Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future

<p>Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.</p

Long-Term Use of Angiotensin Receptor Blockers and the Risk of Cancer

<div><p>The association between angiotensin receptor blockers (ARBs) and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK) General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan) entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years). When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96–1.03) or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06–1.20 and RR: 1.19; 95% CI: 1.12–1.27, respectively). This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.</p> </div

Crude and adjusted rate ratios of cancer associated with antihypertensive agents relative to diuretic and/or beta-blocker use.

<p>Abbreviations: RR, rate ratio; CI, confidence interval; ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; DDD, defined daily doses.</p>*<p>Cases and controls were matched on year of birth, year of cohort entry, sex, prevalent user status, and duration of follow-up.</p>†<p>Adjusted for excessive alcohol use, body mass index, smoking, diabetes, previous cancer, and ever of aspirin, statins, and NSAIDs.</p>‡<p>Defined as receiving prescriptions for both agents on the same day on at least one occasion.</p>§<p>Dose-response analyses conducted among the 5583 cases and 56,817 controls exposed to ARBs. Categories based on tertiles.</p

Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers in combination with angiotensin-converting enzyme inhibitors relative to the use of diuretics or beta-blockers.

<p>Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers in combination with angiotensin-converting enzyme inhibitors relative to the use of diuretics or beta-blockers.</p

Crude and adjusted rate ratios of lung, colorectal, prostate and breast cancer associated with antihypertensive agents relative to diuretic and/or beta-blocker use.

<p>Abbreviations: RR, rate ratio; CI, confidence interval; ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker.</p>*<p>Cases and controls were matched on year of birth, year of cohort entry, sex, prevalent user status, and duration of follow-up.</p>†<p>All models were adjusted for excessive alcohol use, body mass index, smoking, diabetes, previous cancer, and ever of aspirin, statins, and NSAIDs. In addition, cholecystectomy, inflammatory bowel disease and history of polyps for colorectal cancer; benign prostatic hyperplasia, 5-alpha reductase inhibitors, and number of PSA tests for prostate cancer; oophorectomy, use of hormone replacement therapy, and prior use of oral contraceptives for breast cancer.</p>‡<p>Defined prescriptions of both agents overlapping each other for at least one day.</p

Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers relative to the use of diuretics or beta-blockers.

<p>Adjusted rate ratios of specific cancers associated with use of angiotensin receptor blockers relative to the use of diuretics or beta-blockers.</p

Sodium-Glucose Co-Transporter 2 inhibitors and the Short-term Risk of Bladder Cancer: An International Multi-Site Cohort Study

   Objective: To determine whether sodium-glucose co-transporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide-receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP4) inhibitors are associated with an increased risk of early bladder cancer events. Research Design & Methods: We conducted a multi-site, population-based, new-user active comparator cohort study using the United Kingdom Clinical Practice Research Datalink, Medicare fee-for-service, Optum© Clinformatics® Data Mart, and MarketScan Health from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating (1) SGLT2 inhibitors or GLP-1RAs, and (2) SGLT2 inhibitors or DPP4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models. Results: SGLT2 inhibitor (n=453,560) and GLP-1RA (n=375,997) users had a median follow-up ranging from 1.5-2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer, compared with GLP-1RAs (HR=0.90; 95% CI: 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n=853,186), SGLT2 inhibitors (n=347,059) were not associated with an increased risk of bladder cancer (HR: 0.99, 95% CI: 0.91-1.09) over a median follow-up ranging from 1.6-2.6 years. Results were consistent across sensitivity analyses. Conclusions: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer when compared with GLP-1RAs or DPP4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.</p