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CATIE - www.catie.ca

Can metformin also protect arteries?

8 December 2011 - 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 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:

  1. Guaraldi G, Orlando G, Zona S, et al. Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population. Clinical Infectious Diseases. 2011 Dec;53(11):1120-6.
  2. Mangili A, Polak JF, Skinner SC, et al. HIV infection and progression of carotid and coronary atherosclerosis: the CARE study. Journal of Acquired Immune Deficiency Syndromes. 2011 Oct 1;58(2):148-53.
  3. Burdo TH, Lo J, Abbara S, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. Journal of Infectious Diseases . 2011 Oct 15;204(8):1227-36.
  4. Jang JJ, Berkheimer SB, Merchant M, et al. Asymmetric dimethylarginine and coronary artery calcium scores are increased in patients infected with human immunodeficiency virus. Atherosclerosis . 2011 Aug;217(2):514-7.
  5. Guaraldi G, Zona S, Orlando G, et al. Human immunodeficiency virus infection is associated with accelerated atherosclerosis. Journal of Antimicrobial Chemotherapy . 2011 Aug;66(8):1857-60.
  6. Tan ZS, Beiser AS, Fox CS, et al. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care . 011 Aug;34(8):1766-70.
  7. den Heijer T, Vermeer SE, van Dijk EJ, et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia . 2003 Dec;46(12):1604-10.
  8. Aghdassi E, Salit IE, Mohammed S, et al. Chromium supplementation decreases insulin resistance and trunk fat. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections . 3-6 February 2008, Boston, MA. Abstract 936.
  9. Aghdassi E, Salit IE, Fung L, et al. Is chromium an important element in HIV-positive patients with metabolic abnormalities? An hypothesis generating pilot study. Journal of the American College of Nutrition. 2006 Feb;25(1):56-63.
  10. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011 May 19;473(7347):317-25
  11. Fitch K, Abbara S, Lee H, et al. Effects of lifestyle modification and metformin on atherosclerotic indices among HIV-infected patients with the metabolic syndrome. AIDS . 2012; in press .

###

CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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