Using NRTIs to Prevent Type 2 Diabetes

Old drug, new purpose? Analysis found HIV and Hepatitis B patients treated with NRTIs had significantly lower incidence of type 2 diabetes. 

NRTIs (Nucleoside reverse transcriptase inhibitors) are a class of medication commonly used to treat HIV and Hepatitis B. They also block inflammasome activation from Alu-derived RNA and other substances. NLRP3 inflammasome is a protein complex that has been identified as playing a vital role in the pathogenesis of T2D. Patients with T2D have also been shown to have reduced DICER1 protein, a protein known to catabolize Alu RNA. In mouse studies, depletion of DICER1 in adipose or pancreatic cells of diabetic mice triggered insulin resistance and subsequent diabetes development. A new study has shown that NRTIs could potentially reduce and prevent insulin resistance in patients with Type 2 diabetes. 

This study aimed to determine if NRTI use could influence the incidence of T2D by analyzing the health insurance claims of 5 databases, with the Veterans Health Administration being the primary cohort. It also investigated the effect of NRTIs on inflammasome activation and insulin resistance in human cells and provided experimental evidence from mouse studies. VHA (79,744 patients), Truven Database (23,634 patients), PearlDiver database (16,045 patients), Medicare 20% sample (3,097 patients) and Clinformatics dataset (6,341 patients) were analyzed separately and meta-analyzed. A Bayesian meta-analysis was completed to account for between-study variance uncertainty. The study population included patients with HIV or Hepatitis B with no pre-existing diabetes diagnoses. The primary outcome of the study was the incidence of T2D. 

Cox proportional regression models were used to estimate HR with a 95% CI relating to the incidence of T2D in patients taking NRTIs, NNRTIs, INSTIs, or PIs. A propensity score-matched analysis was performed to analyze the incidence of diabetes in the three largest databases (VHA, Truven, and PearlDiver), matching patients 1:1. 

Analyses of the VHA database found that of the 79,744 patients identified as having HIV or Hepatitis B without a diabetes diagnosis, 12,311 patients were later diagnosed with T2D. Adjusted HR demonstrated that the incidence of T2D was 34% lower in patients taking NRTIs (0.665; 95% CI 0.524-0.718). These results were confirmed by the analysis of the other four health insurance databases. Of these databases, the Medicare 20% sample did not show statistical significance (HR 0.828; 95% CI 0.646-1.062), though this could be attributed to the small sample size (3,097 patients) compared to the other cohorts. When meta-analyzed, among the 128,861 patients, NRTI users showed a 33% reduction in the incidence of T2D (p<0.0001). Incidence reduction was also seen in the propensity score matching analysis (Veterans: HR 0.711; p<0.0001; Truven: HR 0.645; p<0.0001; PearlDiver: HR 0.747; p=0.005). 

In the Bayesian meta-analysis, NRTI users also demonstrated a 32% reduced incidence of T2D (p=0.0008), confirming similar results to the cohort meta-analysis. Three sensitivity analyses were performed in the primary VHA cohort. The first averaged hazard ratios from 1, 2, 5, and 10 years of follow-up to account for a possible HR change over time. The second, a competing risk regression analysis, was performed to account for the risk of death precluding diabetes diagnosis. The third analyzed HIV and Hepatitis B patients separately in their risk of T2D incidence. In all three sensitivity analyzes, patients had a significantly reduced incidence of T2D. 

Cells isolated from the adipose and skeletal muscle of patients with and without T2D showed differing Alu RNA and DICER1 protein levels. Cells from patients with T2D had higher levels of Alu RNA and reduced DICER1 levels. These cells were also noted to have impaired phosphorylation of protein kinase AKT, reducing critical signaling events in insulin-dependent glucose uptake and reduced insulin sensitivity. Lamivudine treatment increased insulin sensitivity and reverse resistance caused by impaired AKT phosphorylation in diabetes patient cells and prevented resistance and restored AKT phosphorylation in non-diabetic cells. In mice studies, once-daily lamivudine led to improved insulin and glucose tolerance tests, and AKT phosphorylation in high-fat diet-fed mice was used to model type 2 diabetes. 

This study was able to identify an association between NRTI use and lower incidence of T2D in observation studies and provide biological evidence supporting the effectiveness of lamivudine in reducing insulin resistance in human cells and animal studies. Kamuvidines, a class of modified NRTIs, are of great interest in treating prediabetes and T2D patients due to their inhibition of inflammasome activation and reduced toxicity profile compared to 1st and 2nd generation NRTIs. Randomized clinical trials would be needed to confirm this association and the efficacy of NRTIs in diabetes.  

Practice Pearls: 

• Among 128,861 patients, T2D incidence was significantly reduced by 33% in NRTI users. 
• In human cell and animal studies, lamivudine reversed AKT phosphorylation impairment and reduced insulin resistance. 
• This study provides a foundation for future studies testing the efficacy of modified NRTIs in treating prediabetes or diabetes. 

Ambati, J. et al. “Repurposing Anti-Inflammasome NRTIs For Improving Insulin Sensitivity And Reducing Type 2 Diabetes Development”. Nature Communications,  

Ting, Jenny P-Y et al. “Inflammasomes: Mechanism Of Action, Role In Disease, And Therapeutics.” Nature Medicine,  

Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences