Discussion
stroke, vascular disease, T2DM
STROKE, EVENTS, VASCULAR DISEASE, DYSFUNCTION
In this study, 8-weeks of glargine/exenatide combination therapy decreased BP in patients with T2DM of modest duration, without inducing significant changes in heart rate or RHI. Notably, there were no differences in baseline-adjusted RHI between glargine alone, glargine + lispro and glargine + exenatide after the 8-week intervention or after subsequent 12-weeks washout. These data thus suggest that adding either exenatide or lispro to basal insulin therapy does not affect endothelial function in early T2DM.For determining the cardiovascular risk implications of a glucose-lowering regimen, the optimal evaluation would be provided by a dedicated cardiovascular outcome trial. Though such trials have shown neutral effects of both glargine [To date, there has been limited investigation of this question. In a recent study of 34 glargine-treated patients with T2DM with mean A1c ~ 8.0% at baseline, the addition of either once daily lixisenatide or insulin glulisine (administered only before breakfast) for 8-weeks was found to yield similar effects on systemic hemodynamic measures in the fasted state (including BP, HR, stroke volume, cardiac index, systemic vascular resistance index, and normalized augmentation index) [Our data suggest that, in the setting of basal insulin therapy, the postprandial metabolic coverage provided by exenatide and lispro does not improve endothelial function. However, this interpretation should be coupled with certain caveats. First, with well-controlled T2DM of modest duration and relatively high rates of adoption of cardioprotective medications (renin-angiotensin system blockers, statins), it is possible that this study population may not have had sufficiently advanced vascular disease for demonstration of a therapeutic effect on endothelial function or had insufficient dysfunction for such a demonstration at this sample size. Indeed, at baseline, the mean RHI values in each group (ranging from 1.83 to 1.88) exceeded the threshold that typically reflects abnormal function (< 1.67). Second, since RHI was assessed in only 73 of the 102 participants, it is possible that there was insufficient statistical power to detect differences in this measure. Third, the absence of differences in RHI under fasting conditions (as measured herein) may not exclude differences in endothelial function in the postprandial state. Of note, previous studies have shown that a single dose of exenatide can improve RHI when the latter is measured after a meal challenge [Another consideration is that, in current practice, long-acting GLP1-RAs have surpassed short-acting formulations in popularity (both with and without basal insulin). Interestingly, a recent study in 112 individuals with T2DM showed that the long-acting GLP1-RA dulaglutide (which has been previously shown to reduce the risk of major adverse cardiovascular events in T2DM [In conclusion, 8-weeks of glargine/exenatide combination therapy decreased BP, without significant changes in heart rate or RHI. Importantly, RHI at fasting did not differ between glargine alone, glargine + lispro, and glargine + exenatide either after 8-weeks of treatment or after subsequent washout. These data thus suggest that the prandial metabolic coverage provided by adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM.