IAS 2023: Metabolic and weight changes using GLP-1 agonists in people living with HIV: need for more data
Kirk Taylor and Simon Collins, HIV i-Base
Glucagon-like peptide 1 (GLP-1) agonists have been used for more than 15 years to manage type-2 diabetes but more recently have shown a much wider range of potential indications, including to reduce weight.
However, data in people living with HIV is so far extremely limited.
A poster at IAS 2023 from the University of Cincinnati Medical Centre compared the weight changes after using GLP-1 agonists to treat type-2 diabetes mellitus (T2DM) in adults with (n=15) vs without (n=30) HIV. 
This was a retrospective analysis from 2017 to 2022 that matched participants 2:1 by gender, race/ethnicity, GLP-1 RA, and dose.
Baseline demographics included mean age 57 years (±8), 13% women, 52% Black, 48% white, and mean weight 118 kg (±35) and was balanced between groups. Almost half (46%) had the GLP-1 dose titrated up during the study period. Approximately 70% used dulaglutide, with 15% using semaglutide and 15% liraglutide.
The mean changes in weight were –10.4 (±12.4) kg vs –1.7 (±8.4) kg in the HIV+ vs HIV– groups respectively (p=0.0085). The mean percentage difference in weight was –8% (±9.9%) vs –1.4% (±6.8%), (p=0.013).
Approximately 60% (9/15) vs 33% (10/30) achieved >5% loss in body weight (p=0.1158).
There were no significant differences between groups in haemoglobin A1c: –1.3% (±2.39%) vs –0.49% (±2%), respectively (p=0.2415).
This study only has a small number of participants and a larger study is underway. The signal of greater changes in participants with HIV supports the suggestion in the poster that HIV might reduce GLP-1 and/or that integrase inhibitors might affect metabolic pathways directly, or indirectly due to increased appetite.
This increases the importance of understanding more about the potential use of GLP-1 agonists in management of both HIV-associated weight gain and metabolic changes from lipodystrophy.
Although general reductions in systemic fat might reduce visceral abdominal fat, intramuscular and pericardial fat might have less impact on localised fat deposits including lipoma, buffalo hump and gynaecomastia. There is also the potential to worsen HIV-related lipoatrophy and a concern that lean mass might be reduced. 
HIV was a likely exclusion criteria not only for registrational studies but also for many of the newly proposed studies.
In 2021, the US FDA approved a higher dose of semaglutide with an indication to manage weight, in combination with diet and exercise. 
NHS England also recently agreed to provide semaglutide for weight loss in the UK. 
On 8 August 2023, top-line results from the SELECT study included a 20% reduction in cardiovascular events using semaglutide compared to placebo. 
However, semaglutide has also been associated with a diverse range of potential off-target events that range from reducing hepatic steatosis and reducing use of alcohol and cigarettes to possible signals for increased risks of cancer and suicide. [6, 7, 8, 9]
Early results from other GLP-1 agonists, including retatrutide, are also impressive. In June 2023, the New England Journal of Medicine published results from a randomised double-blind trial on retatrutide to treat obesity and type 2 diabetes. 
Retatrutide is a novel three-hormone-receptor agonist cocktail developed by Eli Lilly that contains a GLP-1 agonist, GIP (glucose-dependent insulinotropic polypeptide) and a glucagon receptor antagonist.
Participants receiving the highest weekly dose of retatrutide (12 mg) experienced a 24% reduction in body weight over 48 weeks. A 5% reduction in body weight was reported for participants on intermediate doses (4 or 8 mg) across the same period.
Pre-diabetic status was reversed for >70% of participants in the retatrutide group.
Participants (n=338) were female (48%), Black (8%), Asian (4%), Hispanic/Latinx (35%), mean age was 48.2 ± 12.7 years and mean BMI was 37.3 ± 5.7 kg/m2. At baseline participants were pre-diabetic (36%), hypertensive (43%) and had dyslipidaemia (33%). Participants were randomised in this double-blind trial to receive weekly injections of retatrutide (1 mg, 4 mg, 8 mg or 12 mg) or placebo control for 48 weeks.
Weight loss was reported for all groups that received retatrutide. Weight loss at 48 weeks was dose-dependent with a 2% loss in the placebo group compared to 5% for intermediate doses (4 and 8 mg) and 24% for those in the 12 mg group. The magnitude of weight loss at week 48 for people in the 12 mg group was greater for women (28.5%) than men (21.9%).
A sub-study of 98 participants investigated the impact of 8 mg or 12 mg retatrutide on non-alcoholic fatty liver disease (NAFLD). 
Participants had MRI imaging of their livers and biomarkers were measured from their blood. Reduced liver fat was reported for 90% of participants at week 48 for those who received either 8 or 12 mg of retatrutide.
Participants who received retatrutide had improved blood pressure, lipid levels and 72% of participants who had pre-diabetes at baseline returned to normoglycaemia. Gastrointestinal side effects (e.g. diarrhoea, vomiting) were common in the retatrutide group. Serious adverse events (n=15) occurred with similar frequency in the placebo and treatment groups. A single case of acute pancreatitis was reported in the retatrutide group but did not lead to discontinuation.
These studies indicate that retatrutide has potential to reduce obesity and NAFLD in non-diabetic and pre-diabetic individuals.
FURTHER HIV RESEARCH
Only two studies are currently registered in the US clinicaltrials.gov registry that evaluate semaglutide in people living with HIV, including one with sites in Dublin and Liverpool. 
There are five registered trials of retatrutide with two that will recruit participants from the UK. 
Most reports of GLP-1 agonists in HIV care are limited to single cases or very small cohorts, with only one study listed for lipodystrophy, despite potential benefit. [14, 15, 16, 17, 18, 19]
But it is difficult to understand the lack of data from larger observational cohorts on the use of GLP-1 agonists in people living with HIV. These drugs have been widely used to treat diabetes for over 15 years and were approved in the US for weight loss in 2021. One in ten US adults have diabetes, a third have prediabetes and 40% of adults are obese – and similar percentages will apply to people living with HIV.
A recent analysis of GLP-1 pricing also suggests that generic manufacturers would be able to make oral versions of semaglutide affordable in low- and middle-income countries. 
A recent review in JAMA reported on the extended patent life of these drugs, with each compound also being linked to numerous patents related to the delivery system. 
Thanks to Dr Graeme Moyle for additional comments.
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- Sargeant JA et al. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019 Sep;34(3):247-262. doi: 10.3803/EnM.2019.34.3.247. (26 September 2019).
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- Sanyal AJ et al. Retatrutide NAFLD – Phase 2 trial results in subset of patients with obesity and NAFLD. 83rd Scientific Sessions of the American Diabetes Association, 23 – 26 June 2023, San Diego, California and hybrid. Symposium CT-1.5-SY26. (26 June 2023).
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This report was first published on 11 August 2023.