ACCORD Trial Researchers Halt Intensive Glucose-Lowering After Increased Deaths

ACCORD Trial Researchers Halt Intensive Glucose-Lowering After Increased Deaths

Researchers exploring the benefits of intensive versus standard glucose-lowering therapy have decided to end the trial's intensive treatment arm after interim analyses found higher mortality there.

The ACCORD researchers randomized 10,250 patients with type 2 diabetes averaging 10 years' duration and at high risk for cardiovascular disease to one of two treatment arms: the standard arm had a hemoglobin A1c target between 7% and 7.9%, and the intensive arm targeted levels under 6%. The trial's data and safety monitoring board recommended ending the intensive arm when it found increased all-cause mortality.

In a Wednesday news conference, researchers said that although the rates of nonfatal cardiovascular events were lower during intensive treatment, "if a heart attack did occur, it was more likely to be fatal." They also said that none of the study drugs used, including rosiglitazone, was conclusively implicated in the increased mortality.

Link: National Institutes of Health press release (Free)

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

N Engl J Med 2008 Feb 7; 358:580.

Peter Gæde, M.D., D.M.Sc., Henrik Lund-Andersen, M.D., D.M.Sc., Hans-Henrik Parving, M.D., D.M.Sc., and Oluf Pedersen, M.D., D.M.Sc.

ABSTRACT

Background

Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes.

Methods

In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause.

Results

Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported.

Conclusions

In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes.

Diabetes Increases Risk Of Heart Disease Death For Women

Diabetes Increases Risk Of Heart Disease Death For Women

Medical News Today

02 Feb 2008

The word is out: women are at risk for heart disease, just like men. In fact, roughly twice as many women in this country will die of heart disease, stroke, and other cardiovascular diseases than from all forms of cancer combined, including breast cancer, according to the American Heart Association.

Risk factors for heart disease and stroke have long been identified. Several risk factors cannot be controlled by the individual, such as sex, increasing age and a family history of heart disease.

Others can be modified and include:

Smoking-- High blood pressure and cholesterol

Diabetes

Sedentary lifestyle

Body weight

Diabetes continues to be a growing problem in the United States for both men and women. A study published in the December 2007 issue of the European Heart Journal reveals that diabetes is a stronger risk factor for heart disease death in women than in men."The reason for the higher relative risk of coronary heart disease in women with diabetes than in men with diabetes is still unclear," explains Ane Cecilie Dale, M.D., the study's lead researcher and head of the Department of Circulation and Medical Imaging at the Norwegian University of Science and Technology in Trondheim. "But research in this field continues to go on."

According to the U.S. Food and Drug Administration, diabetes affects approximately 8.9 percent of American women. The occurrence of diabetes is significantly higher among African American, Hispanic/Latino, American Indian, and Asian/Pacific Islander women than in white women.

Women with diabetes have a two to four times higher risk of dying from heart disease and stroke compared to women without diabetes, according to data from the American Heart Association. Women with diabetes are often overweight and suffer from high blood pressure, also known as hypertension, and high cholesterol levels, which can add to the risk.

"Women with diabetes need to be aware of the associated risk of heart disease. The most important thing to do for all persons with diabetes to protect themselves from heart disease and other diabetes complications is to have a good glucometabolic control with a blood glucose as near normal as possible," Dale said. "They also need to control other risk factors like hypertension and blood cholesterol levels. In addition it is important to quit smoking, have a healthy diet and practice regularly exercise."

Considering how complex the management of diabetes and heart diseases risks are, women should talk to their health care providers to develop a plan of action.

Without the support of health care professionals, patients can easily feel overwhelmed.



February is American Heart Month.

For tips on reducing your heart disease risk, visit the American Heart Association Web site: http://http:/www.heart.org.

For diabetes information, visit the American Diabetes Association: http://www.diabetes.org.

WomenHeart, the National Coalition for Women with Heart Disease, provides patients with education and grassroots support networks. WomenHeart is online at http://www.womenshealthresearch.org.S

Society for Women's Health Research (SWHR)1025 Connecticut Ave. NW, Ste. 701Washington, DC 20036United Stateshttp://www.womenshealthresearch.org

Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes A Randomized Controlled Trial

Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes A Randomized Controlled Trial

John B. Dixon, MBBS, PhD; Paul E. O’Brien, MD; Julie Playfair, RN; Leon Chapman, MBBS; Linda M. Schachter, MBBS, PhD; Stewart Skinner, MBBS, PhD; Joseph Proietto, MBBS, PhD; Michael Bailey, PhD, MSc(stats); Margaret Anderson, BHealthMan

JAMA. 2008;299(3):316-323.

Context Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes.

Objective To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control.

Design, Setting, and Participants Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes.
Interventions Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care.

Main Outcome Measures Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat.

Results Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group.

Conclusions Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed.

Comparison of bypass surgery with drug‐eluting stents for diabetic patients with multivessel disease

Comparison of bypass surgery with drug‐eluting stents for diabetic patients with multivessel disease

International Journal of Cardiology

Volume 123, Issue 1, Pages 34-42 (15 December 2007)

Michael S. Leea, Faizi Jamalb, Gautam Kediab, Gilbert Changb, Nikhil Kapoorb, James Forresterb, Lawrence Czerb, Raymond Zimmera, Michele DeRobertisb, Alfredo Trentob, Raj R. Makkarb


Abstract

Background

This retrospective study of prospectively collected data compared coronary artery bypass graft (CABG) surgery to drug‐eluting stenting (DES) in diabetic patients with multivessel coronary artery disease (CAD). Prior randomized trials and clinical studies have suggested that CABG may be the preferred revascularization strategy in diabetic patients with multivessel CAD. Data are limited regarding the impact of DES vs. CABG on clinical outcomes.

Methods
We included 205 consecutive diabetic patients who underwent either CABG (n=103) or DES (n=102). The primary clinical end points were freedom from major adverse cardiac events (MACE) at 30 days and 1 year.

Results
Baseline characteristics were similar between both groups. At 1 year, the mortality rate was similar in the CABG and DES group (8% vs. 10%, p=0.6) but the MACE rate was lower in the CABG group (12% vs. 27%, p=0.006) due to less repeat revascularization with CABG (3% vs. 20%, p<0.001). Stroke occurred only in the CABG group (4% vs. 0%, p=0.04). Angiographically‐documented stent thrombosis after DES occurred in 3%. Presentation with acute myocardial infarction (hazard ratio [HR], 2.26, 95% CI, 1.13 to 4.55) and DES (HR, 2.4, 95% CI, 1.23 to 4.77) were positive independent predictors, whereas therapy with a statin was a negative independent predictor of MACE (HR, 0.40, 95% CI, 0.21 to 0.76).

Conclusions
Bypass surgery was associated with less MACE primarily due to the higher repeat revascularization rate with DES and is therefore superior to DES despite more extensive CAD in CABG patients.

Primary Aldosteronism Common in Patients With Type 2 DM and Resistant Htn

Primary Aldosteronism Common in Patients With Type 2 DM and Resistant Htn

Study Highlights:

Included were 100 consecutive patients aged 18 to 75 years with type 2 diabetes for more than 3 months and treated for hypertension with at least 3 antihypertensive medications.

Resistant hypertension was defined as blood pressure greater than 140/90 mm Hg despite the use of 3 or more antihypertensive agents.

Excluded were those treated with spironolactone or eplerenone; those with glycated hemoglobin value greater than 9%, severe uncontrolled hypertension (blood pressure > 180/110 mm Hg), a history of heart failure, angina, a serum creatinine level greater than 1.8 mg/dL, hepatic disease, Cushing's disease, hyperthyroidism, or pheochromocytoma; and those who were pregnant or lactating.

Patients were screened for primary aldosteronism while taking their usual medications, because stopping blood pressure medications was considered unethical.

Blood samples were drawn in the morning after 30 minutes of rest in the sitting position.

Patients with serum potassium levels of less than 3.5 mmol/L received KCl (40 mEq) daily for 1 week and were rescreened once the potassium level was at least 3.5 mmol/L.

Screening studies included measurement of PAC and PRA and the calculation of the PAC/PRA ratio.

Patients with hypertension and a PAC/PRA ratio greater than 30 ng/mL/hour underwent further studies to confirm a diagnosis of primary aldosteronism.

Salt loading was used to confirm the diagnosis.

Urinary aldosterone was measured 3 days after a salt load or PAC was measured after an intravenous salt load of 2 L of 0.9% saline infused for 4 hours at 500 mL/hour.

Primary aldosteronism was diagnosed if the 24-hour urinary aldosterone concentration was 12 µg or greater during the third day of salt load or if PAC was 5.0 ng/dL or greater after the intravenous load.
93 patients were black, 5 were white, 1 was Hispanic, and 1 was Native American.

Mean age was 59 years, mean duration of diabetes was 8.9 years, mean duration of hypertension was 16 years, and mean body mass index was 34.4 kg/m2 with 75% having a body mass index greater than 30 kg/m2.

The mean number of antihypertensive agents taken was 3.7.

98% were taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 92% were taking a diuretic agent, 73% were taking a β-blocker, 62% were talking a calcium channel blocker, and 31% were taking an α-blocker.

Mean potassium level was 4.0 mmol/L with 15 subjects having levels below 3.5 mmol/L.

34% had an increased PAC/PRA ratio and received additional testing.

Primary aldosteronism was diagnosed in 14% of patients.

There were no differences in age, years of hypertension, years of diabetes, body mass index, blood pressure, glycated hemoglobin level, or numbers or types of antihypertensive agents used between those with and without primary aldosteronism.

Mean systolic and diastolic blood pressures were 157 and 93 mm Hg in those with primary aldosteronism and 158 and 89 mm Hg, respectively, in those without.

Those with primary aldosteronism had a lower potassium level (3.7 vs 4.0 mmol/L), lower serum creatinine level (0.9 vs 1.0 mg/dL), a higher PAC, a lower PRA, and higher PAC/PRA ratio vs those without primary aldosteronism.

Of those with resistant hypertension, 55% had suppressed PRA or salt-sensitive hypertension.

The authors concluded that patients with diabetes and poorly controlled hypertension should be screened for primary aldosteronism using the PAC/PRA ratio followed by salt-suppression testing in those with a positive ratio.


Pearls for Practice:

Resistant hypertension in patients with type 2 diabetes is defined as a persistent blood pressure of 140/90 mm Hg or higher despite treatment with at least 3 antihypertensive agents.

The prevalence of primary aldosteronism among patients with type 2 diabetes with resistant hypertension is 14%.

AHA - 2007: More Evidence of Cardiovascular Safety of Second-Generation Sulfonylureas

AHA: More Evidence of Cardiovascular Safety of Second-Generation Sulfonylureas


By Peggy Peck, Executive Editor, MedPage Today


Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine.

November 09, 2007


Primary source: American Heart Association

Source reference:

Patch RK, et al "Treatment of diabetes and outcome after myocardial infarction: a community study" AHA Meeting 2007; Abstract 3588.


ORLANDO, Nov. 9 -- Diabetes patients who used second- generation sulfonylureas had no excess one-year mortality after a myocardial infarction, researchers said here.

A community study of patients treated for MI found that the 12-month survival for diabetes patients using second-generation sulfonylureas was about 95%, versus a one-year survival of 90% for non-diabetic MI patients (P0.001), Richard K. Patch, III, M.D., of the Mayo Clinic in Rochester, Minn., and colleagues, reported at the American Heart Association meeting.


Moreover, diabetes patients treated with second-generation sulfonylureas also had significantly better one-year survival than diabetes patients using diet alone or insulin (P0.001).


After adjusting for age, sex, reperfusion, and duration of diabetes, only use of insulin was associated with excess mortality and the risk was greatest among patients with the longest history of diabetes, he said. "There was no association between sulfonylurea use and excess mortality," he said.


The concern about increased cardiovascular mortality with sulfonylureas emerged in the early 1970s, when first-generation drugs in this class began to be widely used. The likely mechanism for increased mortality was the drug's ability to bind to adenosine triphospate-sensitive potassium channels in pancreatic beta cells -- ironically the same mechanism that made the drug effective in treating diabetes.


In pancreatic cells, binding ATP keeps the potassium channels closed, which triggers an influx of calcium ions into the cell, promoting increased release of insulin via exocytosis of insulin-containing granules.


The downside to the first-generation sulfonylurea drugs was that they were not specific to ATP-sensitive potassium channels in the pancreas, but also binded to ATP-sensitive potassium channels in heart cells and vascular smooth-muscle cells. In the heart and the vasculature, this binding action impairs coronary blood flow, which limits control of ischemic damage during myocardial infarction.


But studies of second-generation sulfonylureas have reported that the drugs may reduce the risk of MI.


Against that background, Dr. Patch and colleagues studied the question of the impact of second-generation sulfonylurea on survival following MI.


They analyzed outcomes data from 2,732 MIs that occurred in Olmsted County, Minn., from 1979 through 2002. The average age of patients was 70, and women made up 56% of the cohort.


Four hundred and eighty-six of the MI patients had diabetes and 24% of them used second-generation sulfonylureas, 47% used insulin, while 22% relied on diet alone for management of diabetes.


Five hundred and eight MI patients died within a year of the incident MI.


Compared with non-diabetic MI patients, patients with diabetes were more likely to be overweight or obese, hyperlipidemic, and to have received urgent reperfusion therapy during hospitalization for treatment of the incident MI.

Resolution of Asymptomatic Myocardial Ischemia in Patients With Type 2 Diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study

Resolution of Asymptomatic Myocardial Ischemia in Patients With Type 2 Diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study

Diabetes Care 2007 30: 2892-2898

Frans J. Th. Wackers, MD, Deborah A. Chyun, PHD, Lawrence H. Young, MD, Gary V. Heller, MD, Ami E. Iskandrian, MD, Janice A. Davey, MSN, Eugene J. Barrett, MD, Raymond Taillefer, MD, Steven D. Wittlin, MD, Neil Filipchuk, MD, Robert E. Ratner, MD, Silvio E. Inzucchi, MD for the Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators



ABSTRACT


OBJECTIVE
The porrpose of this study was to assess whether the prevalence of inducible myocardial ischemia increases over time in patients with type 2 diabetes.


RESEARCH DESIGN AND METHODS
Participants enrolled in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study underwent repeat adenosine-stress myocardial perfusion imaging 3 years after initial evaluation. Patients with intervening cardiac events or revascularization and those who were unable or unwilling to repeat stress imaging were excluded.


RESULTS
Of the initial 522 DIAD patients, 358 had repeat stress imaging (DIAD-2), of whom 71 (20%) had ischemia at enrollment (DIAD-1). Of 287 patients with normal DIAD-1 studies, 259 (90%) remained normal in DIAD-2, whereas 28 (10%) developed new ischemia in DIAD-2. Of the 71 patients with abnormal DIAD-1 studies, 56 (79%) demonstrated resolution of ischemia, whereas 15 (21%) remained abnormal. During this 3-year interval, medical treatment was intensified, with more patients using statins, aspirin, and ACE inhibitors than at baseline. Patients with resolution of ischemia had significantly greater increases in these medications than patients who developed new ischemia (P = 0.04).


CONCLUSIONS
Thus, the majority of asymptomatic patients with type 2 diabetes demonstrated resolution of ischemia upon repeat stress imaging after 3 years. This resolution was associated with more intensive treatment of cardiovascular risk factors.

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus


The American Journal of Medicine


Volume 100, Issue 8, Pages 1254-1262 (15 October 2007)


Sripal Bangalore, MD, MHAa, Sanobar Parkar, MD, MPHa, Ehud Grossman, MDb, Franz H. Messerli, MDa


Beta blockers used for the treatment of hypertension may be associated with increased risk for new-onset diabetes mellitus (DM).

A search of Medline, PubMed, and EMBASE was conducted for randomized controlled trials of patients taking β blockers as first-line therapy for hypertension with data on new-onset DM and follow-up for ≥1 year. Twelve studies evaluating 94,492 patients fulfilled the inclusion criteria. Beta-blocker therapy resulted in a 22% increased risk for new-onset DM (relative risk 1.22, 95% confidence interval [CI] 1.12 to 1.33) compared with nondiuretic antihypertensive agents. A higher baseline fasting glucose level (odds ratio [OR] 1.01, 95% CI 1.00 to 1.02, p = 0.004) and greater systolic (OR 1.05, 95% CI 1.05 to 1.08, p = 0.001) and diastolic (OR 1.06, 95% CI 1.01 to 1.10, p = 0.011) blood pressure differences between the 2 treatment modalities were significant univariate predictors of new-onset DM.

Multivariate meta-regression analysis showed that a higher baseline body mass index (OR 1.17, 95% CI 1.01 to 1.33, p = 0.034) was a significant predictor of new-onset DM. The risk for DM was greater with atenolol, in the elderly, and in studies in which β blockers were less efficacious antihypertensive agents and increased exponentially with increased duration on β blockers. For the secondary end points, β blockers resulted in a 15% increased risk for stroke, with no benefit for the end point of death or myocardial infarction.

In conclusion, β blockers are associated with an increased risk for new-onset DM, with no benefit for the end point of death or myocardial infarction and with a 15% increased risk for stroke compared with other agents. This risk was greater in patients with higher baseline body mass indexes and higher baseline fasting glucose levels and in studies in which β blockers were less efficacious antihypertensive agents compared with other treatments.

High BP greatly increases women's diabetes risk

High BP greatly increases women's diabetes risk


MedWire News


10 October 2007


Eur Heart J 2007; Advance online publication


MedWire News: Women with high blood pressure (BP) levels are three times more likely to develop Type 2 diabetes than those with optimal BP levels, irrespective of their body mass index (BMI) and presence of other cardiovascular and diabetes risk factors, US study findings reveal.


The authors report in the European Heart Journal that both baseline BP and BP progression strongly predict incident Type 2 diabetes in initially healthy women, and say their findings highlight the need to consider cardiovascular risk factors in combination.


David Conen (Harvard Medical School, Boston, Massachusetts, USA) and colleagues followed-up over 38,000 female health professionals enrolled in the Women's Health Study for 10 years. The women were all free of diabetes and cardiovascular disease at study entry.


"Despite several studies finding a close relationship between hypertension and Type 2 diabetes, little information exists on the relationship between BP levels and the subsequent development of Type 2 diabetes," explained Conen. "Data for women are particularly limited."


The team divided the women into four groups: those with optimal BP (<120/75 mmHg); those with normal BP (120-129/75-84 mmHg); those with high normal BP (130-139/85-89 mmHg); and those with established hypertension (≥140/90 mmHg), and/or self-reported history of hypertension or antihypertensive treatment.


At follow-up, the incidence of Type 2 diabetes was 1.4% in the optimal BP group, 2.9% in those with normal BP, 5.7% in high-normal BP participants, and 9.4% in the established hypertension group.


Multivariable adjusted hazard ratios (HRs) for diabetes across the BP categories were 0.66, 1.00 (referent group), 1.45, and 2.03 (p for trend <0.0001).


Stratification by BMI gave similar results. "Analyses showed that the relationship... was similar among women who were normal weight, overweight, or obese," Conen reported. "There was a three-fold increase in risk from the lowest to the highest BP category within all three weight categories."


Women whose BP increased over time during the study also had an increased risk for developing diabetes. Adjusted HRs for incident diabetes at 2 years among women who had no BP progression, those in whom BP increased but remained normotensive, and women who developed hypertension were 1.0, 1.26, and 1.64, respectively, compared with 2.39 in women with baseline hypertension (p for trend <0.0001).


The authors conclude: "Our findings provide strong evidence that BP and progression of BP are associated with an increased risk of diabetes. They highlight the fact that cardiovascular risk factors are interrelated and occur in clusters.


"Thus, an important message for physicians and future guidelines is that none of the cardiovascular risk factors should be looked at individually. The combination of all risk factors should be used to make treatment decisions."


Journal

Aerobic, Resistance Training Improve Glycemic Control in Type 2 Diabetes

Aerobic, Resistance Training Improve Glycemic Control in Type 2 Diabetes


Both aerobic and resistance training help lower hemoglobin A1c levels in patients with type 2 diabetes — and a combination of the two is even more beneficial — researchers report in Annals of Internal Medicine.


Some 250 inactive diabetes patients were randomized to one of four groups: aerobic training, resistance training, both, or no exercise. The active-treatment groups exercised 3 times weekly for 22 weeks.

Adjusted absolute HbA1c levels fell significantly with aerobic training (-0.51 percentage point vs. no exercise) and resistance training (-0.38); the combination-exercise group saw additional reductions (-0.46 vs. aerobic training, -0.59 vs. resistance training). Changes in blood pressure and lipids did not differ among the groups.

The authors cite research showing a 15% to 20% reduction in major cardiovascular events with a 1-percentage-point decrease in HbA1c. Editorialists note limitations of the current study but conclude: "Failing to prescribe exercise to patients with diabetes is simply unacceptable practice."


Annals of Internal Medicine article (Free)


Annals of Internal Medicine editorial (Subscription required)

Metformin linked to reduced mortality in diabetic patients with HF

Metformin linked to reduced mortality in diabetic patients with HF

7 September 2007

MedWire News: Metformin is associated with reduced mortality in patients with heart failure (HF) and diabetes, Canadian researchers report in the British Medical Journal.

HF is common in diabetic patients, but few studies have compared the effect of antidiabetic drugs in patients with both conditions, the authors say.

Jeffrey Johnson, from the University of Alberta in Edmonton, and colleagues therefore carried out a meta-analysis of eight studies to evaluate the effects of antidiabetic agents in patients with HF and diabetes.

Four studies evaluated the effect of insulin treatment, three examined metformin, four evaluated thiazolidinediones, and two studies compared sulfonylureas with other agents.

Insulin use was associated with increased risk for all cause mortality in studies that did not adjust for diet and antidiabetic drug treatment (odds ratio [OR]=1.25), and in the studies that accounted for these factors (hazard ratio [HR]=1.66).

• 
  In contrast, all cause mortality was significantly lower in patients treated with metformin, at a HR of 0.86 compared with other antidiabetic drugs and insulin, and at a HR of 0.70 compared with sulfonylureas.

In addition, metformin was not associated with increased hospital admission at 1 year for any cause (HR=0.94) or for HF (HR=0.92). The pooled effect suggested that treatment with metformin might be linked to a reduced all cause hospital admission at 1 year (pooled OR=0.85).
Thiazolidinediones were associated with reduced all cause mortality (pooled OR=0.83), but they were also linked to an increased risk for hospital admission for HF (pooled OR=0.83). The researchers note that this conflicting result might be due to differences in comparator treatments.

Johnson and co-workers conclude: "Our analysis revealed that treatment with metformin may be associated with lower mortality rates."

Nevertheless, they note that the US Food and Drug Administration still recommends cautious use of metformin in this population.

Br Med J 2007; 335: 497

FDA Announces Boxed Warnings on All Thiazolidinediones

FDA Announces Boxed Warnings on All Thiazolidinediones


The entire class of thiazolidinedione drugs used to treat type 2 diabetes must carry boxed warnings about the drugs' ability to cause or worsen heart failure, the FDA announced late yesterday.

The affected drugs are Avandia (rosiglitazone), Actos (pioglitazone), Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).

The action addresses the FDA's worry that "despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure," says the agency's chief of drug evaluation and research.

FDA announcement (Free)
Rosiglitazone alert (Free)
Pioglitazone alert (Free)

Diabetes and Mortality Following Acute Coronary Syndromes

Diabetes and Mortality Following Acute Coronary Syndromes

JAMA. 2007;298:765-775.

Sean M. Donahoe, MD; Garrick C. Stewart, MD; Carolyn H. McCabe, BS; Satishkumar Mohanavelu, MS; Sabina A. Murphy, MPH; Christopher P. Cannon, MD; Elliott M. Antman, MD

Context The worldwide epidemic of diabetes mellitus is increasing the burden of cardiovascular disease, the leading cause of death among persons with diabetes. The independent effect of diabetes on mortality following acute coronary syndromes (ACS) is uncertain.

Objective To evaluate the influence of diabetes on mortality following ACS using a large database spanning the full spectrum of ACS.

Design, Setting, and Patients A subgroup analysis of patients with diabetes enrolled in randomized clinical trials that evaluated ACS therapies. Patients with ACS in 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials from 1997 to 2006 were pooled, including 62 036 patients (46 577 with ST-segment elevation myocardial infarction [STEMI] and 15 459 with unstable angina/non-STEMI [UA/NSTEMI]), of whom 10 613 (17.1%) had diabetes. A multivariable model was constructed to adjust for baseline characteristics, aspects of ACS presentation, and treatments for the ACS event.
Main Outcome Measures Mortality at 30 days and 1 year following ACS among patients with diabetes vs patients without diabetes.

Results Mortality at 30 days was significantly higher among patients with diabetes than without diabetes presenting with UA/NSTEMI (2.1% vs 1.1%, P < .001) and STEMI (8.5% vs 5.4%, P < .001). After adjusting for baseline characteristics and features and management of the ACS event, diabetes was independently associated with higher 30-day mortality after UA/NSTEMI (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.24-2.56) or STEMI (OR, 1.40; 95% CI, 1.24-1.57). Diabetes at presentation with ACS was associated with significantly higher mortality 1 year after UA/NSTEMI (hazard ratio [HR], 1.65; 95% CI, 1.30-2.10) or STEMI (HR, 1.22; 95% CI, 1.08-1.38). By 1 year following ACS, patients with diabetes presenting with UA/NSTEMI had a risk of death that approached patients without diabetes presenting with STEMI (7.2% vs 8.1%). Conclusion Despite modern therapies for ACS, diabetes confers a significant adverse prognosis, which highlights the importance of aggressive strategies to manage this high-risk population with unstable ischemic heart disease.

Hostile Men Could Have Greater Risk For Heart Disease

Hostile Men Could Have Greater Risk For Heart Disease

Brain, Behavior, and Immunity, 21(6), 2007.

05 Aug 2007

Men who are hostile and prone to frequent intense feelings of anger and depression could be harming their immune systems and putting themselves at risk for coronary heart disease as well as related disorders like type 2 diabetes and high blood pressure, a new study finds.

Steven Boyle, Ph.D., of Duke University Medical Center and colleagues studied 313 male Vietnam veterans who were part of a larger 20-year study on the effects of Agent Orange.

For the study, which appears in the August issue of the journal Brain, Behavior, and Immunity, the veterans underwent a standard psychological test used to assess hostility, depression and anger.

The men had a series of blood levels taken on three occasions between 1992 and 2002.

Researchers measured two immune system proteins known as C3 and C4. Both are markers of inflammation, which is the body's response to injury or infection. Changes in C3 and C4 are associated with a number of diseases, including some that negatively can affect the arteries around the heart, such as diabetes.

Men whose psychological screening showed the highest level of hostility, depressive symptoms and anger had a 7.1 percent increase in their C3 levels, while men with low levels of these attributes showed no change over the 10-year study period.

The researchers factored in other risk factors for higher C3 levels such as smoking, age, race, alcohol use and body mass index (a measure of obesity). They also could find no known influence of Agent Orange exposure on the increased C3 levels.

"We showed positives associations between psychological attributes and 10-year changes in C3 among initially healthy middle-aged males," the researchers write. Neither group showed significant increases in C4 levels. "Hostile, depressed and angry people see the world around them in a different way, and sometimes they see it as them against the world," said study co-author Edward Suarez, Ph.D.

"That kind of lifestyle often leads to greater stress and possibly changes in the way the body functions that could lead to disease.

"Could psychological treatment reduce C3 levels? "At present, we do not know if interventions to reduce hostility and anger would lead to a decrease in C3 or other markers of inflammation," Boyle said. However, he added, "Even if inflammation is not decreased by such interventions, lower levels of anger and hostility will likely lead to better relationships and increased well-being.

Boyle SH, Jackson WG, Suarez EC. Hostility, anger, and depression predict increases in C3 over a 10-year period. Brain, Behavior, and Immunity, 21(6), 2007.

The EVASTENT Matched-Cohort Registry

Risk Factors for Stent Thrombosis After Implantation of Sirolimus-Eluting Stents in Diabetic and Nondiabetic Patients

The EVASTENT Matched-Cohort Registry

Objectives: We sought to assess the frequency and causes of stent thrombosis in diabetic and nondiabetic patients after implantation of sirolimus-eluting stents.

Background: Safety concerns about late stent thrombosis have been raised, particularly when drug-eluting stents are used in less highly selected patients than in randomized trials.

Methods: The EVASTENT study is a matched multicenter cohort registry of 1,731 patients undergoing revascularization exclusively with sirolimus stents; for each diabetic patient included (stratified as single- or multiple-vessel disease), a nondiabetic patient was subsequently included. Patients were treated with aspirin + clopidogrel for at least 3 months and were followed for 465 (range 0 to 1,062) days (1-year follow-up in 98.5%). The primary end point was a composite of stent thrombosis (according to Academic Research Consortium definitions), cardiovascular death, and nonfatal myocardial infarction (major adverse cardiac events [MACE]).

Results: During follow-up, MACE occurred in 78 patients (4.5%), cardiac death in 35 (2.1%), and stent thrombosis in 45 (2.6%): 30 definite, 23 subacute, and 22 late, including 9 at >6 months. In univariate analysis, the 1-year stent thrombosis rate was 1.8 times higher in diabetic than in nondiabetic patients (3.2% vs. 1.7%; log rank p = 0.03), with diabetic patients with multiple-vessel disease experiencing the highest rate and nondiabetic single-vessel disease patients the lowest (4.3% vs. 0.8%; p < 0.001). In multivariate analysis, in addition to the interruption of antithrombotic treatment, independent stent thrombosis predictors were previous stroke, renal failure, lower ejection fraction, calcified lesion, length stented, and insulin-requiring diabetes.

Conclusions: The risk of sirolimus stent thrombosis is higher for multiple-vessel disease diabetic patients.

FDA Advisers Vote to Keep Rosiglitazone (Avandia) But Cite Risks

FDA Advisers Vote to Keep Rosiglitazone (Avandia) But Cite Risks

MedPage Today Action Points

GAITHERSBURG, Md., July 30—

FDA advisers agreed today that although rosiglitazone (Avandia) increases ischemic heart risks for type 2 diabetes patients, it should stay on the market.

Members of two FDA advisory panels, meeting jointly, voted 22 to one in favor of continued marketing. Arthur Levin, M.P.H., of the Center for Medical Consumers in New York cast the lone dissenting vote, citing public health issues.

Meanwhile, GlaxoSmithKline, said it applauded the FDA advisers' recommendation as "a positive for patients," according to press release.

Although advisors voted overwhelmingly to recommend that the FDA keep the drug on the market, they also made it clear that they want to see a much narrower market for rosiglitazone.

Almost every one of advisers who said they wanted the drug to stay on the market offered the same advice about future labeling of the drug—additional warnings.

Clifford Rosen, M.D., the Bangor, Me., endocrinologist who chaired the meeting, said the drug should not be used by patients requiring insulin, those with a history of coronary heart disease, those with congestive heart failure, and those who are long-time users of nitrates.

The advisers didn't sort out specifics of the new warnings although nearly all used terms like black box or boxed warning. But Robert Meyer, M.D., director of new drug evaluation at the FDA's Center for Drug Evaluation and Research, said at a press conference that it wasn't clear to him that black box warnings had been recommended.

In any case, Dr. Meyer pointed out, while the FDA might follow the advice given by advisory committees the exact actions—and the timing of those regulatory actions—are up to the agency.

He also noted that the FDA has already asked GlaxoSmithKline and Takeda, which makes pioglitazone (Actos), another thiazolidinedione, to add a boxed warning about the risk of congestive heart failure to the labels of their respective drugs.

In an unusual move for agency officials, who normally are reluctant to make on-the-record comments about drugs under review, both Gerald Dal Pan, M.D., M.P.H., director of the FDA's Office of Surveillance and Epidemiology, and David Graham, M.D., M.P.H. associate director of that office, said during the meeting they thought rosiglitazone should be taken off the market.

Dr. Graham said the "point estimates of the relative risk of cardiovascular deaths and non-fatal MIs range from 1.20 to 1.40 to 1.70 for rosiglitazone.

"Using those estimates, Dr. Graham calculated that there are "1,600 to 2,500 excess MIs and ischemic heart disease deaths for every month that rosiglitazone stays on the market."

The panel also agreed that the strongest evidence of ischemic heart disease risk with rosiglitazone came from three meta-analyses of randomized clinical trials—one by GSK, another by FDA staffers, and an analysis done by Steven Nissen, M.D., of the Cleveland Clinic.

Dr. Nissen's analysis, which was published online May 21 by the New England Journal of Medicine, was widely regarded as the spark that turned mild concern about the cardiovascular safety of the drug into a cause célèbre. The analysis, which included data from 42 trials, found a 43% increase in risk of myocardial infarction with rosiglitazone.

Dr. Nissen was asked to serve as a consultant to the advisory panel, but he functioned under a strict set of ground rules that prevented him from sitting at the table with other consultants. He was also allowed to speak only in answer to questions about his meta-analysis and was instructed to refrain from commenting on any of the data presented at the meeting.

Before the meeting Dr. Nissen hinted broadly that he thought the drug should be pulled from the market, but in an interview immediately after the meeting he said he was pleased with the advisers’ actions. Noting that the advisers agreed with his finding of excess risk with rosiglitazone, he said the recommended warnings will be helpful "physicians follow those warnings."

Avandia raises heart risks, FDA finds

Avandia raises heart risks, FDA finds

The strongest available warning against the widely used diabetic drug is recommended.

By Thomas H. Maugh II and Denise Gellene, Times Staff Writers

July 27, 2007

The widely used diabetes drug Avandia increases the chance of serious heart problems, including a 30% to 40% higher risk of myocardial ischemia, or decreased flow of blood to the heart, according to documents released by the Food and Drug Administration on Thursday.

Diabetics taking the GlaxoSmithKline drug in combination with insulin were at even greater risk, the FDA found in a review of dozens of drug studies.

The analysis also found hints that pre-diabetics taking Avandia with ACE inhibitors, a class of heart drugs used for lowering blood pressure, faced a higher risk of myocardial ischemia.

FDA's division of drug risk evaluation concluded that the agency should issue the strongest available warning about the risk of myocardial ischemia in people who use Avandia, the documents showed.

The proposed "black box" warning would state that patients with heart disease or who are taking insulin should not use the drug.

Actos, or pioglitazone, a drug manufactured by Takeda Pharmaceutical Co. and in the same class as Avandia, carried no similar risks, according to the FDA analysis.

The documents were released in advance of an FDA advisory panel meeting on Monday to review the drug's safety. The panel could recommend stronger warnings or withdraw the drug from the market. The FDA isn't required to follow the advice of its outside experts but typically does.

In May, a study in the New England Journal of Medicine linked Avandia to a 43% increase in the risk of heart attacks. The study was led by Dr. Steven Nissen, a cardiologist at the Cleveland Clinic in Ohio and a nonvoting member of the FDA panel.

After publication of that study, the FDA issued an alert reassuring patients that it had two studies that showed Avandia was safe.

But in the newly released documents, Dr. David Graham, a safety reviewer, said one of the studies was unreliable and could not be used to resolve safety concerns.

Used daily by nearly a million Americans with Type 2 diabetes to control blood sugar, Avandia had sales of $3.4 billion in 2006. However, sales have slumped 20% since May and could further drop if the panel recommends additional warnings.

Dr. Anne Phillips, vice president of clinical development at GlaxoSmithKline, said company studies of 400,000 patients showed "no increase in cardiovascular mortality, no increased risk of myocardial infarctions [heart attacks] and no increase in mortality from all causes.

"The findings were not available to FDA staffers when they prepared the documents released Thursday, she said.

Thiazoladinediones increase HF risk

Thiazoladinediones increase HF risk

27 July 2007

Diabetes Care 2007; 2007: Advance online publication

MedWire News:

Thiazolidinediones used to lower blood glucose levels in Type 2 diabetes patients may double the risk of heart failure (HF), review findings indicate.

Based on the review of studies and case reports, researchers estimate that one additional patient with Type 2 diabetes would develop HF for every 50 patients taking one of the drugs over a 26-month period.

"These drugs are currently used by more than 3 million diabetic patients in the USA alone, suggesting that several thousand could be harmed," said lead author Sonal Singh, from Wake Forest University in Winston-Salem, North Carolina, USA.

Singh and colleagues analyzed evidence from randomized controlled trials (RCTs), controlled observational studies, anecdotal case reports, case-series, and spontaneous reports in the Canadian Adverse Events Database (CADRMP).

They identified three RCTs including 10,731 patients who provided numerical information on HF events. A meta-analysis of these trials revealed an odds ratio for HF of 2.1 (p=0.03) in patients receiving a thiazolidinedione compared with those on placebo.

Based on this odds ratio, the estimated number-needed-to-harm with thiazolidinediones would be 50 over a 2.2 year follow-up period, the authors note in the journal Diabetes Care.

Meanwhile, results of four observational studies including 67,382 patients gave a pooled odds ratio for HF of 1.5 (p<0.00001) for those taking thiazolidinediones.

A Dose-Time-Susceptibility analysis of 28 published reports and 214 spontaneous reports from CADRMP showed that HF was more likely to appear after several months, with a median duration for HF onset of 24 weeks (range 1 to 260 weeks). Patients on low doses were also at risk of developing HF soon after treatment.

One patient on low-dose (=15 mg) pioglitazone and nine patients on low-dose (=4 mg) rosiglitazone developed HF within the first 4 weeks of therapy. And HF did not develop much earlier overall in patients receiving high doses of the drugs compared with those on low doses.

"The occurrence of HF several months after initiation of treatment suggests a long-term effect of the drugs, which may not be avoided by beginning with low doses," Singh commented.

Furthermore, the increased risk was not limited to the elderly, with one-quarter of cases of HF occurring in people younger than 60 years old. HF occurred with equal frequency in men and women.

Package inserts for the drugs warn against their use in patients with severe heart failure, and of an increased risk of HF in patients on insulin. But the current analysis indicates that the risk is not confined to patients with HF risk factors or those who are on insulin, the authors report.

"Our findings support current efforts by the [US] Food and Drug Administration to add a black box warning to the labeling of those agents," commented co-investigator Curt Furberg, also of Wake Forest University.

Rosiglitazone (Avandia) Seen No Better than Other Drugs in Diabetic Control

Teaching Brief® - MedPage Today

Rosiglitazone (Avandia) Seen No Better than Other Drugs in Diabetic Control

Primary source: Cochrane Database of Systematic ReviewsSource reference: Richter B et al "Rosiglitazone for type 2 diabetes mellitus." Cochrane Database of Systematic Reviews 2007; Issue 3 Art.No.: CD006063. DOI: 10.1002/14651858.CD006063.pub2.

In many ways the Cochrane review echoed conclusions of a systematic review published Monday in the Annals of Internal Medicine which found that older drugs were as effective as rosiglitazone and pioglitazone and were less expensive as well. ( See For Type 2 Diabetes, Older Drugs Seem Tried and True)