GLP-1 agonist lowers CV biomarkers in high-risk T2DM patients

Liraglutide effects on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub-analysis of a randomised, placebo-controlled, double-blind, cross-over trial

Literature - von Scholten BJ, Persson F, Rosenlund S, et al. - Diabetes Obes Metab. 2017; published online ahead of print

Background

Type 2 diabetic (T2DM) patients are at high CVD risk, particularly those with albuminuria [1]. Liraglutide has glucose-lowering effects but also supports weight loss, lowers blood pressure (BP), albuminuria and lipid-levels. Moreover it is suggested that liraglutide may have anti-inflammatory and vasodilatory effects [2-4]. Endothelial dysfunction is an early marker of atherosclerosis, and inflammatory processes play an important role in atherosclerotic cardiovascular disease [5].

Therefore, it was hypothesised in current study that liraglutide treatment is associated with the reduction of inflammatory biomarkers and CV risk biomarkers in high-risk patients. To validate this, a randomised, double-blind, cross-over study was performed to evaluate the effect of liraglutide on five CVD-associated biomarkers in 27 T2DM patients with persistent albuminuria. For this, 12 weeks of treatment was followed by a 4-week washout period.

The biomarkers reflect different pathophysiology and included tumour necrosis factor-alpha (TNF-alpha), soluble urokinase plasminogen-activator-receptor (suPAR), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), and copeptin.

Main results

  • LDL-C was 0.21 mmol/L (95% CI: 0.03-0.40) lower after liraglutide treatment compared to placebo (P=0.028), total cholesterol was 0.30 mmol/L lower (95% CI: 0.02-0.58, P=0.034) and there was no significant effect on triglycerides or HDL-C.
  • TNF-alpha was 12% (95% CI: 3-20) lower after liraglutide treatment compared to placebo (P=0.012). In univariate and multivariate models, no associations between change in TNF-alpha and change in HbA1c, weight, 24-hour systolic BP (SBP), urinary albumin excretion rate (UAER), 24-hour heart rate (HR), LDL-C or total cholesterol were observed (P≥0.064).
  • No differences were observed when comparing plasma or urinary suPAR at the end of liraglutide treatment to end of placebo (plasma P=0.61 and urinary P=0.49).
  • MR-proADM was 4% (95% CI: 0-8) lower after liraglutide treatment compared to placebo (P=0.038).
  • In univariate models, change in MR-proADM was associated with change in weight (P=0.022, R2=0.18) but not with HbA1c, 24-hour SBP, UAER, 24-hour HR, LDL-C or total cholesterol.
  • MR-proANP was 13% (95% CI: 4-21) lower after liraglutide treatment compared to placebo (P=0.006).
  • In univariate models, reduction in MR-proANP was associated with an increased 24-hour HR (P<0.001; R2=0.53), but not with change in HbA1c, 24-hour SBP, UAER or weight (P≥0.38).
  • No significant differences were observed when comparing copeptin or norepinephrine at the end of liraglutide treatment to end of placebo (P=0.75 and P=0.58, respectively).

Conclusion

In T2DM patients with albuminuria, liraglutide treatment was associated with reductions in circulating levels of CV risk biomarkers TNF-alpha, MR-proADM and MR-proANP. These findings support the hypothesis that liraglutide treatment may be associated with the reduction of inflammatory and CV risk biomarkers in high-risk patients.

References

1. Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. J Am Soc Nephrol. 2006;17(8):2106-11.

2. Zobel EH, von Scholten BJ, Lindhardt M, et al. Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment. J Diabetes Complications. 2017;31(1):162-8.

3. von Scholten BJ, Persson F, Rosenlund S, et al. The effect of liraglutide on renal function: A randomized clinical trial. Diabetes Obes Metab. 2016. 'In press'.

4. van Genugten RE, Moller-Goede DL, van Raalte DH, et al. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabetes Obes Metab. 2013;15(7):593-606.

5. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74.

Find this article online at Diabetes Obes Metab

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