Cardiovascular risk following metformin treatment

in patients with type 2 diabetes mellitus: Results

from meta-analysis

Kui Zhang a,1, Wenxing Yang b,1, Hao Dai a, Zhenhua Deng

 

https://www.ncbi.nlm.nih.gov/pubmed/31904444/

 

A B S T R A C T

Aim: Pharmacologic therapy for T2DM has proven benefits in terms of reducing elevated

blood glucose levels and reducing microvascular complications. However, the impact of

metformin on adverse cardiovascular outcomes and cardiovascular mortality is less clear.

We carried out this meta-analysis on all published studies to estimate the overall cardiovascular

risk following metformin treatment in patients with T2DM.

 

Methods: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure)

databases for all articles. The odds ratio (OR) corresponding to the 95% confidence

interval (95% CI) was used to assess the cardiovascular risk following metformin treatment

in patients with T2DM. The statistical heterogeneity among studies was assessed with the

Q-test and I2 statistics

 

Results: We collected 16 studies including 25 comparisons with 1,160,254 patients of type 2

diabetes mellitus and 701,843 patients of T2DM following metformin treatment. Our results

found statistical evidence of significantly decreased cardiovascular risk to be associated

with following treatment with metformin in patients with type 2 diabetes mellitus

(OR = 0.57, 95% CI = 0.48–0.68) (shown in Table 1 and Fig. 2), both with the mortality

(OR = 0.44, 95% CI = 0.34–0.57) and incidence (OR = 0.73, 95% CI = 0.59–0.90).

 

Conclusions: Our meta-analysis indicated that following metformin treatment in patients

with T2DM was associated with decreased cardiovascular risk, both with the mortality

and incidence. However, the heterogeneity among studies may potentially affect the final

results.

 

From the article

Discussion

Although intensive control of plasma glucose is associated

with decreased microvascular complications, the benefit of

intensive control of plasma glucose level for reducing cardiovascular

mortality is open to debate [12–14]. Metformin mimics

some of the benefits of calorie restriction, such as

improved physical performance, increased insulin sensitivity,

and reduced low-density lipoprotein and cholesterol levels

without a decrease in caloric intake [15]. Furthermore, many

different mechanisms beyond glycemic control have been

implicated in vascular protection induced by metformin, such

as improvements in the inflammatory pathway, coagulation,

oxidative stress, endothelial dysfunction, and hemostasis

[16,17].

 

Previous meta-analysis found that whether metformin

reduces risk of cardiovascular disease among patients with

T2DM remains uncertainty [18]. Recent meta-analysis

revealed that metformin can reduce cardiovascular mortality,

all-cause mortality and CV (cardiovascular) events in CAD

(coronary artery disease) patients [19]. In the present study,

we collected 16 studies including 25 comparisons with

1,160,254 patients of T2DM and 701,843 patients of T2DM

following metformin treatment. Our results found statistical

evidence of significantly decreased cardiovascular risk to be

associated with following metformin treatment in patients

with T2DM (OR = 0.57, 95% CI = 0.48–0.68) (shown in Table 1

and Fig. 2), both with the mortality (OR = 0.44, 95% CI = 0.3

4–0.57) and incidence (OR = 0.73, 95% CI = 0.59–0.90).

To date, a vast number of studies have supported the protective

effects of metformin in patients with diabetes mellitus.

The main target tissue of metformin is liver and its

major effect is decreasing hepatic glucose output, largely

due to the suppression of gluconeogenesis, which leads to

lower fasting blood glucose levels without insulin stimulation

and weight gain [20]. Metformin has an inhibitory effect on

mitochondrial complex I, inhibition of which has been found

to increase the AMP/ATP ratio [21,22]. The altered cellular

energy status induces activation of AMP-activated protein

kinase (AMPK), a serine/threonine kinase, and acts as an

energy sensor [23]. Activation of AMPK by metformin stimulates

endothelial nitric oxide synthase (eNOS) activity, which

exerts a direct effect on endothelial protection in T2DM [24].

Furthermore, metformin has inhibitory effects on mTOR signaling

and suppresses cell proliferation via AMPKdependent

or AMPK independent manner [25]. Moreover,

Treatment with metformin is associated with decreased

oxidative stress, improved lipid profile, and improved

endothelial and platelet function [26,27]. Therapy with metformin

could decrease plasma triglyceride, total cholesterol

and LDL-C, while serum HDL-C levels is increased or at least

unaffected [27]. Metformin could also decrease blood pressure,

a well-known cardiovascular risk factor [27]. Treatment

of diabetes is aimed at normalizing blood glucose levels to

minimize the short-term effects of hyperglycemia and hypoglycemia

while preventing development of long-term complications

of diabetes [28]. These mechanisms may potentially

benefit cardiovascular complications of T2DM.

A few limitations of our study should be considered.

Although we did not observe significant publication bias, publication

bias is possible in any meta-analysis. Moreover, original

data were acquired to calculate ORs and 95% CIs, that

may omit some valuable studies and ignore potential

adjusted risk factors. Finally, there was heterogeneity among

studies in overall comparisons. Although we performed logistic

meta-regression analyses and stratified analysis to explore

sources of heterogeneity across studies, we still found no possible

factors that may substantially influence the initial

heterogeneity, and the heterogeneity may potentially affect

the final results.

 

In conclusion, our meta-analysis indicated that following

metformin treatment in patients with T2DM was associated

with decreased cardiovascular risk, both with the mortality

and incidence. However, the heterogeneity among studies

may potentially affect the final results. Further studies estimating

the functional effect and side effects may eventually

provide a better, comprehensive understanding.

 

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