More evidence of Metformin benefits in early prediabetes

More good news for metformin. MET-REMODEL trial tested patients with known cardiovascular disease and insulin resistance, but without gross diabetes. Patients received metformin or placebo for 12 months.

Compared to the placebo group, subjects receiving metformin experienced the following improvements in 12 months: Less left ventricular mass index,  less LVM, lower systolic BP, decreased body weight and less oxidative stress.

Early start of metformin could be useful in adults with insulin resistance.  Long term side effects of metformin, however, need to be discussed thoroughly with patients.

GT

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Metformin

Cardiovascular

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E. Heart Journal

Met-Remodel

April 2019

Aim

We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes.


Methods and results

We randomly assigned 68 patients (mean age 65 ± 8 years):

  • Without diabetes

  • who have CAD with IR or pre-diabetes

  • To receive either metformin XL (2000 mg daily dose) or placebo for 12 months.

Primary endpoint was change in left ventricular mass indexed to height^1.7 (LVMI), assessed by MRI.

  • In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (P = 0.033).

  • Metformin also significantly reduced other secondary study endpoints such as:

    • LVM (P = 0.032)

    • Body weight (P = 0.001)

    • Subcutaneous adipose tissue (P = 0.024)

    • Office systolic blood pressure (P = 0.022) and

    • Concentration of thio-barbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04).

      • A1C and fasting IR index did not differ between study groups at the end of the study.


Conclusion

Metformin treatment significantly reduced:

  • LVMI (LV mass index)

  • LVM (LV mass)

  • office systolic BP

  • Body weight

  • Oxidative stress.

Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.


More from the publication

  • LVH is an independent predictor of mortality and is highly prevalent in patients with ischemic heart disease, even in the absence of hypertension.

  • LVH is a common finding in approximately one-third of patients with CAD.

  • Importantly, LVH is one of the most powerful prognostic factor in CAD, after age and coronary disease severity with a prognostic importance equivalent to that of left ventricular (LV) ejection fraction.

  • Regression of LVH can reduce the incidence of major CV events irrespective of BP changes.

  • Controlling BP is only partially effective as LVH persists in 20% of hypertensive patients who attain target BP. Therefore, additional strategies are required.

  • Other than BP, IR and central obesity are implicated in the development of LVH.

    • Dysglycaemia is very common in patients with CAD and is linked to IR.

    • Large studies have reported a significant positive relationship between IR and LVH.

    • Specifically, central obesity has been associated with IR, hypertension, and LVH.

    • Importantly, non-diabetic dysglycaemia (pre-diabetes) perse is associated with substantial CV risk that is now recognized by clinical practice guidelines.

Metformin, an anti-diabetic drug, has been shown to improve insulin sensitivity and reduce IR.

  • In a meta-analysis of randomized controlled trials (RCTs), Salpeter etal. reported a reduction of weight and calculated IR in metformin users.

  • Metformin has multiple modes of actions involving both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms that may be implicated in cardiac hypertrophy.

  • In this respect, metformin has been shown to reduce cardiac hypertrophy in different animal models of hypertrophy.

  • Observational studies have also reported CV benefits in metformin users especially in patients with type 2 diabetes mellitus (T2DM) and heart failure.

  • For these reasons, there is now much interest in the repurposing of metformin for CV diseases.


The main finding of our study is that a modified-release 2000 mg daily dose of metformin treatment significantly reduced LVMI in patients without T2DM who have CAD, LVH and IR and/or pre-diabetes who were optimally treated with evidence-based therapy.

The regression of LVH observed in this study was independent of changes in IR. We also found that metformin reduced measures of obesity, reduced SBP and oxidative stress compared with placebo. All these findings were consistent in both mITT and per-protocol analysis, suggesting a robust beneficial cardio-protective effect of metformin in this group of patients.

To the best of our knowledge, this is the first RCT investigating the effect of metformin on LVH in non-diabetic CAD patients identified to have IR and/or pre-diabetes. Our findings are consistent with experimental animal studies showing that metformin can regress LVH. With regards to clinical studies, a small (n = 40), open-labelled, echocardiographic study reported that 6 months treatment with metformin reduced LVM and relative wall thickness in non-diabetic subjects with metabolic syndrome. Furthermore, in an echocardiographic sub-study of the GIPS III trial, metformin treatment for 4 months was associated with a marginal, but non-significant reduction of LVMI in non-diabetic subjects who have had a myocardial infarction. Conversely, a recent network meta-analysis based on only three metformin trials reported minimal beneficial effects of metformin on LVM in subjects with T2DM. Taking all this together, the data would suggest that metformin might be able to regress LVH.

Left ventricular hypertrophy is regarded as one of the strongest independent predictors of CV outcome and the LIFE study had conclusively shown that LVH regression per se reduces future CV events irrespective of BP changes. However, it remains to be proven on whether metformin-induced LVH regression can deliver the same magnitude of reduction in CV events as the LIFE study since the magnitude of LVH regression was greater in the LIFE study when patients received treatment for at least 4 years. We believe that a CV outcome trial of metformin among subjects without T2DM is needed to change clinical practice. In this regard, the CV benefits of metformin are currently being tested in the VA IMPACT trial, an outcome trial involving close to 8000 patients similarly identified as in MET-REMODEL to have pre-diabetes and established atherosclerotic CV disease including CAD.

There are plausible mechanisms for why metformin produced LVH regression in our study.

  1. Firstly, metformin could mediate LVH regression through its effect on BLOOD PRESSURE. A recent pooled meta-analysis of RCTs of metformin on BP in patients without T2DM reported that metformin can significantly lower SBP, especially in patients with impaired glucose tolerance or obesity (BMI ≥ 30 kg/m2), with a mean reduction of 5 and 3 mmHg, respectively. The magnitude of BP reduction was similar in our study with a reduction of SBP (4.6 mmHg) in metformin group.

  2. A second plausible mechanism for LVH regression may be metformin induced reduction in body weight. In our study, metformin therapy reduced body weight by approximately 4 kg and reduced MRI measured SCAT by 8.8%. Our results are in keeping with the findings of the CAMERA study involving non-diabetic individuals, where metformin significantly reduced all measures of adiposity (body weight, body fat, BMI, waist, circumference) in non-diabetic patients with CAD, with a mean weight loss of 3.2 kg in metformin group.

  3. Thirdly, oxidative stress has been pathophysiologically linked to LVH and in our study, metformin reduced oxidative stress as observed by the reduction of TBARs, a biomarker of oxidative stress. Our findings are in keeping with the study by Esteghamati etal. that reported that metformin is more effective in reducing oxidative stress compared with lifestyle modification alone.

  4. Fourthly, metformin could mediate this through its insulin-sensitizing properties. Insulin resistance is thought to contribute to changes in cardiac tissue seen in LVH. In this study, metformin treatment reduced fasting blood glucose but only resulted in non-significant marginal reductions in FIRI and HbA1c. Previous studies on metformin in non-diabetic individuals also reported none or modest effects on HbA1c.

We did not find any changes to vascular function (FMD) in this group of patients. It is noteworthy that the effect of metformin on endothelial function as assessed by FMD has not been consistent. Finally, as suggested by previous studies with animal models of LVH, it is plausible that activation of AMPK by metformin could have played a role in the regression of LVH.

It is worth noting that other mechanisms such as increasing nitric oxide bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products, and inhibiting myocardial cell apoptosis have also been proposed for metformin’s efficacy in reducing cardiac remodelling and hypertrophy. However, this remains purely speculative and cannot be directly inferred from this clinical study.

 
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