Liraglutide Promotes Natriuresis but Does Not Increase Circulating Levels of Atrial Natriuretic Peptide in Hypertensive Subjects With Type 2 Diabetes

Lovshin, Julie A.; Barnie, Annette; DeAlmeida, Ariana; Logan, Alexander G.; Zinman, Bernard; Drucker, Daniel J.

doi:10.2337/dc14-1958

Cited by 147 publications

(136 citation statements)

References 23 publications

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“…The effects of these agents on surrogate markers of myocardial stress (NT‐proBNP) or injury (cardiac troponin) have not been well studied. One study has reported evidence that liraglutide leads to natriuresis without altering NP concentrations, and another has reported nonsignificant reductions in NT‐proBNP concentrations in patients randomly allocated to liraglutide therapy 40, 41. Data on the effects of these agents on cardiac troponin are scarce.…”

Section: Discussionmentioning

confidence: 99%

Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

Srivastava

Pradhan

Cook

et al. 2017

JAHA

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BackgroundSubclinical myocardial injury, as measured by high‐sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus.Methods and ResultsWe randomized, in a 2×2 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT‐proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1–Q3) plasma concentration was 35.4 (15.7–86.3) ng/L for NT‐proBNP and 6.7 (4.6–10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT‐proBNP concentration was 20.7% (7.9–35.0) in the insulin arm compared with 0.13% (−10.8 to 12.5) in the no‐insulin arm (P=0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT‐proBNP was 7.8% (−3.7 to 20.7) compared with 13.0% (0.72–26.8) in the no‐metformin arm (P=0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms.ConclusionsInsulin glargine was associated with a significant 20.7% increase in NT‐proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00366301.

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Section: Discussionmentioning

confidence: 99%

Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

Srivastava

Pradhan

Cook

et al. 2017

JAHA

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“…16 In patients with type 2 diabetes mellitus, the GLP-1RA liraglutide also increased atrial natriuretic peptide levels after 12 weeks of treatment, 17 although results in humans are inconsistent. 18,19 Liraglutide was furthermore shown to inhibit the effects of endothelin-1 in cultured endothelial cells. 20 Finally, exenatide reduced the effects …”

Section: Discussionmentioning

confidence: 99%

“…19,22 Thus, GLP-1(RA) seem to have effects on many factors known to influence precapillary arteriolar tone, and as such, could alter capillary perfusion.…”

Section: Smits Et Al Exenatide Increases Capillary Perfusion 1541mentioning

confidence: 99%

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

Smits

Muskiet

Tonneijck

et al. 2015

ATVB

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Objective-The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results-We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor l-N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant l-N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=−5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=−0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions-Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in Materials and MethodsIn this mechanistic cross-over study, healthy overweight participants were subjected to continuous intravenous infusion of placebo (isotonic saline), GLP-1RA exenatide, l-NMMA or a combination of l-NMMA and exenatide. During these conditions, microvascular perfusion was assessed using intravital videomicroscopy and laser Doppler fluxmetry. A complete description of Materials and Methods are available in the Online-only Data Supplement. Results Patient CharacteristicsTen healthy overweight men were included in this analysis. Full characteristics of the subjects can be found in the Table. Capillary VideomicroscopyCompared with placebo, exenatide increased baseline capillary density with 8.0 (5.3-10.5) cap/mm 2 (P=0.016) and peak postarterial occlusion capillary density with 6.5 (4.8-7.8) cap/ mm 2 (P=0.016). This corresponds with an increase of 20.1% and 8.3%, respectively. When exenatide was coinfused with l-NMMA, no significant differences compared with exenatide infused alone were observed (Figure 1).Tests were performed during 2 study days. Day-to-day variation for baseline capillary density and postocclusive peak density were 4.7% and 1.7%, respectively. We conducted sensitivity analyses to assess potential interference of day-to-day variation by including unstimulated measurements (before any intervention) in the statistical model. These sensitivity analyses showed no different results compared with the original analyses. Laser Doppler FluxmetryDuring p...

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“…Acute GLP-1 infusion produces a natriuresis in human subjects with T2D or obesity, but the magnitude of any sustained effect in subjects with T2D is modest (42) and appears attenuated over time (43,44). Understanding the mechanisms linking GLP-1R activation to acute or chronic changes in urine sodium excretion is challenging.…”

Section: Blood Pressurementioning

confidence: 99%

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Drucker

2018

Diabetes

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Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

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Liraglutide Promotes Natriuresis but Does Not Increase Circulating Levels of Atrial Natriuretic Peptide in Hypertensive Subjects With Type 2 Diabetes

Cited by 147 publications

References 23 publications

Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

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