This Is the “Weight” Forward: GLP-1 Use in HIV Care

Introduction

People living with HIV (PLWH) face a myriad of risks for comorbidities, including metabolic complications, that extend goal therapeutic outcomes well beyond just maintaining viral suppression. The intersection of HIV infection, antiretroviral therapy (ART), and metabolic disease has created unique clinical challenges that demand preemptive innovative therapeutic approaches.¹ Among emerging treatment options, glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists have garnered increasing attention for their potential to address multiple metabolic complications. Although GLP-1 agonists, such as semaglutide, liraglutide, and tirzepatide (a dual GLP-1/GIP agonist), are FDA approved for several metabolic-related indications beyond adjunct diabetes mellitus treatment, such as reducing the risk of major adverse cardiovascular events and reducing further renal dysfunction for type 2 diabetes and obesity in the general population, their use in PLWH remains a promising yet evolving area of study.^2,3

Metabolic Complications in HIV

The metabolic burden in PLWH encompasses several interconnected conditions. PLWH experience elevated rates of cardiovascular risk factors, including dyslipidemia, insulin resistance, diabetes, and body composition changes, contributing to a 1.5- to 2-fold excess risk of atherosclerotic cardiovascular disease (ASCVD) compared with the general population.⁴ In addition to traditional cardiovascular risk factors, residual inflammation and immune activation may further contribute to cardiovascular risk in PLWH.^5,6 Although current prevention guidelines designate HIV infection as a “risk enhancer,” minimal HIV population– specific cardioprotective recommendations exist.^7,8 In the pre-ART era, patients with HIV commonly experienced cachexia and HIV-associated wasting, followed by lipodystrophy in the early highly active ART era associated with nucleoside reverse transcriptase inhibitors and protease inhibitors.^9,10 More recently, weight gain following ART initiation has emerged as a significant concern, particularly with integrase strand transfer inhibitor (INSTI)– based regimens and tenofovir alafenamide (TAF)–containing combinations.^11,12 Weight gain is consistently observed across ART clinical trials, with patients typically gaining approximately 1 to 2 kg per year; however, the most pronounced increases generally occur within the first 9 months of therapy.¹³ Although an initial “returnto- health” weight gain is expected after starting ART, the body mass index (BMI) of PLWH increases an average of up to 4 times faster within the first 2 years of therapy compared with people without HIV; furthermore, PLWH initiating INSTIs had a 5-fold greater annual weight gain in the first 2 years of therapy compared with the general population.¹⁴ The metabolic effects and underlying mechanisms of ART on indicators such as BMI and waist circumference remain an area of active investigation, with emerging and novel ART options in the pipeline showing potential to more favorably address these outcomes.¹¹

Mechanisms and Rationale for GLP-1 and GLP-1/GIP Receptor Agonist Use

GLP-1 and GLP-1/GIP receptor agonists possess multiple properties that make them attractive for treating metabolic complications in PLWH.¹⁵ These agents mimic physiological incretin hormones by stimulating glucose-dependent insulin release from pancreatic islets, inhibiting glucagon release, and delaying gastric emptying.15 In non-HIV populations, they have demonstrated efficacy in improving glycemic control in type 2 diabetes, reducing visceral and liver fat, improving cardiovascular disease outcomes, and promoting weight loss in individuals with obesity.¹⁵ See the TABLE for a comparison of GLP-1 and GLP-1/GIP receptor agonists.

The potential benefits extend beyond improved glycemic control and simple weight reduction. GLP-1 and GLP-1/GIP receptor agonists may specifically target the abnormal visceral and ectopic fat accumulation characteristic of HIV-associated lipohypertrophy, addressing a pathophysiologic process distinct from general obesity.¹⁵ Furthermore, these agents could simultaneously ameliorate multiple components of metabolic syndrome, including insulin resistance, dyslipidemia, and cardiovascular risk, all of which are elevated in PLWH.²⁶

Clinical Evidence in HIV Populations

Randomized Controlled Trial Data

The most robust evidence comes from a landmark randomized, double-blind, placebo-controlled phase 2b trial examining once-weekly semaglutide in PLWH with lipohypertrophy.¹⁵ This study enrolled 108 participants with controlled HIV-1, a BMI of greater than or equal to 25 kg/m² (overweight), and lipohypertrophy without diabetes. After 32 weeks of treatment with semaglutide, participants experienced a 30.6% reduction in abdominal visceral adipose tissue compared with placebo (β−30.82 cm²; 95% CI, −50.13 to −11.51).¹⁵ Additional benefits included an 11.2% decrease in abdominal subcutaneous adipose tissue and an 18.9% reduction in total body fat.¹⁵ Another study reported that a subset of PLWH in Washington, DC, with an average baseline BMI of 36.3 kg/m2 (class 2 obesity) who initiated a GLP-1 agonist lost an average of 2.5% of body weight over the 2.6-year study period. Nearly one-third of individuals in this subset lost at least 5% of body weight.²⁷ Another multisite study in Seattle, Washington, reported that 743 PLWH who started tirzepatide lost an average of 5.9% of body weight over the first year of therapy.²⁸

Beyond adipose tissue changes, improvements in glucose metabolism, insulin resistance, and lipid profiles have been demonstrated in PLWH.¹⁵ These findings suggest that semaglutide addresses multiple cardiometabolic risk factors simultaneously in this population. The Infectious Diseases Society of America (IDSA) 2024 Primary Care Guidance for HIV references this trial as evidence supporting the potential role of GLP-1 receptor agonists in select patients with obesity.¹¹ Despite this, the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents With HIV still advises to only prescribe GLP-1 or GLP-1/GIP agonists in PLWH based on currently approved indications for the general population.⁸

Case Reports and Observational Data

Case reports have provided additional insights into the real-world use of GLP-1 receptor agonists among PLWH. One report described a 55-year-old woman with HIV and type 2 diabetes who, after 3 months on dulaglutide added to metformin, achieved glycemic control, a reduction in BMI from 20.2 kg/m2 to 18.9 kg/m2 (healthy weight), and improved quality of life, with no adverse effects.²⁹ Another publication described 2 clinical cases of PLWH and diabetes treated with liraglutide, with both patients achieving meaningful weight loss and improved glycemic control; one patient lost 8 kg over 7 months (BMI decreasing from 35.1 kg/m² [class 2 obesity] to approximately 32.7 kg/m² [class 1 obesity]), and the other lost 16 kg over 24 weeks.³

Although limited clinical observations and theoretical considerations support the use of semaglutide and liraglutide in PLWH, the lack of robust evidence highlights the need for larger, longer-term studies across diverse HIV populations.³ Two ongoing phase 2 trials are beginning to address these gaps: one evaluating tirzepatide for weight loss and chronic inflammation in PLWH, and another investigating semaglutide microdosing for cardiometabolic health to determine whether lower maintenance doses can sustain clinical benefit.^30,31 Together, these studies may provide important insight into the role of newer incretin-based therapies, long-term outcomes, inflammation biomarkers, and optimal dosing strategies in this population.

Safety Considerations

General Safety Profile

The safety profile of GLP-1 and GLP-1/GIP receptor agonists in PLWH appears generally favorable, with most adverse events being mild and similar to those observed in the general population.¹⁵ GLP-1 and GLP-1/ GIP receptor agonists are contraindicated in individuals with a personal or family history of medullary thyroid carcinoma and in those with recurrent pancreatitis.^32-34 In the semaglutide trial, there were no statistically significant differences in possibly related or related adverse events between treatment groups.¹⁵ Common adverse effects observed, such as nausea, vomiting, diarrhea, and constipation, would also be expected in PLWH.¹⁵ Additionally, known gastrointestinal adverse effects may be more problematic in PLWH, especially among those with preexisting symptoms such as chronic diarrhea, nausea, or vomiting, though long-term incidence data in this population remain limited.³ The incidence of adverse effects appears to relatively increase for GLP-1 and GLP-1/GIP drugs with longer half-lives.³⁵ In the aforementioned semaglutide trial, 1 case of grade 4 lipase elevation and 2 cases of possibly treatment-related cholelithiasis were reported during the 32-week study period.¹⁵ Although these events were uncommon, they underscore the need for larger, longer-duration studies to better characterize rare but serious adverse effects in PLWH, particularly with higher-dose incretin therapy. Potential loss of lean muscle mass with GLP-1 and GLP-1/GIP receptor agonist therapy also warrants further investigation, particularly in older PLWH who may already be at increased risk for sarcopenia.⁴

Drug-Drug Interactions

GLP-1 and GLP-1/GIP receptor agonists are metabolized by endopeptidases and thus do not generate major drug-drug interactions with most antiretroviral agents.³ This favorable interaction profile represents a significant advantage over many other medications used to treat diabetes and cardiovascular disease. However, GLP-1 and GLP-1/GIP receptor agonists inhibit gastric acid secretion, warranting caution and close monitoring when combined with some oral ARTs that require low gastric pH for optimal absorption.³

Current Clinical Recommendations

The IDSA 2024 Primary Care Guidance recommends that GLP-1 and GLP-1/ GIP receptor agonists for obesity should be reserved for select situations while awaiting results of ongoing trials among PLWH.¹¹ Consideration can be given with shared decision-making and a discussion of known and unknown risks/benefits in patients with significant weight gain and/ or cardiovascular risk. All patients on ART should receive routine counseling on lifestyle modifications, including reducing or abstaining from alcohol use, increasing physical activity, adopting a diet with reduced saturated fat and added sugars, and increasing dietary fiber intake.¹¹ Documentation of weight and BMI every 6 months is recommended for individuals initiating or switching to INSTI- or TAF-based regimens to identify those with excessive weight gain. Changing ART because of weight gain is not currently recommended due to a lack of demonstrated benefit. Instead, lifestyle changes should be emphasized, especially for those at increased risk of weight gain.⁴

Comparative Effectiveness

Few effective interventions exist for HIV-associated lipohypertrophy. Lifestyle modifications, including diet and structured exercise, remain the mainstay, but data on overall efficacy and persistent effects on abdominal visceral adipose tissue are conflicting.¹⁵ The REPRIEVE trial (NCT02344290) demonstrated that statin therapy significantly reduces the incidence of major adverse cardiovascular events (MACEs) in PLWH; similarly, GLP-1 receptor agonists have shown reductions in MACEs in the general population, although population-specific outcomes data in PLWH remain limited.³⁶ Tesamorelin, a synthetic growth hormone–releasing hormone analogue, is the only FDA-approved medication specifically for visceral adipose tissue reduction in PLWH.¹⁵ However, its use is limited by the need for weekly reconstitution, daily subcutaneous injections, modest response rates, reversal of response with drug discontinuation, and possible increased risk of malignancy and glucose intolerance or type 2 diabetes.¹⁵ Nevertheless, tesamorelin has been documented to modestly reduce 10-year ASCVD risk prediction, with an estimated decrease of –0.40%.

This risk reduction was relatively more pronounced in patients with higher baseline CVD scores and was driven predominantly by reductions in total cholesterol.³⁷ Comparatively, once-weekly GLP-1 receptor agonists offer potential advantages in terms of convenience, broader metabolic benefits, and established cardiovascular safety in non-HIV populations.

Future Directions and Research Needs

Although initial evidence is promising, substantial knowledge gaps remain. Largescale, long-duration randomized controlled trials are needed to definitively establish the efficacy and safety of GLP-1 and GLP-1/ GIP receptor agonists across diverse PLWH populations. Such trials should examine various GLP-1 and GLP-1/GIP receptor agonists at different doses, assess long-term cardiovascular outcomes, and evaluate effects in specific subgroups, including women, racial and ethnic minorities, and individuals with varying ART regimens and/ or stages of HIV disease progression. Research should clarify optimal patient selection criteria, timing of initiation, and integration with other metabolic interventions, including statin therapy. The efficacy of GLP-1 and GLP-1/GIP receptor agonists for weight loss among PLWH appears similar to that observed in the general population, but whether this translates to equivalent cardiovascular risk reduction remains to be determined.4 Given that ASCVD risk calculators consistently underestimate risk in PLWH, particularly for women and Black/African American individuals, targeted studies in these populations are essential.⁴

Conclusion

GLP-1 and GLP-1/GIP receptor agonists are promising therapeutic options for metabolic complications in PLWH. Although limited, the available evidence shows significant benefits for HIV-associated lipohypertrophy, including reductions in visceral adipose tissue, improvements in metabolic parameters, and a generally favorable safety profile. The absence of major drug-drug interactions with most antiretroviral agents further supports their potential utility in this population. However, clinicians should exercise caution, reserving GLP-1 and GLP-1/GIP receptor agonists for select evidence-based indications until more data in PLWH are available. Emphasis on lifestyle modifications remains paramount, and careful monitoring for rare but potentially serious adverse events is important. As evidence accumulates, GLP-1 and GLP-1/GIP receptor agonists may become increasingly important tools for managing metabolic comorbidities in PLWH, potentially extending both life expectancy and quality of life for this population. Integrating these agents into comprehensive HIV care represents an important step toward advancing whole-person care and addressing the full spectrum of health challenges faced by PLWH.

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