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A model-based meta-analysis was performed with reported data from obese subjects and patients with type 2 diabetes (T2DM) to characterize the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, gastric inhibitory polypeptides (GIPs), glucagon-like peptide-1 (GLP1), and dual GIP/GLP1 agonists, or a combination of these antidiabetic drugs (ADs) on heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP). A systematic literature search and review after the Cochrane method identified sources for investigational and approved ADs resulted in a comprehensive database with data from 178 clinical studies in obese subjects and patients with T2DM. Results indicated that there were AD class-dependent effects on HR and SBP, whereas no clear AD-related effects on DBP were found. All AD classes, except for DPP4 inhibitors, increased HR. The largest increase of 12 bpm was seen with GLP1 receptor agonists. All AD classes appeared to decrease SBP. DPP4 inhibitors were associated with a marginal decrease of ~ 1 mmHg, whereas GLP1 and GIP/GLP1 dual agonists exhibited the largest decrease of ~ 3 mmHg in SBP. AD-related effects were similar in obese subjects and patients with T2DM. In conclusion, there are clinically relevant AD-related effects on both HR and SBP, but not on DBP. DPP4 inhibitors are associated with the smallest (if at all) effects on HR and SBP, whereas GLP1 inhibitors exhibited the largest effects on these two cardiovascular end points. Additional studies are warranted to further investigate how AD-related SBP decreases combined with HR increases affect long-term cardiovascular mortality., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data.