Hypertension Highlights / Journal of the American Society of Hypertension 11(2) (2017) 68–70
Department of Vascular Care
Renown Institute for Heart and Vascular Health
Reno, NV, USA
michael@bluesprucemed.com, mbloch@aol.com
http://dx.doi.org/10.1016/j.jash.2017.01.001
References
1. Montaniel KR, Harrison DG. Is hypertension a bone
marrow disease. Circulation 2016;134:1369–72.
2. Wang L, Zhao XC, Cui W, Ma YQ, Ren HL, Zhou X, et al.
Genetic and pharmacologic inhibition of the chemokine
receptor CXCR2 prevents experimental hypertension
and vascular dysfunction. Circulation 2016;134:1353–68.
3. McArthur NM, Wang NY, Appel LJ. Lifestyle inter-
ventions reduce coronary heart disease risk: results
from the PREMIER Trial. Circulation 2009;119:
2026–31.
4. Julius S, Nesbitt SD, Egan BM, Weber MA,
Michelson EL, Kaciroti N, et al. Feasibility of treating
prehypertension with an angiotensin-receptor blocker.
N Engl J Med 2006;354:1685–97.
METFORMIN LOWERS BLOOD PRESSURE
IN OBESE AND INSULIN-RESISTANT
INDIVIDUALS WITHOUT DIABETES
The blood pressure (BP, mm Hg) effects of metformin in
nondiabetic subjects were evaluated in a recent meta-anal-
ysis.1 The meta-analysis included 4113 participants from
28 separate studies reported in 26 publications. The authors
found that metformin lowered systolic BP an average of
2.0 mm Hg (95% confidence interval [95% CI
3.6 to

0.4], P ¼ .022) across all studies. The effects of metfor-
min on systolic BP (Figure 1) were most clearly evident
among individuals with impaired fasting glucose (
5.0
[95% CI
9.2 to
0.9]) and with obesity (
3.0 [95% CI

5.6 to
0.4]). Mean diastolic BP value declined, but the
changes were not statistically significant in all subjects
combined or in subgroup analyses. While there was evi-
dence for heterogeneity between studies in metformin’s ef-
fects on systolic BP, exclusion of any single study did not
materially alter the findings. Moreover, publication bias, as-
sessed by funnel plots and Egger’s test, was not found.
A prior meta-analysis, which included 31 studies with
4570 subjects at risk for diabetes and 8267 patient years
of observation, assessed the effects of metformin on multi-
ple cardiovascular risk factors. In this report, metformin
significantly lowered body mass index 5.3%, fasting
glucose 4.5%, fasting insulin 14.4%, calculated insulin
resistance 22.6%, triglycerides 5.3%, and low-density
69
Figure 1. The mean change in systolic BP during treatment
with metformin for 1 to 24 months in various groups of nondi-
abetic individuals at least 17 years old. The groups included all
participants (N ¼ 4113), impaired fasting glucose (IFG,
N ¼ 2283), normal fasting glucose (NFG, N ¼ 1830), obese
(ob, N ¼ 2866), and nonobese (nonob, N ¼ 1227). BP, blood
pressure.
lipoprotein cholesterol 5.6%, while raising high-density li-
poprotein cholesterol 5.0%.2
Metformin is widely recommended for the initial treat-
ment of type 2 diabetes and reduces cardiovascular events
in this at-risk population.3 Prevalent prediabetes has been
increasing and was estimated to impact 38% of US adults
in 2011–2012.4 While metformin has been recommended
for reducing incident diabetes in patients with prediabetes
by the American Diabetes Association since 2008, it is
only prescribed to roughly 1 in 25 adults with prediabetes.5
As one potential barrier to wider use of metformin for dia-
betes prevention, the FDA has not approved metformin for
this indication. Under current regulations, metformin prob-
ably will not receive FDA approval for diabetes prevention
since the application must come from the original patent
holder for a medication, which is widely available as an
inexpensive generic.
Prehypertension, which affects w70 million US adults,6
is associated with doubling of risk for incident diabetes.5
The impact of prehypertension is diminished after adjusting
for body mass index and abnormalities of glucose meta-
bolism and insulin action. This constellation of interrelated
risk factors for diabetes and cardiovascular disease, if any-
thing, strengthens the rationale for using metformin, which
can favorably impact each of these risk components.
The recent paper by Zhou et al1 showing that metformin
lowers systolic BP, especially in patients who are predia-
betic or obese, provides additional evidence for its use in
a large population of individuals at high risk for incident
diabetes. These individuals often have multiple cardiovas-
cular risk factors, including elevated BP. Despite estab-
lished benefits of metformin and the ADA
recommendation for its use in prediabetes to reduce
70 Hypertension Highlights / Journal of the American Society of Hypertension 11(2) (2017) 68–70
incident diabetes, this drug is rarely prescribed to this at-
risk population. Thus, there is a large gap between the ev-
idence on the beneficial effects of metformin on glucose
and lipid metabolism as well as BP, and its very limited
use in the many millions of patients with prediabetes,
many of whom have prehypertension.
Attaining appropriate use of metformin may require a
multifactorial approach that could include the following:
(1) educational initiatives by professional societies aimed
at clinicians and the public, (2) development of quality met-
rics that quantify clinician and health system performance on
appropriate use of metformin for prevention of diabetes, and
(3) policy changes by the FDA that facilitate the approval of
new indications for old medications, for example, metformin,
which are well advanced into their generic years. Pragmatic
trials focused primarily on existing and regularly updated
clinical and claims databases to document the efficacy and
safety of metformin for preventing diabetes, improving mul-
tiple risk factors, and reducing cardiovascular events would
be invaluable in sustaining and growing appropriate use given
the epidemic of obesity and cardiometabolic risk.
Brent M. Egan, MD
Department of Medicine
University of South Carolina School of
Medicine—Greenville
Care Coordination Institute
Greenville, SC, USA
began@ccihealth.org
http://dx.doi.org/10.1016/j.jash.2017.01.002
References
1. Zhou L, Liu H, Wen X, Peng Y, Tian Y, Zhao L. Effects
of metformin on blood pressure in nondiabetic patients.
A meta-analysis of randomized controlled trials. J Hy-
pertension 2017;35:18–28.
2. Salpeter SR, Buckley NS, Kahn J, Salpeter EE. Meta-
analysis: Metformin treatment in persons at risk for dia-
betes mellitus. Am J Med 2008;121:149–57.
3. American Diabetes Association. Standards of medical care
in diabetes—2017. Diabetes Care 2017;40(Suppl 1):S4–5.
4. Moin T, Li J, Duru OK, Ettner S, Turk N, Keckhafer A, et al.
Metformin prescription for insured adults with prediabetes
from 2010 to 2012. Ann Intern Med 2015;162:542–8.
5. Mullican DR, Lorenzo C, Haffner SM. Is prehyperten-
sion a risk factor for the development of type 2 diabetes.
Diabetes Care 2009;32:1870–2.
6. High Blood Pressure Fact Sheet. Available at: https://www.
cdc.gov/dhdsp/data_statistics/fact_sheets/fs_bloodpressure.
htm. Accessed January 31, 2017.