Does Avapro help patients with heart failure?

Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction
Original source: New England Journal of Medicine Volume 359, Number 23
Authors: Barry M. Massie, M.D. (corresponding author), Peter E. Carson, M.D., John J. McMurray, M.D., Michel Komajda, M.D., Robert McKelvie, M.D., Michael R. Zile, M.D., Susan Anderson, M.S., Mark Donovan, Ph.D., Erik Iverson, M.S., Christoph Staiger, M.D., Agata Ptaszynska, M.D., for the I-PRESERVE Investigators
Publication date: online: November 11, 2008 print: December 4, 2008
DOI (digital document ID): 10.1056/NEJMoa0805450
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
There is a need to find a way of improving the outcome of patients with heart failure, whose left ventricles still function to some degree. The investigators wanted to know if irbesartan (brand names Avapro, Aprovel, Karvea) might serve that purpose.

Over 4000 patients, over the age of 60, and classified as having varying degrees of heart failure but at least 45% left ventricular evacuation fraction, were studied for just over 4 years. Some were given irbesartan and others were given a placebo. The investigators wanted to know how many of those patients had subsequent cardiovascular events requiring hospitalization, how many died from heart failure or cardiovascular causes, and how many died overall. The numbers of deaths were similar in both groups, though the number of hospitalizations for cardiovascular events were slightly lower in the group receiving the medication.

Because the numbers of deaths and cardiovascular events overall were not significantly different between the two groups, irbesartan is not considered to be effective for this application.

Reliability:
The study size is reasonable, and the subjects were followed for a reasonably-long period of time. Because of the ages of the subjects, the results may not be valid for younger patients.

The researchers are associated with accredited medical institutions in several countries. The article was published in peer-reviewed journal.

The research was sponsored by two pharmaceutical companies, Bristol Meyers Squibb (BMS) and Sanofi-Aventis. BMS and Sanofi-Aventis both manufacture and market Avapro and have a vested financial interest in its use for reasons in addition to the treatment high blood pressure.

Practical Applications:
Irbesartan has not been proven to be effective in preserving heart function among older patients with heart failure, but with preserved left ventricular function.

For further reading:
This is not the first time additional uses for Avapro have been considered. Avapro has also been studied as a drug with which to preserve kidney function in people with Type 2 diabetes. The following article is one of several published following that train of research:
The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

This synopsis was based on the abstract of the online preprint.

Diabetes and Risk of death from coronary events

Diabetes Mellitus and Mortality after Acute Coronary Syndrome as a First or Recurrent Cardiovascular Event
Original source: PLoS ONE Vol. 3, No. 10
Authors: Richard M. Cubbon, Afroze Abbas, Stephen B. Wheatcroft, Niamh Kilcullen, Raj Das, Christine Morrell, Julian H. Barth, Mark T. Kearney (corresponding author), Alistair S. Hall for the EMMACE-2 investigators
Publication date: 22 October 2008
DOI (digital document ID): 10.1371/journal.pone.0003483
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Diabetes has been associated with problems recovering from, and with higher risk of death from, acute coronary syndrome. The investigators were looking to find whether this increased risk was true for all persons with diabetes, or only for those persons with diabetes who already had cardiovascular disease, compared to people without diabetes (with, or without, diagnosed cardiovascular disease). The investigators wondered whether cardiovascular disease is diagnosed earlier in people with diabetes than in the general population, and if that early diagnosis, plus aggressive preventative treatment, reduced the risk of dying from acute coronary syndrome.

For the purposes of the study, "Acute Coronary Syndrome" covered unstable angina or myocardial infarction (heart attack). "Cardiovascular Disease" was devined as myocardial infarction, angina, stroke, peripheral vascular disease, or coronary revascularization (either the heart's circulatory system rerouting itself, or the need for stents, bypasses, or other surgical techniques to open or replace blocked blood vessels). Note that by these definitions, "acute coronary syndrome" is a subset of "cardiovascular disease".

The researchers looked at the data collected in the EMMACE-II observational study in 2003, which tracked just under 2500 patients. The investigators used the patients' previous medical records to split the patients into four groups: those without diabetes or previously-diagnosed cardiovascular disease; those without diabetes, but who had existing cardiovascular disease; those with diabetes but without a history of cardiovascular disease; and those with both diabetes and a history of cardiovascular disease. The data from these four groups were analyzed separately and compared.

The results showed that while patients with diabetes had an overall increased risk of death from acute coronary syndrome, the rates of death of patients with no history of cardiovascular disease were approximately the same, regardless of whether or not they had diabetes.

After adjusting for age and gender, there was still an increased risk of death for patients with diabetes and a history of cardiovascular disease over patients from the other three groups; however, when the results were adjusted for levels of Troponin I -- which was used to indicate how much of the heart muscle had died due to cardiovascular disease, the correlation between mortality and diabetes disappeared. This lack of correlation remained even when the investigators broadened or narrowed the definition of cardiovascular disease used in their analysis.

These findings suggest that the risk of dying from acute coronary syndrome may be related to the degree to which the heart's blood vessels have been blocked, and that the reduced degree of blockage in patients with diabetes, but no history of cardiovascular disease, may be related to aggressive preventative treatment that is not routinely offered to people without diabetes.

Reliability:
The authors are from accredited medical institutions and the research is published in a peer-reviewed journal. The size of the study is large enough to show potential trends and suggest directions for further research. The authors note limitations of the study include the absence of several key risk indicators (such as albuminuria -- protein in the urine -- and obesity) and details of any preventative therapy the patients may have received. They also note that patients with a history of previous cardiovascular disease are less likely to receive prescriptions for preventative drugs (such as statins and ACE inhibitors) than patients being discharged after their first acute coronary event, and because this is counterintuitive to standard practice, understanding the reasons for this difference would also help to quantify the differences in risk.

Practical Applications:
Understanding the true origins of the risks of death from acute coronary syndrome can help our doctors better treat us and help us reduce those risks to the greatest degree possible.

For further reading:
The British Cardiac Society Working Group definition of myocardial infarction: implications for practice -- abstract describing the EMMACE-II study.

This synopsis was based on the entire article.

Are moderate-protein diets better than low-protein diets for people with metabolic syndrome?

Moderate carbohydrate, moderate protein weight loss diet reduces cardiovascular disease risk compared to high carbohydrate, low protein diet in obese adults: A randomized clinical trial

Original source: Nutrition & Metabolism 2008, 5:30
Authors: Denise A Walker Lasker (corresponding author), Ellen M Evans, and Donald K Layman
Publication date: 7 November 2008
DOI (digital document ID): 10.1186/1743-7075-5-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
This study compares the effectiveness of the standard USDA Food Pyramid diet with a higher-protein, lower-carbohydrate diet for weight loss in general, for fat loss in particular, and for lowering the blood-based indicators of cardiovascular risk and insulin resistance. A total of 50 people completed the testing, split between the two dietary approaches.

Both diets under test had the same amount of calories, with about 30% of total calories coming from fats. Carbohydrates supplied about 55% of the Food Pyramid diet group's caloric intake, and protein, the remaining 15%. The people assigned to this group were instructed to eat whole grains for their bread products. About 30% of the high-protein group's calories came from protein, with the remaining 40% coming from carbohydrates. (This is the same protein-carbohydrate-fat distribution advocated by the Zone Diet.) This group was instructed to eat primarily "high quality protein", including lean meats, dairy, and eggs. Both groups had similar amounts of fruits and vegetables in their daily diets. All subjects were instructed on portion sizes, dietary substitutions, how to weigh foods, and how to keep a food diary. There was no difference in exercise between the two groups.

Baseline measurements (weight, body fat percentage, cholesterol, and postprandial insulin) were taken at the start of the experiment. The subjects followed their assigned diet plans for four months, at which time the same measurements were repeated.

• The moderate-protein group lost about 5 pounds more per person than the USDA group, and more of their weight loss was from fatty tissues.
• Fasting glucose levels were unchanged, but fasting insulin levels decreased in the moderate protein group, while it increased in the USDA group. In addition, postprandial insulin levels dropped 85% for the protein group, but only 50% for the Food Pyramid group. (High plasma insulin levels are indicative of insulin resistance, which is often a predecessor to Type 2 diabetes.)
  
• There was a greater drop in total cholesterol in the USDA group than in the protein group. LDL ("bad") cholesterol dropped in the USDA group but rose in the protein group; on the other hand, HDL ("good") cholesterol dropped in the USDA group but rose in the protein group. The protein group also showed greater improvement in triglyceride levels than the USDA group. (High triglyceride levels are associated with increased risk of heart attack.)
  

Reliability:
The study was small scale, with only 50 people completing the four-month study. While the two groups of subjects were selected to be closely-matched, there is still opportunity for the results to be skewed. An initial run-in period put all subjects on as close to an even footing as possible before the trial started.
The authors are associated with an accredited university; the paper was published in a peer-reviewed journal.
Longer-term studies of larger groups may be needed to determine the long-term safety and effectiveness of high-protein diets.

The principal investigator (Denise A Walker Lasker) received funding from the National Cattleman’s Beef Association, The Beef Board and Kraft Foods. Both Beef associations have a vested interest in increasing protein consumption (in the form of beef).
The investigators have made no comparison between a higher-fat restricted-carbohydrate diet and a higher-protein restricted-carbohydrate diet.

Practical Applications:
The 30/40/30 protein/carb/fat (PCF) ratio is the basis of the Zone Diet. While this diet is higher in protein than traditionally advised for people with diabetes, recent publications suggest that this is not as high a risk as formerly perceived.

For further reading:
WebMD evaluates the Zone Diet
Wikipedia entry on the Zone Diet

This synopsis was based on the entire article.

Are adverse effects of some diabetes drugs related to their suppression of sex hormones?

Are the adverse effects of glitazones linked to induced testosterone deficiency?
Original source: Cardiovascular Diabetology 2008, 7:30
Authors: M. Carruthers (corresponding author), T. R. Trinick, E. Jankowska, and A.M. Traish
Publication date: 15 October 2008
DOI (digital document ID): 10.1186/1475-2840-7-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors pose a theory that the various adverse effects of diabetes drugs in the class called "glitazones" -- including rosiglitazone (RGZ -- brand name Avandia) and pioglitazone (PGZ -- brand name Actos) -- may be related to a separate known action of these drugs -- their suppression of sex hormones. These side effects include heart disease, swelling, weight gain, and anemia.

Glitazones act on sex hormones by reducing the levels to which they are released and by making the body less sensitive to them. These sex hormones are responsible for directing new cell growth to become blood vessels, skin, muscle, and other types of structural cells, rather than fat cells. This might give further weight to an existing theory of how obesity might cause diabetes (called "Ungar's theory of the 'Lipocentric Pathway to Hyperglycemia'"(1)). The authors note evidence that low testosterone levels in men can cause a number of the same side effects that are being observed in diabetes patients treated with glitazones; furthermore, that diabetes and/or cardiovascular disease are often seen to develop where testosterone production has been suppressed in order to treat prostate cancer. Much of this can be tied to the abdominal weight gain related to low testosterone levels. Treatment with testosterone in these cases has been shown to reduce the side effects and lower the statistical occurrence of cardiovascular disease among patients showing a number of these metabolic symptoms.

The authors note a number of known effects of rosiglitazone and troglitazone (Resulin, which has been removed from the US market) on sex hormones and on the development and maturation of new body tissues.

The authors suggest that this hypothesis might be tested by double-blind, placebo-controlled clinical studies examining the endocrine profiles, and levels of sex hormones, in people with Type 2 diabetes both before and while/after being treated with a glitazone. Additionally, studies on treating diabetic men with testosterone might show us whether this might counteract (or at least lessen) the adverse effects of glitazones. They also suggest further research into exactly how glitazones inhibit sex hormones.

Reliability:
The authors are associated with a number of universities and medical research institutes throughout the world. The hypothesis was published in a peer-reviewed journal. The authors are posing a theory, rather than a statement of fact, and suggesting ways that others could determine whether or not their theory is correct.

Practical Applications:
If the theory is correct, and if administering testosterone to men can completely counteract the adverse effects of Avandia and similar medications, that would make Avandia a relatively safer choice to treat Type 2 diabetes than it is now.

For further reading:
(1) Roger H. Unger, MD Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. Journal of the American Medical Association (JAMA), 2008;299(10):1185-1187.
Full text requires paide subscription.
First 150 words available free.

"Evidence-Based Medicine", Patient Pages, Journal of the American Medical Association (JAMA)

This synopsis was based on the entire article.

Metabolic syndrome increases risk of heart attack and stroke

Effect of metabolic syndrome or type II diabetes mellitus on the occurrence of recurrent vascular events in hypertensive patients
Original source: Journal of Human Hypertension (2008) 22, 358–365
Authors: A L M Vlek, Y van der Graaf, W Spiering, F L J Visseren (corresponding author), SMART study group
Publication date: published online 14 February 2008
DOI (digital document ID): doi:10.1038/jhh.2008.5
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
People with high blood pressure and vascular disease (diseases of the blood vessels) are at increased risk for recurrences of vascular disease, and for developing additional cardiovascular diseases such as heart disease, stroke, peripheral artery disease, and aneurysms. This study aims to find out whether having metabolic syndrome, and/or Type 2 diabetes, increases those risks even further.

Over 2000 people who were part of the Second Manifestations of Arterial Disease study (SMART) were followed for up to 10 years afterward for death, strokes, and heart attacks. These were used to calculate the risks of cardiovascular disease for people with high blood pressure only, for high blood pressure and metabolic syndrome, and for people with high blood pressure and diabetes.

Of this group, patients with metabolic syndrome (but without diabetes) had higher rates of stroke, heart attack, and sudden deaths related to cardiovascular issues. Patients with Type 2 diabetes had even higher risks than those with metabolic syndrome (but without diabetes). The increased risk of people with metabolic syndrome was not explainable by diabetes.

Further lowering of blood pressure did not seem to reduce the increased risk of heart attack and stroke in patients with metabolic syndrome.

Because people with metabolic syndrome have been shown to have higher risk of cardiovascular disease, investigators suggest more attention should be paid to diagnosing metabolic syndrome and treating it aggressively.

Reliability:
A large number of people were observed over a relatively long period of time. The authors work in a university medical center. The research was published in a peer-reviewed journal. The results should be relatively reliable.

Practical Applications:
Patients and healthcare providers should pay more attention to identifying the signs of metabolic syndrome and treating it with diet, exercise, and drugs (where appropriate).

Health insurance and life insurance actuaries will want to account for this relationship in their risk tables when determining coverage and premiums.

This synopsis was based on the entire article.

Metabolic syndrome increases risk of heart disease and diabetes

Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study
Authors: C M Ballantyne (correpsonding author), R C Hoogeveen, A M McNeill, G Heiss, M I Schmidt, B B Duncan and J S Pankow
Original source: International Journal of Obesity Volume 32, Supplement 2, pp. S21-S24
Publication date: May, 2008
DOI (digital document ID): doi:10.1038/ijo.2008.31
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
The investigators studied over 15,000 middle-aged Americans in four communities for a period of approximately ten years to try to determine the role of metabolic syndrome in the development of cardiovascular (heart and artery) disease and diabetes. The particular study is called Atherosclerosis Risk in Communities (ARIC).

Metabolic syndrome is diagnosed by the presence of three or more of the following characteristics: waist circumference greater than 40" in men or 35" in women; high triglycerides (over 150 mg/dl); low HDL or "good cholesterol" (less than 40 mg/dl in men or 50 mg/dl in women); high blood pressure (over 130/85 mm Hg); and high fasting glucose levels.

The investigators studied the numbers of those with and without metabolic syndrome to determine how much greater a risk someone with metabolic syndrome has of developing atherosclerosis, heart disease, stroke, or diabetes.

• ARIC participants who had metabolic syndrome were two to three times more likely to have coronary heart disease than those without, with the highest additional risk in black men and white women.
• The walls of the carotid arteries of persons with metabolic syndrome were about 5% thicker than those without.
• The increased risk of stroke for those with metabolic syndrome was an additional 35-40 cases per 10,000 person years.
• Of those participants with three or more indicators of metabolic syndrome, who did not have diabetes, those with obesity and/or elevated fasting glucose levels had significantly increased risk of developing diabetes.

Reliability:
This is a large study, conducted over a long period of time, and the article was published in a peer-reviewed journal. Both this, and the academic credentials of the authors, result in high levels of confidence in the results.

Further reading:
More information on the design of the ARIC study and publications based on information collected during the study can be found at the ARIC home page.

This synopsis was based on the entire article.