[Viva] Fwd: CATIE-News - Can metformin also protect arteries?

[Tami Starlight]

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From: <mailing at mercury.catie.ca>
Date: Thu, Dec 8, 2011 at 2:45 PM
Subject: CATIE-News - Can metformin also protect arteries?
To: cosmictami at shaw.ca


*CATIE-News - Can metformin also protect arteries?*

Reports suggest that cardiovascular disease is becoming common among
HIV-positive people. Even in otherwise-healthy HIV-positive adults, at
least one study has found an increase in the sticky deposits called plaque
that can build up in arteries. Plaque is made from cholesterol, collagen,
dead cells, cellular debris and calcium. Over time, as plaque deposits
increase, the supply of fresh blood to tissues is slowly restricted. This
can reduce the vitality of organs such as the brain and heart. The
discovery of plaque deposits in the arteries of young HIV-positive adults
raises the possibility of accelerated cardiovascular disease. Other studies
have found that metabolic issues such as pre-diabetes (gradual loss of
sensitivity to the hormone insulin), abnormal levels of cholesterol,
higher-than-normal blood pressure and excess belly fat appear to be growing
problems in some HIV-positive people, particularly as they age.

One group of metabolic researchers in Boston, Massachusetts, has focused on
the body’s ability to control blood sugar levels and the role that the loss
of blood sugar control can play in increasing the risk for cardiovascular
disease.
 About insulin

Insulin is a hormone produced by the pancreas gland in the abdomen. This
hormone helps cells absorb sugar in the blood so that they can convert
sugar into energy.

As people age, their bodies become less sensitive to the effects of
insulin—an effect called insulin resistance. To compensate for this, the
pancreas gland produces more insulin; for a time this works, but gradually
ever-higher amounts of insulin are needed to compensate for growing insulin
resistance. Eventually, this is insufficient and the pancreas gland becomes
exhausted and the concentration of sugar in the blood remains excessive for
prolonged periods—diabetes has developed.

In pre-diabetes, frequent spikes in blood sugar levels affect many tissues
and prolonged elevation of blood sugar triggers other problems that are
initially minor but intensify over time, including the following:

   - weight gain
   - nerve damage
   - kidney dysfunction
   - cognitive impairment

 Focus on blood sugar

Changes to the diet and engaging in regular aerobic exercise are some of
the best ways of preventing type 2 diabetes (as well as other health
conditions). Additionally, doctors can also prescribe drugs that can help
reverse, at least to a degree, insulin resistance and normalize blood sugar
levels. These drugs are called insulin-sensitizing agents and one commonly
used drug is metformin.
 Enter metformin

In the 1990s researchers in the UK assessed the impact of the following
randomly assigned interventions on blood sugar control and survival in
1,704 HIV-negative people with type 2 diabetes:

   - changes to the diet
   - the insulin-sensitizing agent metformin
   - other insulin-sensitizing drugs (chlorpropamide, glibencamide)
   - insulin

 After an average of 10 years of monitoring, the UK researchers found that
participants who received metformin were 32% less likely to having
increasing blood sugar levels, had a 42% reduced risk for diabetes-related
death and a 32% reduced risk of dying from any cause.
 Back to Boston

Based on past studies about the importance of controlling blood sugar
levels and the survival benefit associated with metformin, the Boston
researchers conducted a randomized, placebo-controlled trial of what they
termed “lifestyle modification” (improved diet and an exercise program)
with or without metformin among HIV-positive participants who did not have
serious heart disease or diabetes. The researchers found that participants
who received metformin did not have further deterioration in the health of
their arteries. This finding is important and robust and suggests that
controlling blood sugar can have a major impact on arterial health and
cardiovascular disease.
 Study details

Researchers at Massachusetts General Hospital recruited 50 HIV-positive
adults who had the following average profile at the start of the yearlong
study:

   - 76% males, 24% women
   - age – late 40s
   - CD4+ count – 600 cells
   - viral load – less than 100 copies/ml
   - body mass index (BMI) – 30
   - duration of HIV infection – 14 years
   - duration of exposure to anti-HIV drugs – 4 years

 Researchers randomly assigned participants to one of the following four
groups:

   - Group 1 – no lifestyle modification + placebo
   - Group 2 – lifestyle modification + placebo
   - Group 3 – no lifestyle modification + metformin
   - Group 4 – lifestyle modification + metformin

 About lifestyle modification

The study team educated participants about improving their dietary habits.
Specifically, participants were taught how to assess the fat content of
foods and were encouraged to eat less than one-third of daily calories from
fat and cut back on saturated fat. They were also encouraged to eat between
25 and 30 grams per day of fibre and foods containing omega-3 fatty acids
(good sources of these are anchovies, mackerel, sardines, salmon, and nuts
and some seeds).

Additionally, participants received guidance and supervision from a
physical trainer so that they could regularly engage in resistance and
aerobic exercise at least three times weekly.
 Metformin

This drug was taken orally at a dose of 500 mg twice daily for the first
three months of the study. If there were no adverse reactions to this dose,
in the fourth month of the study the dose was increased to 850 mg twice
daily.
 Scanning the arteries

Using high-resolution X-ray scans (64-slice CAT scans) technicians took
images of participants’ arteries. These images were used to assess the
amount of calcium in plaques—a calcium score. Ultrasound scans were used to
assess the thickness of arteries.
 Results—Plaque

Participants who received metformin with or without lifestyle modification
maintained the health of their arteries. Participants who did not receive
metformin had an increase in the amount of plaque in their arteries.
Metformin’s beneficial effects proved superior to improvements in diet and
exercise alone.

Metformin was also effective in a sub-group of participants who entered the
study with higher-than-normal levels of plaque.

Participants who changed their diet and engaged in regular exercise did not
have significant changes to the amount of plaque in their arteries compared
to participants who did not make changes to their diet and exercise
regimens.
 Results—Better lungs and endurance

Participants who exercised showed measureable and significant improvement
in their lung capacity, endurance and strength. Use of metformin did not
affect these results.
 Results—Lab tests

Levels of good cholesterol (HDL-C) improved modestly among participants who
engaged in exercise and who improved their diets.

Participants who received metformin had significantly less insulin
resistance compared to participants who received placebo. Decreased insulin
resistance was maximal in participants who exercised and who received
metformin.

Levels of high-sensitivity C-reactive protein (hsCRP) in the blood rise
with inflammation. In some studies, rising hsCRP has been linked to
increased risk of cardiovascular disease. Participants who engaged in
exercise and changed their diets had significantly reduced hsCRP levels.
Lifestyle modification also reduced the likelihood of unnecessary blood
clots forming. Such clots can clog blood vessels and lead to heart attack
and stroke.

Participants who engaged in lifestyle modification alone had their CD4+
count decrease by 15 cells. Although statistically significant, this change
was so minor that it had no impact on their overall health. Exercise and
dietary changes did not affect HIV viral load.

Metformin did not affect CD4+ counts or viral load.
 Safety

Two participants taking metformin at a dose of 850 mg twice daily had minor
signals of kidney dysfunction in their lab tests. These normalized once
their dose was reduced to 500 mg twice daily.

In rare cases metformin can cause an increase in lactic acid in the blood.
If lactic acid levels become very high, dangerous complications can
develop. However, in the present study no one had such high levels of
lactic acid and no dangerous side effects occurred.

Metformin can also cause nausea, vomiting, diarrhea and other
gastrointestinal symptoms. Such problems occurred in five (10%)
participants who had to interrupt their use of metformin. They resumed
taking it at lower doses of 500 mg once or twice daily.

Two participants who engaged in resistance exercises developed muscle
strain and had to reduce their weight training. Apart from this, no adverse
effects of exercise were reported.
 Bear in mind

According to the study team, “metformin had a robust effect” in its ability
to prevent the growth of plaque in the arteries while improving the body’s
ability to use insulin and control blood sugar. In contrast, people who did
not receive metformin had an increase in plaque. This suggests that HIV
infection itself can have an adverse effect on the health of arteries.

Helpful changes to diet and engaging in regular exercise improved good
cholesterol levels and reduced inflammation but did not reduce plaque in
the arteries.

Metformin is relatively inexpensive and has been proven effective in
HIV-negative people. The results from the present study suggest that
metformin has much potential to not only decrease insulin resistance but
also to prevent the worsening of cardiovascular disease in HIV-positive
people. Although the Boston study was small, it was well designed and now
paves the way for a longer, larger study.

Other studies are needed to assess the long-term effect of metformin with
or without other therapies such as statins, Aspirin and high-dose fish oil,
changes to the diet and exercise programs—all of which have
anti-inflammatory activity. These interventions will become increasingly
important in the future as HIV-positive people age, a factor that increases
cardiovascular risk.

It may also be useful to assess the impact of the supplement chromium on
blood sugar together with metformin. A placebo-controlled pilot study in
Toronto<http://www.catie.ca/en/treatmentupdate/can-chromium-supplements-help-body-shape>has
found that chromium nicotinate at a dose of 400 micrograms per day was
able to reduce insulin resistance in some HIV-positive people.


*—Sean R. Hosein*

REFERENCES:

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   7. den Heijer T, Vermeer SE, van Dijk EJ, et al. Type 2 diabetes and
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   8. Aghdassi E, Salit IE, Mohammed S, et al. Chromium supplementation
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   9. Aghdassi E, Salit IE, Fung L, et al. Is chromium an important element
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