Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes

Abstract

Aims: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.

Methods: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.

Results: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.

Conclusions: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.

Clinicaltrials: gov (NCT03893526).

Keywords: GLP-1; clinical trial; drug mechanism; glucagon; glycaemic control.

FIGURE 1

(A,B) Glucose, (C,D) insulin and (E,F) C‐peptide responses to a standardized mixed meal test, during control (black line and circle), sacubitril/valsartan treatment (red line and squire), sitagliptin treatment (blue line and upward triangle), sacubitril/valsartan plus sitagliptin treatment (orange line and downward triangle). (A,C,E) Data are shown as mean ± SEM. (B,D,F) Calculated iAUC_{0‐240 min}, control (black and white box), sacubitril/valsartan treatment (red box), sitagliptin treatment (blue box), sacubitril/valsartan plus sitagliptin treatment (orange box). Data are means ± Tukey whiskers with outliers shown as symbols. *p < .05, ***p < .001 by iAUC_0‐240 using a one‐way ANOVA correcting for multiple testing by Sidak algorithm. N = 12 (male subjects). iAUC, incremental area under the curve

FIGURE 2

Plasma concentrations of (A,B) total glucagon‐like peptide‐1 (GLP‐1), (C,D) intact GLP‐1 and (E,F) glucagon during a standardized mixed meal test. Control (black line and circle), sacubitril/valsartan treatment (red line and squire), sitagliptin treatment (blue line and upward triangle), sacubitril/valsartan plus sitagliptin treatment (orange line and downward triangle). (A,C,E) Data are shown as mean ± SEM. (B,D,F) Calculated iAUC_{0‐240 min} control (black and white box), sacubitril/valsartan treatment (red box), sitagliptin treatment (blue box), sacubitril/valsartan plus sitagliptin treatment (orange box). Data are means ± Tukey whiskers with outliers shown as symbols. *p < .05 by iAUC_0‐240 using one‐way ANOVA correcting for multiple testing by Sidak algorithm. N = 12 (male subjects). iAUC, incremental area under the curve

FIGURE 3

Plasma concentrations of (A,B) total glucose‐dependent insulinotropic polypeptide (GIP) and (C,D) intact GIP during a standardized mixed meal test. Control (black line and circle), sacubitril/valsartan treatment (red line and square), sitagliptin treatment (blue line and upward triangle), sacubitril/valsartan plus sitagliptin treatment (orange line and downward triangle). (A,C) Data are shown as mean ± SEM. (B,D) Calculated iAUC_{0‐240 min}, control (black and white box), sacubitril/valsartan treatment (red box), sitagliptin treatment (blue box), sacubitril/valsartan plus sitagliptin treatment (orange box). Data are means ± Tukey whiskers with outliers shown as symbols. **p < .01 by iAUC_0‐240 using one‐way ANOVA correcting for multiple testing by Sidak algorithm. N = 12 (male subjects). iAUC, incremental area under the curve