for People With HIV Suman Srinivasa MD MS Massachusetts General Hospital Harvard Medical School Boston MA Financial Relationships With Ineligible Companies Formerly Described as Commercial Interests by the ACCME Within the Last 2 Years ID: 1047079
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1. “Weighing” in on GLP-1 Receptor Agonists for People With HIVSuman Srinivasa, MD, MSMassachusetts General HospitalHarvard Medical SchoolBoston, MA
2. Financial Relationships With Ineligible Companies (Formerly Described as Commercial Interests by the ACCME) Within the Last 2 YearsDr Srinivasa reported receiving research grant funding from Gilead Sciences. (Updated November 13, 2023)
3. Learning ObjectivesOn completion of this activity, learners will be able to:Implement GLP-1 receptor antagonists (GLP-1RAs) as a novel therapeutic class for weight lossSummarize recent studies of GLP-1RA use among people with HIVDescribe off-target effects of GLP-1RAs, which may be of potential benefit to the HIV population
4. OutlineWeight gain among persons with HIV (PWH)Therapeutic potential of GLP-1 receptor agonists (GLP-1RAs) in diabetes and weight lossImportance of body composition in weight lossStudies of GLP-1RAs in HIVOff target benefits of GLP-1RAs
5. Weight gain in the era of contemporary ARTWeight gain has been associated with ART initiation and generally does not improve with switching ART regimens. The NA-ACCORD study demonstrated that after 3 yrs of ART: almost 1/5 of those who were normal weight became overweight and 1/5 of those who were overweight became obese.The ADVANCE study demonstrated that among ART-treated individuals, women with HIV gain more weight than men with HIV. Pooled analysis of 8 RCTs of treatment-naive PWH initiating ART reported a higher weight gain in those receiving INSTI or TAF-containing regimens than in those receiving TDF, abacavir or zidovudine. Dolutegravir and bictegravir have been most consistently implicated with INSTI-associated weight gainAdditional risk factors for weight gain include: low CD4 count, high viral load, black raceGodfrey, JID 2019; Koethe, Nature Reviews 2020; Koethe, AIDS Res Hum Retro 2016; Koethe, HIV Med 2015; Sax, CID 2019; Bourgi, CID 2020; Bares, J Women Health 2018
6. Weight gain after ART initiation and metabolic riskBares, CID 2023Clinical EventHR (95% CI)Diabetes mellitus (n=130)2.01 (1.30, 3.08)Metabolic syndrome (n=360)2.02 (1.55, 2.62)Cardiometabolic event (n=424)1.54 (1.22, 1.95)Adjusted Cox Proportional Hazard Models of Weight Change at Week 48 and Subsequent Clinical Events Among Participants With >10% Weight GainParticipated were included were on any of the following antiretrovirals: tenofovir disoproxil fumarate emtricitabine lamivudine abacavir efavirenz atazanavir darunavir raltegravir Mean weight gain from 0–48 weeks: 3.6 kg (SD 7.3)Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome: HR 0.67, 95% CI [0.42, 1.07].
7. GLP-1 receptor agonists (GLP-1RAs): Mechanism of ActionFigure adapted from Cignarelli, Front Endo 2022 and myendoconsult.comSuppress appetiteSlow gastric emptyingStimulate insulin secretionInhibit glucagon releaseDecrease glucose productionGLP-1 receptor agonism
8. Broad Potential Benefits of GLP-1RAsDecrease hepatic steatosisCardioprotectionIncrease cardiac outputImprove endothelial functionIncrease glucose uptakeIncrease diuresis Increase natriuresisIncrease glucose uptakeDecrease lipogenesisIncrease lipolysisFigure adapted from Cignarelli, Front Endo 2022 and myendoconsult.com
9. GLP-1RAs: Preparations and FDA IndicationsNameRouteFrequencyMax DosingFDAIndicationSemaglutide (Wegovy)SQweekly2.4mgWeight LossSemaglutide (Ozempic)SQweekly2.0mgType 2 DiabetesSemaglutide (Rybelsus)PO (30min before eating)daily14mgType 2 DiabetesLiraglutide (Saxenda)SQdaily3.0mgWeight LossLiraglutide (Victoza)SQdaily1.8mgType 2 DiabetesDulaglutide (Trulicity)SQweekly4.5mgType 2 DiabetesExenatide ER (Bydureon)SQweekly2.0mgType 2 DiabetesExenatide (Byetta)SQBID10mcgType 2 DiabetesLixisenatide (Adylxin)SQdaily20mcgType 2 DiabetesLong actingGLP-1RAShort actingGLP-1RA
10. GLP-1RAs: Efficacy on HbA1c/co-morbidities among individuals with DMNameRouteFrequencyMax DosingReduction in HbA1c% pointsCardiovascular mortalitybenefitin existing/high risk CVDNephropathybenefitSemaglutide (Ozempic)SQweekly2.0mg-1.5 to -2.0Semaglutide (Rybelsus)POdaily14mg-0.7 to -2.0Liraglutide (Victoza)SQdaily1.8mg-0.8 to -1.5Dulaglutide (Trulicity)SQweekly4.5mg-1.0 to -1.5Exenatide ER (Bydureon)SQweekly2.0mg-1.5 to -1.6Exenatide (Byetta)SQBID10mcg-1.0Lixisenatide (Adylxin)SQdaily20mcg-0.8 to -1.0
11. STEP8 Trial: Efficacy on weight lossRubino, JAMA 2022Results from the STEP 8 Trial (n=338)overweight/obese without DM(68 weeks)Absolute Mean Weight Change (95% CI): Semaglutide 2.4mg: -15.3 (-17.3 to -13.4)kgLiraglutide 3.0mg: -6.8 (-8.8 to -4.9)kgParticipants Achieving >10%, >15%, >20% weight loss:Semaglutide 2.4mg: 70.9%, 55.6%, 38.5%Liraglutide 3.0mg: 25.6%, 12.0%, 6.0%-15.8%-6.4%-1.9%
12. SELECT Trial: CV outcomes in obesity without DMLincoff, NEJM 2023Results from the SELECT Trial (n=17,604)BMI≥27, Pre-existing CVD, No known DMMean duration exposure to semaglutide: 34.2±13.7 monthsMean duration follow up: 39.8±9.4 monthsPrimary CV endpoint (composite death from CV causes, nonfatal MI, or nonfatal CVA) 6.5% in the semaglutide SQ group 8.0% in the placebo group *20% risk reduction with semaglutide SQ
13. OASIS-1 Trial: Oral Semaglutide 50mg for weight lossMean weight change with semaglutide 50mg PO vs. placebo after 68 weeks: -15.1% vs. -2.4% Increased GI adverse effects were reported in the semaglutide vs. placebo groups: 80% vs. 45%A trend towards a higher reduction in hsCRP was seen in semaglutide vs. placebo treated groups: -57% vs. -14%Knop Lancet 2023*Semaglutide 50mg--currently under investigationResults from the OASIS-1 Trial (n=338)BMI>30 or BMI>27 + weight related complications. No known DM
14. GLP-1RA: Current Clinical Indications for PatientsClinical Indications for GLP-1RAsType 2 Diabetes Mellitus*With established atherosclerotic CVD (ASCVD) or kidney diseaseWithout established ASCVD or kidney disease and HbA1c>9%Without established ASCVD or kidney disease and HbA1c≤9%, but weight gain is a concernObesityBMI ≥30 kg/m2 BMI of 27 to 29.9 kg/m2 with weight-related comorbidities+not met weight-loss goals (5% loss of total body weight over 3-6 months) with comprehensive lifestyle intervention alone*Not for use in type 1 diabetes
15. GLP-1RA: Potential Adverse Side EffectsInjections site reactionsRisk of hypoglycemia is low (may occur when used in combo with sulfonylureas, insulin, glinides)Gastrointestinal: nausea, vomiting, diarrhea (most common, reported in 10-50%)Symptoms may lessen with duration of therapy and dose titrationPancreatitisUse is contraindicated if prior history of pancreatitisBiliary disease: cholelithiasis, cholecystitisAcute renal insufficiency (infrequent, usually in setting of GI symptoms)Medullary thyroid cancer (black box warning)Use is contraindicated with personal/family history
16. GLP-1RAs: More about Potential Malignancy RiskSeveral meta-analyses indicated that GLP-1RAs did not increase the risk of malignancyIn 2021, STEP 3 and STEP 4 trials reported the incidence of malignancy in obese adults as 1.1% (6/535) in the semaglutide group and 0.4% (1/268) in the control groupYang et al. explored the association of GLP1RA and neoplasms by mining the FDA Adverse Event Reporting System (FAERS) database GLP-1RA did not cause a disproportionate increase in all tumor cases. Significant signals were detected between GLP-1RA and certain tumors--including thyroid cancers, pancreatic neoplasms, and neuroendocrine tumorsCao, 2019; Liu, 2019; Elashoff, 2011; Wadden,2021; Rubino, 2021; Yang, Frontiers Pharm 2022
17. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonistCurrently approved for use in type 2 diabetes Recently approved (11/2023) for use in obesityGreater reduction in A1c than GLP-1RA alone, HbA1c dec 2-2.5%Mean body weight loss 7-11 kgGLP-1, GIP, glucagon receptor agonistCurrently under investigation for use in type 2 diabetesGreater reduction in A1c than GLP-1RA alone, HbA1c dec 2%Mean body weight loss 17.2 kgRetatrutide: Triple action agonistTirzepatide: Dual action ‘twincretin’Combination GLP-1RAs: Twincretins and beyond……Brandt, J Int Med 2018; Rosenstock, Lancet 2023; Nogueiras, Nature Metab 2023GIPGlucagonAppetite Suppressionincrease appetiteyesSlow Gastric Emptyingno effectyesStimulate Insulin SecretionyesyesGlucagon InhibitionIncrease glucagon--Decrease Glucose ProductionIndirect effects through glucagonIncrease glucose productionOther--Lipolysis,increased energy expenditure,may activate GLP-1RRole of Gut Hormone Co-agonists and Potential Synergistic Effects
18. Discerning Phenotypes with Excess Adiposity in HIVAdapted from Depres 2012; Godfrey JID 2019*Ideal Clinical Strategy:Reduce VATPreserve SATGrowth hormone releasing hormone analogue (tesamorelin)*Ideal Clinical Strategy:Reduce VATReduce SAT? GLP1 receptor agonismSATVAT
19. Weight Loss with GLP-1As: fat vs. lean massErlandson, Top Antiviral Med 2020; Oliveria, Euro J Clinic Nut 2020; Wilding, JES 2021With the use of contemporary ART, the HIV population is aging and the prevalence of frailty is increased. Sarcopenia risk may be 6-fold higher among PWH when compared to matched individuals without HIV. In addition, sarcopenia may occur at a younger age among PWH. In the STEP 1 trial (semaglutide SQ weekly), an exploratory analysis showed: %change body weight from baseline to week 68 was: -15.0% with semaglutide vs -3.6% with placebo. In the semaglutide group: Relative total fat mass decreased -19.3% Relative regional visceral fat mass decreased -27.4% Relative total lean body mass decreased -9.7%However, the proportion of total lean body mass relative to total body mass increased by 3.0%-points. Increasing improvement in lean body mass:fat mass ratio was seen with semaglutide with increasing weight loss. *Ideal Clinical Strategy:Preserve Lean Body Mass
20. Do people living with HIV lose weight on GLP-1RA therapy?Retrospective study assessing GLP-1RA initiation on weight and HbA1c among persons with HIV, n=35 (LSU) Baseline CharacteristicsMean BMI (SD): 35.7 (9.8) kg/m2Mean HbA1c (SD): 9.5 (2.6) %INSTI use: 89%Concurrent use of metformin: 57%Tauhid, OFID 2022 Dec; 9(Suppl 2): ofac492.518/ ID Week 202266% lost weight (n=23)9% stable weight (n=3)26% gained weight (n=9)Breakdown of weight changes with GLP-1RA useMean duration GLP-1RA use (SD): 20.6 (14.0) months9/20 (45%) PWH with duration use >12 months lost >5% body weight
21. GLP-1 RAs Promote Weight Loss Among People With HIVRetrospective study assessing the impact of GLP-1RA initiation on weight, BMI and HbA1c, n=225 (UCSD)Preparations included: semaglutide (60%--53% SQ/7% PO), liraglutide (3%), dulaglutide (31%), tirzepatide (6%)41% achieved maximal dosing; mean duration on GLP-1RA :15.4 (4.5-26.4) monthsAdapted from slides Nguyen, ID Week 2023
22. GLP-1 RAs Promote Weight Loss Among People With HIV53 PWH (24%) had >5% weight loss41 PWH (18%) transitioned from the obese to overweight category Factors associated with >5% weight loss −Higher baseline BMI: OR 1.07 (1.02-1.3) −Longer duration of treatment (months): OR 1.04 (1.01-1.07)The use of dulaglutide was associated with decreased odds of achieving >5% weight loss [OR 0.33 (0.17-0.66)] as compared to the other GLP-1 RAs.Adapted from slides Nguyen, ID Week 2023
23. Impact of GLP-1RAs on body weight in patients with type 2 diabetes and HIVRetrospective study assessing the impact of GLP-1RAs on metabolic outcomes in individuals with type 2 diabetes mellitus and HIV (DM+HIV) compared to DM without HIV (DM), n=45 (University of Cincinnati)Conclusion: PWH and DM had significantly greater weight loss compared to people with DM alone. DM+HIV (n=15)DM (n=30)Mean Change Weight (SD) *-10.4 (12.5) kg-1.7 (8.5) kgMean %Change Weight (SD) *-8.0 (10.0) %-1.5 (6.8) %Achieved >5% weight loss60%33%Mean Change HbA1c (SD)-1.3 (2.4) -0.5 (2.0) *significantly differentLloyd, IAS 2023: https://programme.ias2023.org/Abstract/Abstract/?abstractid=3399
24. Effects of Semaglutide in HIV-Associated LipohypertrophyRandomized, double-blind, placebo-controlled study of semaglutide SQ vs. placebo (full max dose 24 weeks) among PWH with BMI≥25 and increased waist circumference, n=108 (Case Western/Medical University of South Carolina)Primary Endpoint: VAT by CT; Other endpoints: weight, SAT by CT, DXA for total fat, limb fat, trunk fat, lean massAdapted from slides McComsey, ID Week 2023
25. Effects of Semaglutide in HIV-Associated Lipohypertrophy For every 1% lean mass reduction, the semaglutide group lost 2.4% fat mass and the placebo group gained 2.0% fat massNo improvement in pericardial or liver fatOverall excellent adherence, study-related AEs similar between groups; only 3 AEs lead to discontinuationAdapted from slides McComsey, ID Week 2023
26. Other Ongoing Studies of GLP-1RAs in HIVSemaglutide's Efficacy in Achieving Weight Loss for Those With HIV (SWIFT) University College DublinPersons with BMI ≥30kg/m2 or BMI ≥27kg/m2 and hypertension, dyslipidemia or type 2 diabetes mellitus randomized to semaglutide+diet/exercise vs. diet/exercise (open label) Outcome: Effect on total body weightOther measures: immune function, inflammation, gut microbiome, glucose and lipid metabolismClinicaltrials.gov
27. Potential Interactions between GLP-1RAs and ARTsGLP-1RAs are not expected to pose significant drug interactions via their metabolism (degraded by endopeptidases)GLP-1RAs are known to inhibit gastric acid secretion and to delay gastric emptying Treatment with liraglutide reduced gastric acid secretion by 18.7% and prolonged gastric emptying time by 25 min. The dissolution and absorption of atazanavir and oral rilpivirine may be affected by elevated gastric pH.With such a small difference in gastric acid secretion and emptying time though, GLP-1RAs are thought to have a minimal effect. A separated intake of orally administered GLP-1RA by 4 hrs before oral rilpivirine, and by 2–4 hrs before atazanavir intake, has been recommendedZino, HIV Med 2023; Quast, Diabetes Care 2020; Cope, Pharmacotherapy 2019
28. Semaglutide in NASHRCT conducted at 96 sites enrolling patients with/without DM, BMI>25, and biopsy-confirmed non-alcoholic steatohepatitis (NASH) were treated with semaglutide 0.1-0.4mg vs. placebo over 72 weeks. (n=320)Treatment with semaglutide 0.4mg resulted in a significantly higher percentage of patients with NASH resolution vs placebo: 59 vs. 17%Mean percent weight loss was 13% in the semaglutide 0.4-mg group and 1% in the placebo groupNewsome, NEJM 2021
29. Step-HFpEF: Semaglutide in HFpEF and ObesitySemaglutide 2.4mg SQ vs. placebo over 52 wksAmong those with HFpEF and obesity, semaglutide led to: -larger reductions in symptoms and physical limitations -greater improvements in exercise function -greater weight lossStudy was not powered to evaluate clinical events, such as hospitalization from HFKosiborod, NEJM 2023Results from the Step-HFpEF Trial (n=338)Heart failure with preserved ejection fraction (HFpEF), BMI≥30
30. The role GLP-1RA in addictive disordersGLP-1 is also produced in the nucleus tractus solitarius of the brain stem and is released as a neurotransmitterGLP-1 receptors are expressed in brain regions involved in reward and addiction and its stimulation modulates dopamine (decreases dopamine)Preclinical research has identified potent reductions in substance use and attenuation of drug-seeking behavior with several different GLP-1RAs, mainly in rodent modelsSuppresses motivation to consume alcohol, alcohol-seeking behaviors, relapse drinking and withdrawal symptoms Suppresses nicotine intake and rewardDecreases some opioid seeking and withdrawal symptomsDecrease cocaine and amphetamine reward, decrease cocaine intakePreliminary clinical studies of alcohol use disorder suggest that GLP-1RAs reduce alcohol consumption in a subset of individuals with obesity**Clinical studies are needed to assess the use of GLP-1RAs in addictive disorders.Jerlhag, Front Pharm 2023; Hernandez, Neuropyschpharm 2018; Hernandez, Addict Biol, 2019; Egecioglu, PLOS one, 2013; Egecioglu, Psychneuroendo, 2013; Marty, Front Neuro, 2020; Vallof, Addict Biol, 2015; Klausen JCI Inight, 2022; Tuesta, Nat Neurosci 2017; Douton, Behav Pharm 2021; Zhang, Neuorpsychopharm, 2020
31. Clinical Questions with GLP-1RAsAre these chronic medications? Is there reaccumulation of fat mass after GLP-1RA discontinuation?Will the amount of lean mass lost have significant clinical contributions to frailty?Will weight loss secondary to GLP-1RA use reduce metabolic risk among PWH?Are there cardiovascular, kidney, and liver benefits associated with GLP-1RA use among PWH?Will GLPs demonstrate efficacy in addiction disorders in human studies?Will there be increased insurance coverage for weight loss medications?
32. Q and A Session