Impact of Glucagon-like Peptide 1 Receptor Agonists on Body Weight in People with HIV and Diabetes Treated with Integrase Inhibitors

Abstract

Background/Objectives: We evaluated the effects of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on body weight and metabolic parameters in people with HIV and diabetes (PWHD) receiving maintenance therapy with integrase inhibitor, using a real-world study design. Methods: PWHD on integrase inhibitors-based antiretroviral therapies for at least 6 months, and treated with GLP1-RAs for at least 3 months, were included in this retrospective study. The primary study outcome was the absolute and relative change in body weight, as assessed during routine outpatient visits. Secondary analyses included evaluating the impact of GLP1-RAs on additional metabolic parameters, such as serum glucose, glycated hemoglobin, and LDL-cholesterol. Results: A total of 25 PWHD (74% males, mean age 65 ± 7 years, with 16% having a body mass index > 30 Kg/m²) receiving GLP1-RAs-based antihyperglycemic therapy were identified from our hospital database. No significant effects of GLP1-RAs on body weight were observed (absolute reduction −1.9 ± 3.0 Kg; relative reduction −2.2 ± 3.7%). Treatment with GLP1-RAs was associated with a progressive and significant reduction in serum glucose and glycated hemoglobin, with no observed impact on LDL cholesterol. Conclusions: Long-term GLP1-RA treatment significantly reduced serum glucose and glycated hemoglobin in overweight PWHD with no effects on body weight.

1. Introduction

The advent of potent antiretroviral therapies has led to a significant increase in the lifespan of people with HIV (PWH) in recent years. As a result, PWH are now developing comorbidities similar to those seen in the aging general population, such as dyslipidemia, hypertension, weight gain and type 2 diabetes mellitus (DM) [1,2,3,4]. The prevalence of HIV in patients with type 2 DM is influenced by several factors, including geography, demographic factors, and access to healthcare, ranging from 5% to 15%. However, it can be higher in certain regions or among specific subgroups [1,2,3,4]. Conversely, PWH have a two- to threefold higher risk of developing type 2 DM compared to the general population [1,2,3,4].

Initially, metabolic complications in PWH were attributed to dietary and lifestyle factors, as well as to a general state of well-being associated with a rapid improvement in immune-virologic status [5,6,7,8]. However, recent evidence suggests that integrase inhibitors (mainly dolutegravir and bictegravir) may directly contribute to weight gain [5,6,7,8,9]. If unaddressed, these effects can ultimately lead to metabolic and cardiovascular complications.

The treatment of type 2 DM has been revolutionized by the discovery of glucagon-like peptide 1 receptor agonists (GLP1-RAs) [10]. These agents improve glucose control, promote weight loss and reduce the risk of major cardiovascular events. Furthermore, significant and sustained weight loss with GLP1-RAs has also been observed in patients without DM [11,12,13,14]. Accordingly, GLP1-RAs, initially approved as glucose-lowering drugs, have also been recently proposed for long-term weight loss management in people with obesity.

Preliminary evidence also suggests the potential benefits of GLP1-RAs for body weight reduction in PWH [15,16,17]. However, these studies have not formally investigated the potential confounding effects of antiretroviral therapy. To address this gap, we performed a retrospective cohort study to evaluate the metabolic effects of GLP1-RAs in people with HIV and DM (PWHD) on maintenance integrase inhibitor-based therapy, in a real-world setting.

2. Materials and Methods

2.1. Study Design and Patient Selection

This retrospective, observational study aimed to describe the metabolic effects of GLP1-RAs in PWHD in a real-life, naturalistic setting. To address this issue, we searched in our hospital database for adult PWHD on integrase inhibitors-based antiretroviral therapies for at least 6 months and treated with GLP-1RAs for at least 3 months. Demographic, pharmacologic and clinical data were collected.

As the primary study outcome, we estimated the absolute and relative (%) change in body weight by comparing the last assessment before starting GLP1-RAs with values measured at each follow-up visit after starting treatment with this class of antihyperglycemic agents. As secondary analyses, we assessed the effect of GLP1-RAs on other routine metabolic parameters including serum glucose, glycated hemoglobin, and LDL-cholesterol. The study was approved by the local Ethical Committee (IRB approval N 11903). All data used in the study were anonymized prior to sending the database to statisticians, according to the requirements of the Italian Data Protection Code (leg. decree 196/2003) and by the general authorizations issued by the Data Protection Authority. All patients signed a written informed consent for medical procedures/interventions performed for routine treatment purposes, according to the Ethics Committee (Comitato Etico Interaziendale Area 1, Milan, Italy).

2.2. Statistical Analyses

Continuous variables were expressed as mean ± standard deviation (the normal distribution of the continuous variables was confirmed by the Kolmogorov–Smirnov test) and compared using an unpaired t-test; categorical variables were expressed as an absolute number or as a percentage, and their frequencies were compared using the chi-squared test. Statistical significances were set at p < 0.05 (significant difference) and p < 0.01 (highly significant difference).

3. Results

3.1. Patient Characteristics

Overall, 29 PWHD on maintenance GLP1-RAs-based antihyperglycemic therapy were identified in our hospital database. Of these, 25 met the inclusion criteria and were included in the present study (4 of the 29 PWHD were not on integrase inhibitors). The main demographic and clinical features are presented in

Table 1. Demographic and clinical characteristics of the 25 people with HIV and diabetes receiving integrase inhibitor-based and GLP1RAs-based therapies.

Characteristics	Data
PWHD, n	25
Females, %	24%
Age, years	65 ± 7
Body weight, Kg	79 ± 11
Body mass index, Kg/m2	28.1 ± 4.4
HIV RNA > 100 copies/mL (%)	4%
Concomitant comorbidities, %	100%
- dyslipidemia, %	100%
- hypertension, %	88%
- ischemic cardiomyopathy, %	24%
- gout, %	20%
- chronic renal insufficiency, %	16%
- obesity, %	16%
- obstructive chronic bronchitis, %	16%
On treatment with integrase inhibitors, %	100%
- dolutegravir/lamivudine, %	24%
- bictegravir/TAF/emtricitabine, %	20%
- dolutegravir/abacavir/lamivudine, %	16%
- dolutegravir/rilpivirine, %	16%
- raltegravir based ARVs, %	16%
- others, %	12%
Treatment with GLP1-RAs
- dulaglutide (0.75–1.5 mg/w), %	52%
- exenatide, %	8%
- liraglutide (0.6–1.8 mg/day), %	8%
- semaglutide tablets (3–7 mg/w), %	20%
- semaglutide sc. injection (0.25–0.5 mg/w), %	12%
On treatment with other antihyperglycemics, %	96%
- metformin, %	40%
- insulin + gliflozin, %	12%
- metformin + gliflozin, %	8%
- metformin + insulin, %	8%
- gliflozin, %	8%
- glitazon, %	8%
- others, %	16%

PWHD: people with HIV and diabetes; GLP1RAs: glucagon-like peptide 1 receptor agonists; ARVs: antiretroviral therapies; TAF: tenofovir alafenamide, sc: subcutaneous; w: weekly.

. The majority were male (74%), with a mean age of 65 ± 7 years (40% were over 65 years old). At the last available visit before starting treatment with GLP1-RAs (baseline), the mean body weight and body mass index (BMI) were, respectively, 80.8 ± 10.7 Kg and 28.1 ± 4.4 Kg/m² (16%, 68% and 16% had, respectively BMI < 25, 25–30 and >30 Kg/m²).

All PWH had at least one comorbidity in addition to diabetes, which had been diagnosed 10.4 ± 7.7 years before starting GLP1-RAs therapy. The most common comorbidities were dyslipidemia (100%), hypertension (88%) and ischemic cardiomyopathy (24%).

3.2. Pharmacologic Therapies

Sixty-four percent of the PWHD were on dolutegravir-based antiretroviral regimens. These included dual therapies with lamivudine (24%) or rilpivirine (16%), as well as triple therapy with abacavir and lamivudine (16%). Of the remaining patients, 20% were treated with bictegravir/tenofovir alafenamide/emtricitabine and 16% with raltegravir-based therapies.

The PWHD were on maintenance treatment with GLP1-RAs for 745 ± 722 days (treatment duration range: 97–3167 days); most of them were treated with dulaglutide (52%) followed by semaglutide, either as oral tablets (20%) or subcutaneous injection (12%), and by exenatide and liragutide (8% for each). As shown in Table 1, the majority (96%) of the PWHD received GLP1-RAs in combination with other antihyperglycemic agents, mainly metformin (56%). Thirty percent of the patients were given insulin.

3.3. Effect of GLP1-RAs on Body Weight

As shown in

Table 2. Time-course of metabolic parameters in the 25 people with HIV and diabetes receiving integrase inhibitor- and GLP1-RAs-based therapies.

	Baseline	Visit 1	Visit 2	Visit 3	Visit 4	Visit 5
PWHD, n	25	25	16	10	5	3
Days on GLP1-RA	-	229 ± 117	540 ± 223	1052 ± 368	1476 ± 493	2221 ± 484
Body weight (BW), Kg	80.8 ± 10.7	79.8 ± 11.1	80.0 ± 7.9	80.8 ± 6.8	76.8 ± 6.5	75.7 ± 8.3
Delta BW, Kg *	-	−1.9 ± 3.0	−4.3 ± 8.9	−4.6 ± 10.6	1.2 ± 7.5	2.3 ± 10.1
Delta BW, % *	-	−2.2 ± 3.7	−4.3 ± 8.7	−3.9 ± 11.4	2.5 ± 11.7	4.5 ± 15.7
Serum glucose, mg/dL	175 ± 51	138 ± 42 **	157 ± 68	132 ± 23 *	132 ± 23	125 ± 62
HbA1c, mmol/L	59 ± 16	49 ± 15 *	48 ± 12	42 ± 8 *	50 ± 8	51 ± 1
LDL, mg/dL	96 ± 43	78 ± 26	89 ± 30	93 ± 17	92 ± 35	89 ± 8

PWHD: people with HIV and diabetes; GLP1-RAs: glucagon-like peptide 1 receptor agonists; * difference versus baseline values; HbA1c: glycated hemoglobin; * p < 0.05 and ** p < 0.01 versus baseline values.

, no significant effects of GLP1-RAs on body weight were found. A not significant trend for both absolute (−1.9 ± 3.0 and 4.3 ± 8.9 Kg) and relative (−2.2 ± 3.7 and −4.3 ± 8.7%) reduction in the body weight was observed in the first two visits after starting treatment with GLP1-RAs (at 229 ± 117 and 540 ± 223 days). This trend was almost exclusively driven by data from two PWHD (see Figure 1). Both patients were treated with dulaglutide 1.5 mg administered once weekly via subcutaneous injection in combination with a restriction on caloric intake. At the last visit (respectively, 1206 and 881 days after starting dulaglutide), patient 1 and patient 2 lost, respectively, 19 Kg (−19%) and 23 Kg (−21.9%).

3.4. Effects of GLP1-RAs on Other Metabolic Parameters

Treatment with GLP1-RAs was associated with a progressive reduction in serum glucose and glycated hemoglobin, which reached statistical significance at Visit 1 and Visit 3 (Table 2). No significant effects of GLP1-RAs on LDL cholesterol levels were observed. Treatment was well tolerated, with no patients withdrawn from GLP1-RA therapy.

4. Discussion

Our retrospective study showed that long-term treatment with GLP1-RAs significantly reduced serum glucose and glycated hemoglobin in PWHD, confirming the findings recently reported by Haidart et al. [17]. This is not surprising considering that 100% and 77%, respectively, of the patients in both studies had DM. However, Haidart et al. reported also that 1.1 years of treatment with semaglutide was associated with substantial weight loss (−6.5 Kg), whereas we found no significant effects of GLP1-RAs on body weight. The discrepancy between the two studies may mainly be related to differences in the study population. Indeed, in our study, only 16% of PWHD were obese (68% were overweight) compared to 79% of the patients included in the study by Haidart et al. (with 21% overweight). Accordingly, it can be assumed that the GLP1-RAs-related weight loss may be more pronounced in obese patients.

Furthermore, in our study, we considered the presence of integrase inhibitor-based antiretroviral therapies as mandatory inclusion criteria, whereas, in the other study, no restrictions on antiretroviral regimens were applied [17]. Therefore, the possibility that the presence of integrase inhibitors could have hampered the positive effects of GLP1-RAs on body weight reduction cannot be ruled out. Indeed, growing evidence now suggests that the use of integrase inhibitors is associated with metabolic complications, such as weight gain and impaired glucose homeostasis (reviewed in [18]). These antiretrovirals have a mild to moderate effect on weight gain in both antiretroviral-naïve and experienced PWH, with a more pronounced effect in certain groups (i.e., women, individuals of Black African ethnicity, those with lower socioeconomic status, and older people), particularly for second-generation integrase inhibitors (dolutegravir and bictegravir). Very recently, a prospective study from the RESPOND Cohort Consortium, which involved 20,865 PWH (with 785 with DM), confirmed that the current use of integrase inhibitors is associated with an increased risk of DM, with an incidence rate ratio of 1.58 [19], which was partially attenuated when adjusted for changes in BMI. The mechanisms underlying the potential effects of integrase inhibitors on adipocytes, liver and/or muscle cells are still poorly understood and are primarily based on experimental observations. Elevated fibrosis, adipocyte size, and adipogenic marker expression were initially observed in biopsies of subcutaneous and visceral adipose tissue from noninfected macaques treated with integrase inhibitors [20]. In vitro, dolutegravir and raltegravir were associated with increased extracellular matrix production, lipid accumulation, enhanced oxidative stress, and mitochondrial dysfunction in adipose stem cells. Subsequent studies demonstrated that dolutegravir and bictegravir inhibited beige differentiation in human adipose stromal cells, as evidenced by the reduced expression of beige markers, lower cell respiration, and promotion of a hypertrophic, insulin-resistant state associated with a pro-fibrotic phenotype [21]. Using an in vitro model of adipogenesis (with 3T3-L1 cells), Perna et al. supported the evidence that integrase inhibitors can enhance adipocytic differentiation and drive some of these cells toward the expression of fibroblastic features [22]. More recently, Garcia-Martinez et al. showed that mice treated with bictegravir exhibited higher glucose levels, a slower decrease during a glucose tolerance test, altered cellular response to insulin, and a higher gluconeogenic-favoring profile [23]. In the same study, the authors also documented how bictegravir significantly reduced hepatocyte glucose uptake in a concentration-dependent manner and significantly altered the mRNA expression of enzymes related to glucose metabolism [23].

Finally, in the study by Haidart et al., all PWH were treated with semaglutide, a GLP1RA associated with the highest degree of weight loss in the general population, whereas the majority of our PWHD were treated with dulaglutide given at low doses. Consequently, it can be speculated that the lack of a significant effect on body weight observed in our study may be related to differences in the doses of GLP1-RA given. This hypothesis is indirectly supported by the results of a randomized, double-blind, placebo-controlled phase 2b clinical trial, which included adult PHW with a BMI of 25 Kg/m² or more and lipohypertrophy without DM [15]. In this study, the authors reported that 32 weeks of treatment with once weekly subcutaneous semaglutide (8-week dose titration followed by 24 weeks at 1.0 mg) decreased abdominal visceral tissue, abdominal subcutaneous adipose tissue and total body fat. Similarly, Nguyen E et al. found that, overall, 13 months of GLP1-RAs therapy resulted in a modest reduction in body weight (around 5 Kg) [16].

This study has important limitations. First, 30% of the patients were also given insulin. Therefore, it cannot be excluded that the lack of weight reduction may be attributable, at least in part, to insulin use. Additionally, we included PWH who had been on GLP-1 RA treatment for at least 3 months, a relatively short period, to observe the effects of these drugs at the highest dose. Given the retrospective and observational design of the present study, we were also unable to assess whether GLP-1 RAs directly and/or indirectly address the potential mechanisms of weight gain in HIV on integrase inhibitors. It should be also noted that the data used in this study were extracted from the database of the Infectious Diseases Department, that included patients followed by us for the management of HIV, while diabetes care is managed at different hospitals, usually those closest to the patient’s home This explains the long interval between visits, as it reflects the timing of the infectious diseases visits. Lastly, no data on abdominal circumference were available in our database.

In conclusion, our retrospective, observational study provides preliminary evidence that long-term treatment with GLP1-RAs significantly reduced serum glucose and glycated hemoglobin in overweight PWHD, with no effects on body weight.