Scientific advances and effective treatment regimens have transformed HIV from the “near-certain death sentence” it represented in the 1980s to a chronic disease. Today, people with HIV (PWH) have a near-normal life expectancy. As this population ages, however, they are increasingly susceptible to age-related conditions, including type 2 diabetes (T2D), a key contributor to long-term morbidity and mortality in PWH.

“Some of the causes for the development of diabetes in PWH are similar to those in the general population, such as changes in body composition, with adiposity playing a central role,” Todd Brown, MD, PhD, professor of medicine and epidemiology in the Division of Endocrinology, Diabetes, and Metabolism at Johns Hopkins Medicine in Baltimore, told Medscape Medical News. “But there are also areas of susceptibility that are specific to PWH.”

A Complex Interplay

The intersection of HIV and diabetes reflects a complex interplay between traditional metabolic risk factors and HIV-specific factors, including inflammation and antiretroviral therapy (ART).

“Even when HIV is well controlled with medication, it remains a chronic inflammatory state, making PWH particularly at risk for conditions such as diabetes,” said Brown, who serves as the primary endocrine consultant to the Johns Hopkins HIV Clinic and directs a laboratory focused on metabolic and skeletal complications of HIV.

Systemic inflammation results from several factors, including viral replication, immune activation, T-cell depletion, and T-cell loss within the gastrointestinal tract.

“The sources of inflammation are related to HIV replication in reservoirs of the body that cannot be accessed by HIV medications,” Brown explained. “There’s constant low-level replication leading to an immune response. Additionally, early in the HIV infection, there’s a breakdown in the gut barrier, with microbial products translocated across the gut membrane, further driving inflammation.”

Coinfection with other viruses, including hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, may also contribute to systemic inflammation, Brown noted.

The Role of ARTs

“PWH are at higher risk for developing prediabetes and diabetes, which is further increased by use of ARTs that can worsen insulin resistance and contribute to elevations in blood glucose and other metabolic changes,” Joshua Neumiller, PharmD, CDCES, senior vice president of medical affairs at the American Diabetes Association, told Medscape Medical News.

Brown noted that some of the earliest ART regimens, introduced in the mid-to-late 1990s, had substantial metabolic consequences.

“The medications that were critical to longevity and survival in PWH affected glucose metabolism and caused insulin resistance,” he said.

Protease inhibitors (PIs), for example, have been independently associated with a fivefold higher incidence of hyperglycemia. In addition, PIs have also been linked to hypertriglyceridemia and lipodystrophy. Potential mechanisms behind this include beta-cell impairment, reduced function of the glucose transporter GLUT4, and changes in adiponectin, a hormone associated with improved insulin sensitivity.

“We don’t typically use these drugs anymore, which is good,” Brown said.

Indeed, PI use has declined from over 40% to about 12% over the past two decades. Although some newer-generation PIs have not been associated with increased risk for T2D, older agents contributed significantly to metabolic complications. Similarly, PIs were often used in combination with nucleoside reverse transcriptase inhibitors (NRTIs) such as stavudine, zidovudine, and didanosine, which have been associated with higher rates of incident T2D and are no longer guideline recommended due to toxicity concerns. 

Much of the decline in PI use is attributable to the emergence of integrase strand transfer inhibitors (INSTIs), which are highly effective and generally better tolerated. However, Brown cautioned that even INSTIs have metabolic consequences.

“Even the newest class of anchor drugs, the INSTIs, are associated with weight gain and incident diabetes, independent of the weight gain,” he said.

A recent study of more than 13,000 PWH found that switching to INSTIs was associated with a higher risk for incident diabetes, especially among patients previously treated with PIs.

Brown also noted that some older ARTs caused lipodystrophy and that the metabolic consequences may persist long after the medications themselves have been discontinued.

Diagnosing and Monitoring Diabetes in PWH

Diabetes is typically diagnosed and monitored using plasma glucose measurements or A1c. In PWH, however, A1c has been found to underestimate glycemia.

According to Brown, this discrepancy may be attributable to lower CD4 counts; hematologic parameters; and exposure to certain ART agents, including PIs, non-NRTIs, and zidovudine.

As a result, plasma glucose measurements may be more reliable than A1c for diagnosing and monitoring T2D in these patients.

Pharmacotherapy Considerations

“The goals of treating diabetes in PWH are the same as the goals of treating diabetes without HIV,” Brown said.

Neumiller agreed but emphasized that PWH experience more cardiometabolic complications than the general population and, when diabetes is also present, face heightened risks for cardiovascular and kidney disease. As a result, risk reduction becomes a particularly important treatment objective.

Metformin remains a cornerstone of T2D treatment. However, clinicians should be aware that dolutegravir, an INSTI, can increase plasma levels of metformin, potentially requiring dose adjustments when dolutegravir treatment is initiated.

Brown highlighted SGLT2 inhibitors and GLP-1 receptor agonists (RAs) as especially important therapeutic options, given their impact on systemic inflammation.

SGLT2 inhibitors have “demonstrated reductions in adverse cardiovascular outcomes, including cardiovascular death and hospitalization, for heart failure in general population studies and have also been shown to reduce risk or renal disease progression,” Brown said.

Similarly, the American Diabetes Association recommends GLP-1 RAs not only for glycemic managements but also for lowering cardiovascular risk and slowing progression of kidney disease in select patients.

Evidence supporting GLP-1 RAs in PWH is still emerging. Semaglutide and related agents appear to produce meaningful weight loss and glycemic improvement in PWH, including those with HIV-associated lipohypertrophy and metabolic disease, without major safety concerns or significant interactions with ART.

A retrospective cohort study of PWH receiving GLP-1 RAs found mean reductions of 5.4 kg in body weight and 0.6% in A1c. Greater weight loss was associated with higher baseline BMI, longer treatment duration, and use of tirzepatide. Other studies have found improvements in glucose control, lipohypertrophy, and inflammatory markers, independent of weight changes.

Brown also emphasized the importance of statin therapy, which he described as being “critical in decreasing cardiovascular risk.”

He noted, however, that general population cardiovascular risk calculators do not account for HIV as a risk factor. Specific recommendations regarding the use of statins in PWH are set forth in guidelines issued in 2025 by the U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV, in collaboration with several other societies.

Because both HIV and diabetes increase the risk for microvascular complications, Brown said that “appropriate surveillance is warranted.”

A Comprehensive Care Model

According to “American Association of Clinical Endocrinology Consensus Statement: Algorithm for Management of Adults With Type 2 Diabetes – 2026 Update,” lifestyle modification remains the foundation of T2D management. Recommendations include increased physical activity; healthy dietary changes; smoking/tobacco cessation; assessment of sleep hygiene; and management of mood disorders, sleep disorders, diabetes-related stress, and internalized weight bias.

These recommendations may be especially relevant for PWH. Research suggests that PWH may have lower-quality diets and may be less likely to achieve recommended levels of physical activity than the general population without HIV, highlighting the importance of nutrition counseling and addressing patients’ barriers to exercise.

Consistent with this holistic approach, a 2024 guideline from the HIV Medicine Association of the Infectious Diseases Society of America recommends a multidisciplinary care model that integrates physical and behavioral health professionals.

The guideline emphasizes addressing the broad medical and psychosocial needs of PWH to individualize treatment plans that encompass HIV and comorbid conditions, including T2D, while also maximizing adherence and engagement with care.

Neumiller reported having no relevant financial relationships. Brown has served as a consultant to ViiV Healthcare, Gilead Sciences, Janssen, and EMD Serono.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Life in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).