 10% weight gain by week 48 had twice the risk of subsequently developing diabetes compared to those who gained less than 5% in weight or lost weight (to -5%).
However, analysis by sex showed that while men who gained at least 10% of body weight had a 2.5 times higher incidence of diabetes compared to men who gained less than 5% of body weight or lost less than 5% of body weight, women who gained more than 10% of body weight did not have an increased incidence of diabetes compared to women who gained less weight.
Lipids: After adjusting for the clinical trial, initial ART drug class, baseline and nadir CD4, viral load, baseline body mass index and smoking, every 1kg increase in weight to week 48 was associated with a total cholesterol increase of 0.63mg/dL, an LDL cholesterol increase of 0.39mg/dL and a triglyceride increase of 1.42mg/dL.
Metabolic syndrome: During follow-up, 360 people developed metabolic syndrome. People who experienced at least 5% weight gain were 50% more likely to develop metabolic syndrome and those who gained at least 10% in body weight were twice as likely to develop it compared to those who gained less than 5% in weight or lost less than 5% in weight. The association between weight gain of 5-10% and raised risk of metabolic syndrome was only significant in those of White race.
Cardiometabolic events: During follow-up, 424 people developed a cardiometabolic event. The risk of experiencing a cardiometabolic event was 54% higher in people who gained at least 10% of body weight by 48 weeks compared to a weight gain of less than 5% or weight loss of less than 5%. Weight gain of between 5% and 10% was not associated with an increased risk of a cardiometabolic event. Weight change of greater than 10% was associated with an increased risk of cardiometabolic events in White and Black participants, but not in other races.
Cardiovascular events: During follow-up, 28 people experienced cardiovascular events. After adjusting for age, history of diabetes, hypertension, dyslipidaemia, family history of cardiovascular disease, smoking, baseline CD4 count and viral load, weight change was not associated with an increased risk of cardiovascular events.
The study found that in every case, total weight gain and changes in waist circumference produced similar results.
Conclusion
The study investigators say that the strength of their findings lies in the long-term follow-up and the large number of participants followed from the time they were randomly assigned to an antiretroviral regimen. The randomisation eliminates any bias caused by selecting regimens based on the characteristics of the patient. However, the study was not able to control for diet or physical activity, which might affect weight gain and the study outcomes of interest.
Although the study provides clean data about the impact of weight gain on the risk of developing new conditions, it doesn’t provide information about the ways in which weight gain may exacerbate cardiovascular risk in people who already had metabolic syndrome or who developed it soon after starting treatment, as these participants were excluded from the analyses. For example, 40% of cohort participants either had metabolic syndrome at baseline (n=707) or developed it within 48 weeks of starting treatment (n=375).
Similarly, the analysis of weight change and cardiometabolic events excluded 699 people who had already experienced a cardiometabolic event prior to baseline and 285 who experienced an event in the first 48 weeks on treatment. Knowing what happened to this especially vulnerable group of participants subsequently is critical for understanding the consequences of weight gain, given the high prevalence of these comorbidities in people with HIV. Further analysis is needed to investigate these issues.
Bares SH et al. Weight gain after antiretroviral therapy initiation and subsequent risk of metabolic and cardiovascular disease. Clinical Infectious Diseases, published online 12 September 2023.