Rationale and design: the VALsartan In Diastolic Dysfunction (VALIDD) Trial: evolving the management of diastolic dysfunction in hypertension.

BACKGROUND: Although 50% of hypertensive patients in the community are estimated to have diastolic dysfunction, there is no specific guideline for diastolic dysfunction therapy at present despite the condition's clear association with increased cardiovascular risk. Although the efficacy of angiotensin II receptor blockers (ARBs) in hypertension and left ventricular hypertrophy regression has been established, the effect of angiotensin II receptor blockade on intrinsic parameters of diastolic function has not been evaluated in large-scale studies. METHODS: The VALIDD Trial is an investigator-initiated randomized, controlled, double-blind clinical trial on approximately 350 patients designed to explore whether antihypertensive therapy with the ARB valsartan, in addition to standard therapy, would improve intrinsic diastolic properties of the myocardium in patients with hypertension and evidence of diastolic dysfunction. The result of such therapy will be compared with placebo after 38 weeks of treatment. The primary efficacy variable is change in early diastolic lateral mitral annular relaxation velocity measured by tissue Doppler imaging on week 38. CONCLUSIONS: We expect the VALIDD Trial to provide novel insights into the specific effects of ARBs on diastolic dysfunction, as assessed by tissue Doppler imaging, in hypertensive patients. The trial may provide clinically useful data on whether such therapy can directly improve diastolic function in patients with hypertension.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on C-peptide kinetics.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of ß-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-%B], meal tolerance test-based indices). However, use of these ß-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 µg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal ) and renal clearance (CLrenal ), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [93.0%; 99.3%]). Other kinetic parameters, including CLrenal , were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing ß-cell function in canagliflozin-treated participants.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial.

OBJECTIVE: Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin. MATERIALS/METHODS: Patients (N=37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B-D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period. RESULTS: A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B-D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC0-2h, -7.5% for B vs A; -18.5% for C vs A; -12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC0-2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated. CONCLUSIONS: These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.