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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