Summarizing SGLT-2 Inhibitor Usage in People With Diabetes and HIV

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Diabetes presents a significant health challenge for people living with HIV. Among persons with HIV, the prevalence of diabetes is over 2-fold higher than in individuals without HIV.¹ There is also an earlier onset of diabetes among persons with HIV than in those without HIV.² Diabetes is associated with a variety of macrovascular and microvascular effects, including cardiovascular disease (CVD), neuropathy, nephropathy, and retinopathy.³ Diabetes is particularly concerning for persons with HIV, as there is an additive effect on atherosclerosis, inflammation, and endothelial function.² Further, HIV itself is associated with an increased risk of CVD, and diabetes adds to this risk.²

There are other issues that need to be considered in persons with HIV and diabetes, such as accelerated aging, immune impairment, medication regimen complexity, and adherence challenges.² There is a need to explore the use of newer glucoselowering medications with known benefits on CVD outcomes in persons with both HIV and diabetes. This is especially important given the potential interaction between select integrase strand transfer inhibitors—the most commonly used antiretroviral treatment (ART) anchor to treat HIV—and metformin. In addition, weight gain associated with sulfonylureas may additively elevate the overall CVD risk.² The sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of medications that have demonstrated robust activity in reducing hemoglobin A1C (HbA1C) levels as well as improving important cardiorenal outcomes that are worsened by diabetes across broad populations, including those with chronic kidney disease (CKD) and heart failure (HF).^4-9

This article summarizes the existing literature surrounding the use of SGLT-2 inhibitors in persons with both diabetes and HIV and highlights some considerations when prescribing SGLT-2 inhibitors in this population.

Guidelines regarding the use of glucose-lowering medications for the management of type 2 diabetes in the general population are goal dependent.¹⁰ For glycemic management, metformin or agents including combination therapy that provide efficacy to achieve/maintain treatment goals are recommended. Some agents with very high evidence include monotherapy with highdose dulaglutide, semaglutide, tirzepatide, or insulin as well as combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with insulin.

Monotherapy with SGLT-2 inhibitors, sulfonylurea, and thiazolidinediones is considered to have high efficacy. For achievement/maintenance of weight goals, monotherapy with GLP-1 RAs is considered to have high or very high efficacy, whereas SGLT-2 inhibitors are considered to have intermediate efficacy. In scenarios where the goal is cardiorenal risk reduction, the guideline-recommended agents vary.¹⁰ For individuals with atherosclerotic CVD risk factors or CKD, the guidelines recommend SGLT-2 inhibitors or GLP-1 RAs with demonstrated efficacy.¹⁰ Moreover, the guidelines recommend SGLT-2 inhibitors with proven benefit for persons with HF.¹⁰ Persons with CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min or albuminuria) should take SGLT-2 inhibitors with primary evidence of reducing CKD progression or GLP-1 RAs if SGLT-2 inhibitors are not tolerated.

The literature is scant regarding SGLT-2 inhibitors among persons with HIV. The uptake of newer cardioprotective glucose-lowering medications appears to be low. There are only a few single-center cohort studies that have evaluated use of SGLT-2 inhibitors in persons with HIV. The overall proportion of persons with HIV prescribed an SGLT-2 inhibitor is 4% to 8.8%.^10,11 When examining persons with conditions known to be positively affected by SGLT-2 inhibitors, the rates of use are 3.8% for CKD, 13.2% for proteinuria, and 8.2% for HF.¹¹ The low overall use of SGLT-2 inhibitors is somewhat alarming given that more than half (51%) were concomitantly followed by an endocrinologist during the study period.¹⁰ The underuse of these agents underscores that the management of diabetes in this population is lagging behind the evidence contained in the guidelines and that clinical inertia is not limited to nonendocrinologist providers.¹⁰ The underuse of SGLT-2 inhibitors also underscores an opportunity to improve clinician familiarity/comfort with these agents. In addition, clinical inertia can be reduced through education on the additive cardiorenal risk that persons with HIV have relative to persons with diabetes alone, drugdrug interactions between SGLT-2 inhibitors and antiretroviral regimens recommended for most persons with HIV, and the occurrence of adverse effects being infrequent. The efficacy of SGLT-2 inhibitors for achieving glycemic targets and proven CVD benefits in patients with CKD and HF are well documented in the general population.^4-9 Limited data exist on the effectiveness of SGLT-2 inhibitors in persons with diabetes and HIV.^12,13 One prospective observational study was performed in Spain among persons with HIV and inadequately controlled diabetes (HbA1C level > 7% or those with a BMI [body mass index] > 27 kg/m2).¹³ Eight individuals in the study were being treated either with metformin, sulfonylureas, or incretin mimetics, and 2 patients receiving concomitant basal insulin were treated with canagliflozin, with a dose titrated up to 300 mg daily and followed for 24 weeks. Among the 8 participants, 75% were male, with a median age of 56.5 years. Seven individuals had BMI values associated with obesity and 1 participant with an overweight BMI, with the median BMI being 35.5 kg/m.2 At the start of the study, the median HbA1C level was 8.57%. The most commonly used ART regimens were tenofovir/emtricitabine/raltegravir and abacavir/lamivudine/efavirenz. After 24 weeks of canagliflozin therapy, there were significant changes in weight (−6.12 kg), BMI (−2.0 kg/m2), abdominal circumference (−7.9 cm), systolic blood pressure (BP; −17.4 mm Hg), fasting glucose level (−42.1 mg/dL), HbA1C level (−1.0%), eGFR (+14.1 mL/min/1.73 m2), and high-density lipoprotein cholesterol level (+8.8 mg/dL). None of the patients discontinued canagliflozin or modified their ART during the study.

Although this study was small, its findings demonstrate an effect of canagliflozin in persons with HIV, uncontrolled diabetes, and overweight/obesity. There appeared to be additional benefits for eGFR, systolic BP, cholesterol, and body size descriptors. However, the effects on systolic BP may be driven by the underlying BP.¹⁴ Canagliflozin was the only SGLT-2 inhibitor evaluated in this study. However, there is no overt biologic reason to expect a heterogeneous response with any of the other SGLT-2 inhibitors or on other types of ART regimens. Safety and tolerability may be of concern for clinicians caring for individuals with HIV and diabetes.

There are boxed warnings, namely for diabetic ketoacidosis, in the prescribing information for all SGLT-2 inhibitors.¹⁵ An increased risk of lower limb amputation has an additional boxed warning that is specific to canagliflozin. Some of the other nonboxed warnings contained in the prescribing information for SGLT-2 inhibitors include necrotizing fasciitis of the perineum (Fournier gangrene), acute kidney injury (AKI), genital mycotic infections, urinary tract infections (UTIs), and bone fracture risk. In findings from the study by Sise et al, the frequencies of the aforementioned adverse events were compared between recipients of an SGLT-2 inhibitor or GLP-1 RA among persons with HIV and diabetes.¹¹ With the exception of AKI (11.3% for SGLT-2 inhibitor vs 9.9% for GLP-1 RA; P = .81), the overall frequencies of these adverse events were low. Further, there were no statistically significant differences in the occurrence of each adverse event between SGLT-2 inhibitors and GLP-1 RA recipients. There is 1 published case report of a 55-yearold man with HIV and diabetes who was admitted to the hospital after developing Fournier gangrene while taking empagliflozin 12.5 mg daily.¹⁶ The individual’s ART regimen consisted of daily darunavir/ cobicistat/emtricitabine/tenofovir alafenamide, and his viral load had been consistently suppressed with a well-preserved CD4 count greater than 700 cells per μL.

The individual initially presented with an ulcer in the right inguinal area, which spread to the groin area and involved his right testicle. He had begun taking empagliflozin 12.5 mg daily 88 days prior to the hospital admission. Wound cultures grew Streptococcus anginosus and Staphylococcus epidermidis, and empiric antimicrobial therapy with piperacillin/tazobactam, vancomycin, and clindamycin was narrowed to ampicillin/sulbactam for 11 days. The individual underwent multiple surgical interventions and was discharged from the hospital with a regimen of amoxicillin/ clavulanate for 21 days. The wound subsequently healed. Six weeks prior to the hospital admission, the patient had presented with a fungal rash in the bilateral axillary and groin region, which was treated with topical antifungal agents. This adverse event is unsurprising, as genital tract infections (non-UTIs) were observed more frequently in persons receiving empagliflozin vs placebo in pooled phase 3 clinical trial data.¹⁷ The majority of these genital tract infections were mild in nature, whereas this case was much more severe. This is an item that clinicians should be cognizant of, as persons with HIV are more likely to develop Fournier gangrene than persons without HIV.¹⁸ Collectively, these data demonstrate a low rate of adverse events among SGLT-2 inhibitor recipients who have HIV and diabetes. There are some other items that should be considered when prescribing SGLT-2 inhibitors to persons with HIV and diabetes. First, drug-drug interactions should be screened for with the addition of any new medication. None of the commercially available SGLT-2 inhibitors have clinically significant drug-drug interactions with ART regimens that are recommended for most persons with HIV.^15,19 Second, all the SGLT-2 inhibitors are eliminated via the kidneys and have dose adjustments based on eGFR.15 With the exception of dapagliflozin, which has dosing recommendations based on kidney function and indication, the remaining SGLT-2 inhibitors should not be used in persons with an eGFR less than 30 mL/min.¹⁵ Third, polypharmacy is an issue that many persons with HIV encounter and the addition of another medication may introduce some adherence challenges.²⁰ Efforts to reduce medication regimen complexity should be made to maintain adherence.²¹ Finally, there is an administrative element to prescribing SGLT-2 inhibitors to persons with HIV and diabetes, as not all third-party payers will have every SGLT-2 inhibitor on their formulary. It will be important for clinicians to understand which medication is covered to ensure affordable medication access.

Overall, the literature surrounding the use of SGLT-2 inhibitors in persons with HIV is limited due to low uptake. However, SGLT-2 inhibitors have demonstrated robust outcomes in findings from clinical trials. Given their preferred positioning in diabetes guidelines, low potential for adverse effects and drug-drug interactions, and convenient dosing, clinicians should consider the use of SGLT-2 inhibitors in persons with HIV and diabetes who may be appropriate candidates. Regular monitoring is essential, and health care providers should carefully evaluate how adding these medications might affect the overall complexity of a patient’s treatment regimen.⁹

References

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14.Tsukamoto S, Kobayashi K, Toyoda M, et al. Pretreatment body mass index affects achievement of target blood pressure with sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Hypertens Res. 2024;47(3):628-638. doi:10.1038/s41440-023-01464-y

15.Prescribers’ Digital Reference. Accessed November 9, 2024. https://www.pdr.net/

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