Patients taking rosiglitazone have a similar risk for acute myocardial infarction (AMI), acute heart failure (AHF), and all-cause mortality as patients taking pioglitazone, US researchers suggest.

Previous studies have reported that rosiglitazone increases the risk for AMI compared with other thiazolidinediones (TZDs) and hypoglycemic agents, and as a result, additional warnings and restrictions were issued against rosiglitazone by the US Food and Drug Administration (FDA) in July 2010.

However, Debra Wertz (HealthCore, Inc, Wilmington, Delaware) and team explain that their findings may help to rectify rosiglitazone’s current reputation as a high-risk drug.

They say: “Given that rosiglitazone is scheduled for review with the FDA later this year, it will be important for the FDA to have available all evidence for consideration at that time.”

Wertz et al assessed the occurrence of AMI, AHF, and all-cause mortality among 36,628 patients with diabetes who were newly treated with rosiglitazone (n=18,319) or pioglitazone (n=18,309) between 2001 and 2005.

During this period, 4.16% (602) and 4.14% (599) of patients treated with rosiglitazone and pioglitazone, respectively, had an AMI, AHF, or died.

After adjusting for confounding factors, such as age and gender, the team found very similar rates of adverse outcomes associated with each drug, with an event rate per 1000 person-years of 6.18 and 6.74 for AMI, 13.23 and 11.86 for AHF, and 11.44 and 11.22 for all-cause death, in patients taking rosiglitazone and pioglitazone, respectively.

In the journal Circulation: Cardiovascular Quality and Outcomes, the researchers say: “Besides its findings that rosiglitazone and pioglitazone have comparable risks, what distinguishes this latest study from other claims-based is its analysis of death records, which include out-of-hospital deaths.”

They add: “This study provides valuable results that contrast previously published observational data and adds to the body of evidence available for risk-benefit profile assessment of TZDs in the treatment of diabetes.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

Dutch researchers report that slightly elevated B-type natriuretic peptide (BNP) levels are associated with increased left ventricular (LV) mass and diastolic dysfunction in patients with Type 2 diabetes.

This association persists irrespective of age and other traditional cardiovascular disease (CVD) risk factors, and is also present, but less pronounced, in patients without diabetes.

Katja van den Hurk and colleagues from the VU University Medical Center in Amsterdam, say their findings imply “that potential risk estimations based on BNP levels should take the presence or absence of Type 2 diabetes into account, since it amplifies the associations.”

The team recruited 197 participants with normal glucose metabolism (NGM), 128 patients with impaired glucose metabolism (IGM), and 204 patients with Type 2 diabetes.

All patients had normal LV wall motion and BNP levels <50 pmol/l (median 4.2 pmol/l).

As reported in the European Journal of Heart Failure, van den Hurk and colleagues found that BNP levels positively correlated with LV mass and LV diastolic dysfunction, with a mean LV mass of 37 and 45 g/m^2.7 among males and 39 and 43 g/m^2.7 among females with BNP levels <2.8 and >6.7 pmol/l, respectively.

Of note, age and blood pressure also increased with BNP.

After adjustment for CVD risk factors such as age and smoking, the team found a stronger association between elevated BNP levels and LV diastolic dysfunction among patients with diabetes compared with those with IGM or NGM.

The researchers say that their findings imply that “the higher CVD and mortality risk associated with higher BNP levels in a non-heart failure (HF) range [of <200 pmol/l] result from a deteriorated LV diastolic function and LV hypertrophy but not from LV systolic function.”

They conclude that the mildly elevated BNP levels in patients with diabetes may help identify and treat Type 2 diabetes patients at high risk for CVD mortality.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

Results from the Heart and Soul Study show that patients with stable coronary artery disease (CAD) who have diabetes are at increased risk for developing heart failure (HF) compared with nondiabetics with CAD.

The researchers also found that among those with diabetes, each 1% increase in the concentration of glycated hemoglobin (HbA1c) was associated with a 36% increase in relative risk for being hospitalized with HF.

Joost van Melle (University of Groningen, The Netherlands) and team enrolled 839 participants with stable CAD, but no history of HF. Of these, 200 (23.8%) had Type 2 diabetes.

The participants were followed up for a mean of 4.1 years for incidence of HF. The researchers found that those with diabetes at baseline had a significant 2.17-fold increased risk for developing HF over the study period compared with nondiabetics.

Adjustment for CAD risk factors, myocardial infarction in the interim, and myocardial ischemia did not significantly alter the association between diabetes and HF in these patients.

Following further adjustment for HF risk factors such as left ventricular ejection fraction, diastolic dysfunction, and C-reactive protein, as well as use of medication, the association grew stronger, with diabetic CAD patients having a significant 3.34-fold increased risk for HF compared with their nondiabetic peers.

Within the group with diabetes, higher levels of HbA1c were associated with increased HF risk, note the authors.

The Heart and Soul Study was set up to study longitudinal psychosocial factors and health outcomes in patients with stable CAD from the San Francisco area in the USA. van Melle and team excluded 185 patients from the original study cohort due to existing HF or unknown HF status.

Various theories have been suggested to explain the link between diabetes and HF. “In our study, the strength of the association between diabetes and HF did not attenuate after adjustment for established risk factors for HF, suggesting that traditional risk factors are not responsible for the detrimental association, giving fuel to the diabetic cardiomyopathy hypothesis,” conclude the investigators.

The results of this study are published in the journal Diabetes Care.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

Variation in the NFATC2 (nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2) gene is associated with increased risk for rosiglitazone-associated edema, show results from a subanalysis of the DREAM trial.

The Diabetes REduction and Assessment with ramipril and rosiglitazone Medication (DREAM) trial was set up to assess whether rosiglitazone could prevent progression to Type 2 diabetes in patients with impaired fasting glucose and/or tolerance.

Consistent with previous findings, patients who were assigned to take rosiglitazone had a higher rate of congestive heart failure and peripheral edema than those who did not. Overall, 22.3% of the rosiglitazone versus 14.5% of the placebo group experienced peripheral edema.

In this study, James Engert (McGill University, Montreal, Quebec, Canada) and colleagues tested the hypothesis that the increased rate of edema with rosiglitazone could have a genetic basis. They genotyped 965 European participants in the DREAM trial for 32,088 single nucleotide polymorphisms (SNPs) with a possible association with edema.

Among the participants, 26.2% of those who received rosiglitazone and 16.1% of those who received placebo experienced edema.

One SNP, rs6123045, located in the NFATC2 gene, was significantly associated with edema in Europeans.

Among individuals treated with rosiglitazone, those with two copies of the risk allele were 2.89-fold more likely to have edema than those with two copies of the protective allele. Heterozygous individuals (one copy of each allele) had an intermediate risk. There was also an association between rs6123045 and an increased risk for edema in the participants treated with placebo, but it was nonsignificant.

The researchers tested for an interaction between the effects of rs6123045 and rosiglitazone on the risk for edema using logistic regression analysis and found that there was a significant association.

The team notes that “rs6123045 was not significantly associated with thiazolidinedione (TZD)-induced edema in Latin Americans,” but says that six other SNPs in NFATC2 did show an association with edema in both Europeans and Latin Americans.

“Identifying the specific genetic variants interacting with TZDs and resulting in edema or cardiovascular events may have important clinical consequences and enable genetic variant directed use of TZD drugs among people with dysglycemia,” suggest the authors in the journal Diabetes Care.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

Patients with mild to moderate heart failure (HF) who also have Type 2 diabetes gain no apparent survival benefit from being obese, show study results.

These findings are in contrast with previous results obtained for obese nondiabetics with HF showing a paradoxical survival benefit in these patients compared with nonobese individuals with HF.

As obesity complicates treatment for Type 2 diabetes, Ali Ahmed (University of Alabama at Birmingham, USA) and colleagues assessed whether the “obesity paradox” was present in patients with HF and diabetes.

They report results from 7788 patients with chronic mild to moderate HF with a body mass index (BMI) above 20 kg/m², 2153 (29%) of whom had Type 2 diabetes. The participants were followed up for 38 months on average.

Overall, 798 (37%) and 1162 (22%) of the diabetic and nondiabetic patients, respectively, were obese (BMI of 30 kg/m² or above) at baseline.

Obese and nonobese pairs with and without diabetes were compared by the researchers.

Writing in the European Journal of Heart Failure, the team reports that all-cause mortality occurred in 38% of obese and 39% of nonobese patients with HF and diabetes.

In contrast, 23% of obese versus 27% of nonobese patients with HF but no diabetes died from any cause over the follow-up period, a statistically significant difference.

“The lack of association between obesity and mortality in HF patients with diabetes mellitus is intriguing,” say Ahmed and team.

“Recent evidence suggests that obesity may not be an independent predictor of mortality but its effects are mediated through variables such as diabetes mellitus and hypertension which are on the biological pathway of obesity and cardiovascular disease,” they explain.

“Therefore, it is possible that the presence of diabetes mellitus is a much stronger predictor of outcome than obesity per se and largely offsets any effect of obesity, even a protective one. This hypothesis is further corroborated by the striking difference in mortality between obese patients with and without diabetes mellitus.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

High systolic (S) and low diastolic (D) blood pressure (BP) increase the risk for cardiovascular disease (CVD) events in patients with Type 2 diabetes, report researchers from the Veterans Affairs Diabetes Trial (VADT).

Previous research has demonstrated the health benefits of lowering BP in both diabetic and nondiabetic patients with higher than normal values. However, specific SBP and DBP targets for preventing CVD events in diabetic patients have not been confirmed.

Robert Anderson (Veterans Affairs Medical Center, Omaha, Nebraska, USA) and colleagues therefore evaluated the CVD event risk of 1791 Type 2 diabetic participants of the VADT who received treatment for hypertension to achieve a BP below 130/80 mmHg.

BP levels of the participants were assessed at baseline, at a mean age of 60.4 years, and after 7 years of treatment. At baseline, the mean body mass index was 31 kg/m2 and average glycated hemoglobin was 9.4%.

The team found that having a SBP at or above 140 mmHg both at baseline and on-study increased the risk for CVD events (myocardial infarction, stroke, congestive heart failure, vascular surgery, coronary artery disease, amputation for ischemic gangrene, or CVD death) by a significant 51% and 47%, respectively, compared with lower levels.

Conversely, having a DBP below 70 mmHg at baseline and during the study was associated with corresponding significant increased risks of 48% and 49% for CVD events versus higher levels.

Having both a SBP at or above 140 mmHg and a DBP below 70 mmHg at baseline or during the study raised the risk further and resulted in increased risks for CVD events of 1.79- and 2.04-fold, respectively, compared with having a lower SBP and higher DBP.

“Our results raise awareness of the increased CVD risk of DBP below 70 mmHg with 105-129/70-79 mmHg as a reasonable BP target range for patients with Type 2 diabetes,” write the authors in the journal Diabetes Care.

They add: “Future research questions include whether BP control changed outcomes for individual patients in higher-risk SBP or DBP categories. We also plan to investigate the potential associations of these high-risk BP categories with microvascular events.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

Free abstract

Diabetes is serious. And high blood glucose can be a scary thing. But mainline medicine embraces the idea that you can take control and lower blood sugar naturally. Here are two keys to get you off on the right path.

1. Keep the faith. For a diabetic or a pre diabetic, it’s not pablum. Your attitude makes a measurable difference in your risk factors.

The paradox is that a diabetic (or pre diabetic) who is making good choices and controlling their blood glucose may end up healthier than a non diabetic who isn’t conscious of their lifestyle (and insurance companies are realizing this, so don’t think you can’t get insurance!). And it’s not just your discipline. Your attitude makes a huge difference as well.

When you’re positive - engaging your problems with glucose as a challenge - you’re more likely to plan, to schedule, and to stay on your regimen. You’re also putting chemicals in your body that make you healthier. In a study published in 2001, Dr. LS Berk showed that laughing reduces epinephrine levels and arterial inflammation which decreases a diabetic’s risk of heart failure and other complications.

Wherever you are in your process with diabetes, the more you treat it as manageable, the more it will be.

2. Keep exercising! Don’t become complacent. For some reason there’s myth floating around that people with diabetes shouldn’t exercise. Like all myths, it has its root in fact. There are particular situations that would indicate you should stop exercising - if you have hemorrhaging in your eye or severe neuropathy. And there are times when you should consult your doctor first - if you have retinopathy, are coming off an injury, or are over 40 and haven’t exercised in a while, for instance.

But in general every person with diabetes ought to exercise regularly. Add 5,000 walking steps a day (about 2 1/4 miles) to your normal routine, and strengthen your muscles - lift light weights, do mountain climbing or cross-country skiing, or play some tennis. Do something where you’re using your arms.

While diabetes is still the leading cause of blindness and kidney failure in America, that’s not the final destination for every diabetic journey. In fact, you have more resources than ever to reverse the damage glucose is doing to your body.

Here’s your third key:

3. Get on a regimen that you can absolutely depend on to help you lower blood sugar naturally and help you keep it low so you stop the damage as soon as possible and start to heal.

Quick-release (QR) bromocriptine is a well tolerated and effective therapy for Type 2 diabetes and is not associated with increased cardiovascular (CV) risk, report researchers.

Bromocriptine, a D2 dopamine receptor agonist, is used to treat conditions such as pituitary tumors and Parkinson’s disease. It has recently been shown to significantly reduce glycated hemoglobin (HbA1c) levels by around 0.5% and is now indicated for treatment of patients with Type 2 diabetes.

However, previous studies have been underpowered to assess cardiovascular safety of the drug. To test the overall safety and tolerability of bromocriptine for treatment of Type 2 diabetes, J Michael Gaziano (Harvard Medical School, Boston, Massachusetts, USA) and colleagues randomly assigned 3095 patients with Type 2 diabetes in a 2:1 fashion to take QR bromocriptine (titrated to a maximum of 4.8 mg/day) or placebo, both in addition to their usual diabetes therapy, for a period of 52 weeks.

All adverse events were assessed, with a particular focus on CV disease events - including a combined endpoint of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure.

As reported in the journal Diabetes Care, 89% of the bromocriptine group and 83% of the placebo group reported some form of adverse events. In addition, 176 (8.6%) people in the bromocriptine group reported serious adverse events and 98 (9.6%) in the placebo group.

The combined CV disease endpoint was reported by 37 (1.8%) of the bromocriptine group compared with 32 (3.2%) of the placebo group.

The most commonly reported bromocriptine associated adverse event was nausea, reported in 7.6% of the bromocriptine treated patients compared with only 1.0% of the placebo group.

“Nausea was the chief limiting adverse event in this trial. For the majority of patients experiencing nausea, the symptoms occurred during the initial titration of the drug and lasted less than 2 weeks,” write the authors.

“Bromocriptine-QR represents a new treatment modality for Type 2 diabetes,” conclude Gaziono et al. “This first-in-class therapy may provide a new approach to addressing the comorbidities associated with Type 2 diabetes.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Free abstract

New results from a post-hoc analysis of the
BARI-2D trial show no association between rosiglitazone and
cardiovascular (CV) events.

However, the results confirmed previously reported links between
rosiglitazone and fracture.

Richard Bach (Washington University School of Medicine, St
Louis, Missouri, USA) presented the results of a post-hoc study of
2368 patients enrolled in the BARI-2D (Bypass Angioplasty
Revascularization Investigation 2 Diabetes) study at the American
Diabetes Association 2010 Scientific Sessions held in Orlando,
Florida.

The patients all had Type 2 diabetes and
angiographically-confirmed coronary artery disease (CAD) plus at
least one significant lesion suitable for revascularization. The
trial aimed to assess the long-term outcomes of rosiglitazone
therapy.

The main results of BARI-2D have already been published.
Patients were randomized to treatment with prompt revascularization
and medical therapy versus medical therapy and delayed or no
revascularization, and to insulin sensitization versus insulin
provision. The findings showed that the rate of overall survival
and freedom from CV events did not vary significantly between the
different treatment groups, as previously reported by MedWire
News.

For the purposes of this study, Bach and team compared 992
patients treated with rosiglitazone with 1199 patients who were not
treated with a thiazolidinedione (TZD).

At baseline, the patients were aged 62 years on average, had a
mean glycated hemoglobin level of between 7.5% and 7.8%, and had
had diabetes for approximately 10 years. In addition, a quarter of
patients in both groups had undergone prior revascularization.

Bach reported that, at 4.5 years, patients taking rosiglitazone
had a significantly lower rate of stroke and the combination of
death, myocardial infarction (MI), and stroke per 100 patient years
compared with patients not treated with TZDs. In addition, the rate
of death and MI were non-significantly lower, and chronic heart
failure was non-significantly higher in rosiglitazone-treated
patients.

Co-administration with insulin, metformin, nitrates, and
angiotensin-converting enzyme inhibitors, did not significantly
influence the rate of CV outcomes in rosiglitazone treated
patients.

Notably, as found in previous studies, the relative risk for
fracture was a significant 62% higher in rosiglitazone-treated
patients than in those who took no TZDs. When stratified by gender,
the increase in relative risk was statistically significant in
women only, at 82%.

Bach acknowledged that the study was limited by its
non-randomized nature and added that the fact that many patients on
the study were taking more than one anti-diabetic drug might have
limited the ability of the researchers to discriminate the effects
of any one drug from another.

“I think these data are important because they suggest there is
no significant cardiovascular harm posed by taking rosiglitazone
for patients with Type 2 diabetes and coronary heart disease,” said
Bach.

These new data “contribute to the scientific inquiry regarding
associated events with rosiglitazone.”

He added: ” There is an increase in fractures, but when one
considers the dramatic morbidity and mortality associated with
ischemic cardiovascular events in patients with diabetes, these
data are reassuring.”

MedWire (www.medwire-news.md) is an independent clinical news
service provided by Current Medicine Group, a trading division of
Springer Healthcare Limited. © Springer Healthcare Ltd;
2010

Meeting website

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Revascularization no better than medical therapy for stable IHD in Type 2 diabetics

IMPERCEPTIBLE DOES NOT MEAN HARMLESS

The perceptible type 2 diabetes symptoms are frequently absent, soft or intermittent, causing this disease to go unnoticed, sometimes for years. Nevertheless, serious long-term complications will result from these imperceptible type 2 diabetes symptoms anyway. These complications include vascular disease, coronary artery disease, renal failure due to nephropathy, vision problems due to retinopathy, tingling or loss of sensation, burning feet or feet pain due to neuropathy, heart failure from cardiomyopathy, and liver damage from steatohepatitis, among others.

Type?2 diabetes is habitually treated at the start by just escalating corporal activity and diminishing carbohydrate intake and body weight. These can bring back insulin sensitivity even when the mass loss is modest, for instance around 10 or 15?lb, particularly when it is in abdominal overweight.

It is frequently possible to attain long-term acceptable blood glucose control and lessen the diabetes symptoms with these measures alone. However, the core tendency to insulin resistance is not gone, and so consideration to diet, weight loss and exercise must persist. The customary next step, if required, is treatment with oral antidiabetic medication.

TAKE CONTROL: DO NOT PROCRASTINATE

When the ailment progresses, the inability of insulin secretion worsens too, and therapeutic substitution of insulin frequently becomes indispensable. There are abundant theories as to the precise mechanism in type?2 diabetes and its origin.

Fat located around the waist in relation to abdominal organs, called central obesity, is known to incline individuals to insulin resistance. Abdominal fat is especially vigorous hormonally, secreting a set of hormones called adipokines that may probably damage glucose tolerance.

Obesity is present in more than 50% of patients diagnosed with type?2 diabetes. Other possible causes include aging and family history: almost 20 percent of aged patients in the USA suffer from diabetes, and type?2 is much more widespread in those with relatives who have had it.

Type?2 diabetes has begun to affect more and more children and adolescents in the last 10 years, probably in association with the increased occurrence of childhood obesity seen in some places in recent decades.

Low levels of blood sugar, called hypoglycemia, one of the most dangerous symptoms of diabetes, may lead to seizures or episodes of coma and must be treated immediately, via an emergency high-glucose gel positioned in the patient’s oral cavity, or an injection of glucagon or intravenous dextrose.

Type?2 diabetes mellitus is due to insulin insensitivity or reduced sensitivity, combined with comparatively reduced insulin emission which in some cases becomes complete. The imperfect openness of body tissues to insulin almost unquestionably involves the insulin receptors in the cell membranes. Nevertheless, the exact defects are not known yet.

At the start, insulin production is only somewhat impaired in type?2 diabetes, so oral medication, often prescribed in a variety of combinations, can be taken to improve insulin production, to regulate excessive release of glucose by the liver and to soothe insulin resistance to some extent as well. At the same time, to diminish the symptoms of diabetes. But if you do not act fast, the story can be completely different.