Can HIV drugs prevent diabetes?

Nucleoside reverse transcriptase inhibitors (NRTIs), a class of drugs approved for treating HIV-1 and hepatitis B, may be repurposed for the prevention of type 2 diabetes (T2D), a study suggests.

“The NLRP3 inflammasome … is implicated as a key driver of T2D … NRTIs block inflammasome activation,” said the researchers. [Sci Transl Med 2011;doi:10.1126/scitranslmed.3001902; Nat Med 2011;17:179-188] However, it remains unclear whether inhibiting inflammasome activation is beneficial in treating diabetes.

“We identified an association between exposure to NRTIs and lower rates of development of T2D among persons with HIV-1 or hepatitis B infection … [Our evaluation] collectively suggests a potential beneficial effect of NRTIs in forestalling diabetes onset,” said the researchers.

The team evaluated data from five* US databases (n=128,861). Of these, 16,783 individuals developed incident T2D. Among the NRTIs evaluated were abacavir, adefovir, didanosine, emtricitabine, entecavir, lamivudine, stavudine, tenofovir, and zidovudine. [Nat Commun 2020;doi:10.1038/s41467-020-18528-z]

Over the time periods studied (2000–2017), the risk of developing incident diabetes was 33 percent lower in individuals with NRTI exposure after adjusting for potential confounders (adjusted hazard ratio [adjHR], 0.67, 95 percent confidence interval [CI], 0.64–0.71; p<0.0001).

“[T]he pooled summary estimate of the adjusted HR across the five databases and CI provide information on how well we have determined the mean effect,” said the researchers.

“The fact that the protective effect [of NRTIs] against the development of diabetes was replicated in multiple databases in studies from multiple institutions enhances confidence in the results,” noted study lead investigator Dr Jayakrishna Ambati from the University of Virginia School of Medicine, Charlottesville, Virginia, US, in a press release.

Bayesian meta-analysis revealed a similar trend, showing a 32-percent median reduced hazard of developing T2D among individuals exposed to NRTIs (adjHR, 0.68; p_HR>1=0.0008). “[This] approach … has advantages in terms of accounting for parameter uncertainty and the generation of credible intervals that account for the prior distribution,” explained the researchers. “[This analysis] parallels the results of the frequentist meta-analysis results, thereby increasing confidence in the main finding that NRTI exposure is associated with a [reduced] risk in incident T2D.”

Finding alternatives

Almost half a billion people worldwide have T2D, and this number is expected to rise dramatically in the years to come. [www.diabetesatlas.org/en, accessed December 1, 2020] Moreover, T2D is associated with several comorbidities, thus underlining the need to explore better ways to manage and prevent this disease.

Drug repurposing is an urgent priority for revitalizing, accelerating, and optimizing drug development. [Nat Rev Drug Disco 2011;10:397] The findings underpin the possibility of either repurposing NRTIs or exploring modified, less toxic NRTIs for treating prediabetes or diabetes, noted Ambati and colleagues.

“However, not all NRTIs are suitable for repurposing,” they stressed. First-generation NRTIs (ie, didanosine, stavudine), for instance, are more toxic than more recent NRTIs (ie, emtricitabine, lamivudine, tenofovir), and are tied to increased T2D risk and insulin resistance induction in individuals with HIV, particularly in combination with protease inhibitors. [AIDS 2003;17:1993-1995; Diabetes Care 2008;31:1224-1229; AIDS Res Ther 2013;10:32]

Nonetheless, the rate of didanosine and stavudine usage in the databases evaluated only ranged between 3 and 9 percent, thus limiting the likelihood of their influence in the findings, noted the researchers.

Considering the rare adverse events (ie, lactic acidosis, hepatomegaly, steatosis) tied to lamivudine, [J Acquir Immune Defic Syndr 2018;78:125-135] the researchers recommended prospective trials exploring the potential of Kamuvudines – modified, less toxic NRTIs that retain the ability to inhibit inflammasome activation – in managing prediabetes or diabetes. [Science 2014;346:1000-1003]

“[However,] we caution against advocating use of NRTIs in prediabetes or diabetes in the absence of prospective randomized clinical trials,” they stressed. Cost-benefit analyses of NRTI use following prospective studies should also look into their potential to induce viral resistance, and how they compare to certain diet and/or exercise regimens, which can benefit individuals with prediabetes. [Rev Diabet Stud 2016;13:226-235; Diabetes Metab Syndr Obes 2014;7:521-529]