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03/02/2012 11:41 PM

DIABETES & LYME articles; anyone improved?(page 20)

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Prediabetes Not to Blame for Nerve Damage: Study

Doctors should seek other causes of condition known as polyneuropathy

By Robert Preidt

Friday, February 24, 2012

FRIDAY, Feb. 24 (HealthDay News) --

A new study finds that people with prediabetes are no more likely to have a type of nerve damage called small fiber polyneuropathy than healthy people, a finding that contradicts two decades of medical reports.

The Mayo Clinic researchers said the results from their five-year study of 550 people suggest that doctors should look for causes other than prediabetes in patients with painful small fiber polyneuropathy.

Prediabetes, also called borderline diabetes, is higher than normal blood sugar levels, but not high enough to be considered diabetes.

"It is highly unlikely that impaired glucose or associated metabolic derangements cause polyneuropathy, at least not to the high frequency previously reported," lead author and neurologist Dr. Peter Dyck said in a Mayo news release.

The study was published in the February issue of the journal Diabetes Care.

Diabetic polyneuropathies can damage nerve fibers throughout the body, but usually affect the feet and legs. This painful and potentially life-threatening nerve damage can lead to problems with sensation, movement and bodily function.

Due to the risk of complications from overtreatment, doctors should not treat prediabetes if their intention is to prevent the development of diabetic polyneuropathy, the researchers said.

SOURCE: Mayo Clinic, news release, Feb. 22, 2012 fullstory_122306.html

Copyright (c) 2012 HealthDay. All rights reserved.


03/04/2012 04:52 AM
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FDA Slaps Merck on Skipped Januvia Study

By John Gever, Senior Editor, MedPage Today

Published: February 29, 2012

In a warning letter, the FDA upbraided Merck & Co. for failing to conduct a promised animal study of pancreatitis risk associated with its diabetes drug sitagliptin (Januvia, Janumet).

The company "failed to comply with the approved timetable and ... failed to show good cause for not conducting the additional testing required to further assess whether a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin, represents a public health risk," according to the Feb. 17 letter, made public this week.

Under an earlier agreement with the FDA, Merck was supposed to have completed the study and submitted results to the agency by June 15, 2011.

Merck said Wednesday that it would submit a final design for the study within 30 days and begin it in six months.

"Merck is fully committed to complying with FDA's requirement and is confident that the company will complete the requirement within the time frame outlined in the Feb. 17 letter," according to a company statement.

Increased risk of acute pancreatitis has been a longstanding concern with the incretin class of diabetes drugs, including exenatide (Byetta), linagliptin (Tradjenta), and liraglutide (Victoza) as well as sitagliptin.

Several studies have shown higher rates of acute pancreatitis in patients taking these drugs, and labeling for the drugs includes statements about the possible increased risk.

The FDA had required Merck to conduct the rodent study when it approved use of sitagliptin in combination with glitazone drugs for diabetes in February 2010.

Specifically, the agency called for a three-month study of pancreatitis risk in a diabetic rodent model.

Merck's initial design proposal was rejected by the FDA as inadequate, and the firm never submitted a revised protocol.

Instead, the company said it would provide data from a separate, investigator-initiated study in mice.

Those data were finally submitted in January 2012, but the agency determined that they did not satisfy its original requirements, according to the warning letter. It noted that Merck had not secured the FDA's approval ahead of time to use this study in place of the originally agreed-upon study.

Furthermore, the letter said, Merck never gave a good reason for missing the deadlines spelled out in the original agreement and subsequent exchanges.

"As a result, you are more than 20 months late in achieving the June 15, 2010, final protocol submission milestone and more than eight months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays," the letter said.

Failure to submit a final protocol for the three-month rodent study within 30 days and to win the agency's approval and initiate it within six months would expose Merck to a fine of $250,000 and other unspecified actions. 31420?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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03/04/2012 05:31 AM
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Duration of Diabetes Raises Stroke Risk

By Todd Neale, Senior Staff Writer, MedPage Today

Published: March 01, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

Diabetes at baseline and duration of diabetes both significantly increased the risk of an ischemic stroke, according to a longitudinal study.

Having diabetes for 10 years or more tripled the risk of an ischemic stroke in this racially and ethnically diverse population.

The risk of ischemic stroke increased by 3% for each additional year a patient had diabetes, researchers found.

Compared with nondiabetics in the longitudinal study, those who had the disease for at least 10 years had a threefold higher stroke risk (HR 3.2, 95% CI 2.4 to 4.5), Mitchell Elkind, MD, of Columbia University in New York City, and colleagues reported online in Stroke: Journal of the American Heart Association.

Although stroke rates have been dropping among diabetics, more people are developing the disease -- and at younger ages -- because of the obesity epidemic. That means that the stroke burden is growing heavier, particularly as the population ages and people live longer.

"It is thus important to better understand the dynamics between diabetes, time, and stroke, and to emphasize the importance of interventions to prevent early diabetes," the authors wrote.

"Minimizing the number of years a patient has diabetes would help combat the increase in stroke risk with each year of the disease."

Elkind and colleagues examined data from 3,298 individuals participating in the Northern Manhattan Study who had never been diagnosed with a stroke. The average age was 69. Half of the participants were Hispanic, 21% were white, and 24% were black.

About one-fifth (22%) had diabetes at baseline and another 10% reported new-onset diabetes during an average follow-up of nine years.

There were 244 ischemic strokes recorded during the study.

After adjustment for demographics and cardiovascular risk factors, ischemic stroke was predicted by the presence of baseline diabetes (HR 2.5, 95% CI 1.9 to 3.3) and diabetes as a time-dependent variable (HR 2.4, 95% CI 1.8 to 3.2), which takes into account the development of diabetes during follow-up.

The researchers had hypothesized that incorporating incident diabetes would change the magnitude of the association, but it did not, possibly because these older individuals already had a high cardiovascular risk burden at baseline that did not change much with the development of diabetes.

Other possible reasons incident diabetes did not improve risk prediction included greater compliance with therapy among those newly diagnosed, a shorter duration of diabetes among the incident cases, which might not be long enough to translate into a higher stroke risk, and the potential for missing cases during follow-up because of the use of self-report.

Compared with nondiabetics, the risk of ischemic stroke was similar for those who had diabetes for up to five years (HR 1.7) and those who had the disease for five to 10 years (HR 1.8). The risk was greater for those who had diabetes for a decade or more (HR 3.2).

The growing stroke risk that accompanies a longer duration of diabetes could be mediated through several mechanisms, according to the researchers:

Greater carotid plaque thickness

Accelerated microvascular and macrovascular complications from long-term hypertension

Greater risk of microalbuminuria, which has been shown to be a risk factor for stroke in patients with diabetes

Endothelial dysfunction

Abnormalities in fibrinogen and clotting mechanisms

The finding "warrants steps to institute long-standing and sustainable lifestyle changes for primary prevention and appropriate long-term management after diagnosis," the authors wrote.

They acknowledged some limitations of the study, including the lack of information on fasting blood glucose and glycated hemoglobin during follow-up and possible confounding of the association between diabetes duration and stroke risk by age.

The Northern Manhattan Study is funded by a grant from the National Institute of Neurological Disorders and Stroke.

The authors reported that they had no conflicts of interest.

From the American Heart Association:

Guidelines for the Primary Prevention of Stroke

Primary source: Stroke: Journal of the American Heart Association

Source reference:

Banerjee C, et al "Duration of diabetes and risk of ischemic stroke: The Northern Manhattan Study" Stroke 2012; DOI: 10.1161/STROKEAHA.111.641381. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

03/15/2012 03:07 AM
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Prediabetes Cutoff to 5.7 A1C Called Cost-Effective

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: March 13, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

The American Diabetes Association recommended adoption of hemoglobin HbA1c testing for identifying diabetes and prediabetes and an HbA1c value of 6.5% was selected as the diagnostic cutoff.

Point out that this study using a simulation model suggests that lowering the HbA1c cutoff for prediabetes to 5.7% would be cost effective.

Using hemoglobin A1c (HbA1c) to catch prediabetes may be cost-effective if the threshold for diagnosis set at 5.7%, according to an analysis led by the CDC.

The cost of treating patients for an HbA1c level less than 5.7% would likely outweigh the savings from improvement in long-term outcomes, according to an analysis by Xiaohui Zhuo, PhD, of the CDC in Atlanta, and colleagues largely at the same agency.

Those diagnostic cutoffs wouldn't fall within the $50,000 per quality life-year gained, typically considered cost-effective, they reported in the April issue of the American Journal of Preventive Medicine.

"Lowering the cutoff from 5.7% to 5.6% also may be cost effective, however, if the costs of preventive interventions were to be lowered," the group noted.

The threshold for diagnosing prediabetes became controversial in 2009, when the American Diabetes Association recommended using hemoglobin A1c as the new standard diagnostic test for diabetes and prediabetes.

That organization indicated 6.5% as the cutoff for frank diabetes, but the level indicating prediabetes has variably been set anywhere from 6.0% to 5.5% by different professional groups.

"Establishing an HbA1c cutoff for prediabetes, however, has been more challenging than for diabetes because the relationship between the incidence of type 2 diabetes and HbA1c below 6.5% is continuous, with no clearly demarcated threshold that is associated with an accelerated risk of diabetes or other morbidities," Zhou's group explained.

They ran simulations using a nationally-representative sample of the nondiabetic adult population in the National Health and Nutritional Examination Survey (NHANES 1999 to 2006), modeling the impact of each 0.1% increment in the threshold for prediabetes from 6.4% to 5.5%.

Each lower threshold progressively improved health of the population considered over a lifetime from the healthcare system perspective but also increased costs.

Assuming that prediabetes found in that population was treated with a higher-cost approach similar to that seen in the Diabetes Prevention Program study averaging about $1,000 a year, moving the cutoff for prediabetes diagnosis as low as 5.7% was cost-effective.

The cost per quality life-year gained was:

$27,000 to go from 6.0% to 5.9%

$34,000 to further drop from 5.9% to 5.8%

$45,000 to go from 5.8% to 5.7%

But bringing the threshold for diagnosis down further exceeded the $50,000 mark per quality life-year gained, at $58,000 to go from 5.7% to 5.6% and $96,000 to go from 5.6% to 5.5%.

The numbers were better assuming use of lower cost interventions averaging about $300 per year to treat prediabetes as in the Promoting a Lifestyle of Activity and Nutrition for Working to Alter the Risk of Diabetes (PLAN4WARD) study.

The cost per quality life-year gained in that analysis was just $24,000 to lower the HbA1c cutoff from 6.0% to 5.9% and $34,000 to get down to 5.7%.

Even going from 5.7% to 5.6% would be considered cost-effective in that less expensive scenario, costing $43,000 per quality life year gained, although the next increment to 5.6% wasn't at $70,000.

The group cautioned that use of hemoglobin A1c for diagnosis isn't universally agreed upon and does have some limitations.

Limitations of the study included possible bias if the cost per quality life-year gained was higher with age and a lack of data on other measures like body mass index that may also play into clinical decisions on treatment of prediabetes.

The analysis used data for predicting transition of prediabetes to diabetes from the Atherosclerosis Risk in Communities Study, which is supported by National Heart, Lung, and Blood Institute contracts.

The researchers reported having no conflicts of interest to disclose.

From the American Heart Association:

Diagnosis and Management of the Metabolic Syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

Creating a 21st Century Global Health Agenda: The General Assembly of the United Nations High Level Meeting on Non-Communicable Diseases

Primary source: American Journal of Preventive Medicine

Source reference:

Zhuo X, et al "Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention: a cost-effectiveness perspective" Am J Prev Med 2012; DOI: 10.1016/j.amepre.2012.01.003. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

03/16/2012 01:55 PM
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Diabetes Risk: White Rice Joins White Bread

By Kristina Fiore, Staff Writer, MedPage Today

Published: March 15, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

1 comment(s)

Action Points

A meta-analysis of four cohort studies found that consumption of higher amounts of white rice was associated with an increased risk of type 2 diabetes compared to eating the lowest amounts.

Note that the association was highest for the Asian population.

Eating more white rice may up the risk of type 2 diabetes, especially for Asian populations, researchers said.

Patients who ate the greatest amounts of the grain had a 27% greater risk of developing the disease than those who ate the least, and the relative risk was higher among Asian patients, Qi Sun, PhD, of Harvard, and colleagues, reported in BMJ.

"Although rice has been a staple food in Asian populations for thousands of years, this transition [to more sedentary lifestyles and greater availability of food] may render Asian populations more susceptible to the adverse effects of high intakes of white rice, as well as other sources of refined carbohydrates, such as pastries, white bread, and sugar sweetened beverages," they wrote.

The glycemic index of white rice is higher than that of other whole grains, largely due to processing. It's also the primary contributor to dietary glycemic load for populations that consume rice as a staple food, such as Asians.

Sun and colleagues conducted a meta-analysis of four prospective cohort analyses in Asian and Western populations, totaling 352,384 patients with follow-up ranging from 4 to 22 years.

During that time, there were 13,284 incident cases of type 2 diabetes.

Asians generally had a higher level of white rice consumption than Western populations.

Overall, Sun and colleagues found a positive association between white rice intake and type 2 diabetes (RR 1.27, 95% CI 1.04 to 1.54, P=0.001), which was stronger in Asian populations.

Asians with the highest intake had a 55% greater risk of diabetes than Asian patients who ate the least rice (RR 1.55, 95% CI 1.20 to 2.01).

The risk was also heightened in Western populations, but the confidence interval straddled 0 and wasn't significant (RR 1.12, 95% CI 0.94 to 1.33).

The researchers noted that study heterogeneity in these analyses was low.

They also found a dose-response effect -- with each increase in rice serving per day, risk of type 2 diabetes rose by 11% (95% CI 1.08 to 1.14, P<0.001).

In secondary analyses, the association appeared to be more pronounced in women than in men, they added.

They cautioned, however, that the meta-analysis was limited by the observational nature of the included studies and by their reliance on food frequency questionnaires to assess dietary intake. Also, they did not analyze consumption of brown rice, since only one of the four studies examined this food.

Still, they concluded that the dose-response relationship may indicate that "even for Western populations with typically low intake levels, relatively high white rice consumption may still modestly increase risk of diabetes."

In an accompanying editorial, Bruce Neal, MD, of the University of Sydney in Australia, cautioned that the "interpretation of the observed association, and, in particular, determination of the likelihood of causality, are problematic."

Neal warned that the highest and lowest levels of rice intake varied greatly between studies, and that what's really needed is a "more sophisticated analysis based on primary rather than summary data."

He continued that there are "few immediate clinical implications," since "further research is needed to develop and substantiate the research hypothesis" -- even though funding is likely a challenge.

"Public health nutrition awaits the discovery of the model that will secure the investment needed to answer questions about the role of nutrition in health using large randomised studies," Neal wrote. "Until then, the effect of the consumption of white rice on the development of type 2 diabetes will remain unclear."

A researcher was supported by a grant from the National Heart, Lung, and Blood Institute.

Neither the researchers nor the editorialist reported any conflicts of interest.

Primary source: BMJ

Source reference:

Hu EA, et al "White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review" BMJ 2012; DOI: 10.1136/bmj.e1454.

Additional source: BMJ

Source reference:

Neal B "White rice and risk of type 2 diabetes" BMJ 2012; DOI: 10.1136/bmj.e2021. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

03/16/2012 02:00 PM
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Coconut Oil: A Different Kind of Saturated Fat

Written by

David Mendosa

Thu, March 08, 2012

Coconut oil is a special kind of saturated fat. The trouble with saturated fat in general, as I wrote here last week, is that our bodies find them harder to burn than other kinds of fat, like the monounsaturated fat in food like avocados, olive oil, and macadamia nuts.

We manage our diabetes by controlling the spikes in our blood glucose levels. And nothing has a more dramatic affect on our levels than the starches and the sugars of high carbohydrate food. Therefore, many of us now follow a very low-carb diet.

But when we start getting most of our energy from fat rather than from carbohydrates, our bodies are just beginning to learn how to convert fat to the energy we need. So we have to make it easier for ourselves, Ron Rosedale, M.D., told me. Dr. Rosedale is a physician and scientist who wrote The Rosedale Diet.

Dr. Rosedale says to limit the amount of saturated fat during our first few weeks on a very low-carb diet. Otherwise, we will feel our lack of energy and tire easily.

But this isn't true of coconut oil, he says. “Coconut oil is a saturated fat so it has the benefit of being less likely to turn rancid than other fats.”

Coconuts Drying

It may be true that “a rose is a rose is a rose,” as Gertrude Stein wrote in one of her poems. But as our nutrition knowledge expands, we now know that we can't equate different kinds of fats. Even those that we tend to lump as saturated fats have different properties that affect our health differently.

Coconut oil is mostly a shorter chain saturated fat, which our bodies burn more easily than most saturated fat. Fats in general have from chains of 4 to 28 carbon atoms. About two-thirds of coconut oil fat has chains of 12 carbons or less.

“By being a shorter chain saturated fat, coconut oil doesn't have to be cut down to 12 carbons or less,” Dr. Rosedale says. “Many of the fatty acids in coconut oil are already in the short chain length and can therefore go right into the mitochondria to get burned. So it is the exception to the rule that saturated fat is more difficult to burn.”

But I wondered how coconut oil compares in its burning ability with unsaturated fats.

“Easier to burn,” Dr. Rosedale replied. “Unsaturated fats still have to be cut down. Mitochondria can't burn anything that's more than 12 carbons long. The cells can burn it, but they have to be processed first.”

He told me that most of the fatty acids that are in a typical human diet are longer than 12 carbons, so they have to first be cut down and processed, and it takes time and energy to do that.

And once they are chopped into pieces so they can be transported into the mitochondria, then they can be burned in the mitochondria as an energy source.

Coconut oil is 86.5 percent saturated fat, according to the USDA's National Nutrient Database. But 68 percent of its saturated fat are medium-chain fatty acids of 6 to 12 carbons.

Only one other oil has more medium-chain fatty acids.

Next week I will compare coconut oil with that fat and the other fats that our bodies burn best. saturated

Copyright © 2012 Remedy Health Media, LLC. All Rights Reserved.

03/25/2012 01:32 AM
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Adding Drug to Insulin May Drop Blood Sugar

By Kristina Fiore, Staff Writer, MedPage Today

Published: March 20, 2012

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

Action Points

Dapagliflozin -- a selective inhibitor of sodium–glucose cotransporter 2 -- reduces renal glucose reabsorption, increases renal glucose excretion, and reduces hyperglycemia in a dose-dependent manner.

It therefore may improve glycemic control when given with a lower-than-usual dose of insulin.

In this study of patients with inadequately controlled type 2 diabetes receiving at least 30 U of insulin daily, dapagliflozin was associated with improved glycemic control, stabilized insulin dosing, and reduced weight.

The investigational type 2 diabetes drug dapagliflozin may help patients rein in their blood sugar when insulin alone doesn't do the trick, researchers found.

Those who added dapagliflozin to their insulin regimens had better HbA1c control after 24 weeks than those who added placebo, John Wilding, MD, of University Hospital Aintree in Liverpool, England, and colleagues reported in the March 20 issue of the Annals of Internal Medicine.

Those differences were maintained through 48 weeks, but they may come at the price of a higher risk of hypoglycemia and genitourinary infections -- and breast and bladder cancer risk remains an open question, the researchers said.

Risk of these cancers was cited as a main concern in FDA's decision to deny approval of the compound last January.

The drug is an inhibitor of sodium-glucose cotransporter 2 (SGLT2), which blocks the ability of the kidneys to hold on to sugar and instead excretes it in urine.

Many type 2 diabetics eventually require insulin, but patients who aren't well-controlled on the hormone are hard to treat because upping the dose increases the risk of weight gain, hypoglycemia, fluid retention, and congestive heart failure.

To investigate whether adding dapagliflozin to unsuccessful insulin regimens could improve glucose control, the researchers assessed 800 patients who weren't adequately controlled on at least 30 U of insulin a day; patients also could be taking up to two oral antidiabetic drugs.

The trial was conducted at 126 centers in Europe and North America from April 30, 2008 to Nov. 19, 2009, and patients were randomized to placebo or to 2.5 mg, 5 mg, or 10 mg of dapagliflozin once a day for 48 weeks.

Insulin doses weren't titrated before starting the trial, and the primary outcome was change in HbA1c over 24 weeks.

Wilding and colleagues found that patients who'd had dapagliflozin added to their insulin regimens had significantly better HbA1c control than those on placebo and insulin at 24 weeks, with the most rapid declines occurring during the first eight weeks.

Mean HbA1c fell by 0.79% to 0.96% in the dapagliflozin groups, compared with 0.39% with placebo. Mean differences compared with placebo were as follows:

-0.40% in the 2.5-mg group

-0.49% in the 5-mg group

-0.57% in 10-mg group

Those differences were maintained through 48 weeks, the researchers added.

Dapagliflozin patients were also on lower doses of insulin by the end of the trial; daily insulin dose fell by 0.63 to 1.95 U with dapagliflozin and rose by 5.65 U with placebo at 24 weeks, an effect that was maintained through 48 weeks.

Patients on the investigational agent also lost more weight: a drop of 0.92 kg to 1.61 kg (2 lbs to 3.5 lbs) compared with an increase of 0.43 kg (about 1 lb) in the placebo group over 24 weeks (P<0.001), with a mean difference of -2.43 kg (5.4 lbs) by the end of the study (P<0.001).

But there was more hypoglycemia in the dapagliflozin groups: a pooled 56.6% of patients had hypoglycemic episodes versus 51.8% of those on placebo.

There also were more events suggestive of genital and urinary tract infections in the active drug group compared with placebo (9% versus 2.5% for genital infections and 9.7% versus 5.1% for urinary tract infections).

The researchers noted that, in the entire dapagliflozin study program, there was no overall increase in carcinogenicity, although there were "numerical imbalances" in breast and bladder cancer with the agent.

It's highly selective for sodium glucose cotransporter 2, which isn't known to be expressed in bladder and breast tissue, they said, but further surveillance is required to fully assess the risk.

The study was limited because insulin doses weren't titrated to target at the outset, requiring baseline therapy to remain unchanged unless absolutely necessary for glycemic control.

Also, P-values were considered post hoc, and the majority of patients were white, so the findings may not be generalizable. Nor was the study powered to fully assess breast or bladder cancer risk.

In an accompanying editorial, Steven Smith, MD, of the Mayo Clinic in Rochester, Minn., wrote that the "understanding of the SGLT system, cellular glucose transport, and the ability to induce glycosuria as a potential management option for type 2 diabetes has been evolving over the past two centuries."

For instance, regarding breast and bladder cancer, it's still not clear what kind of effects occur via metabolites or expression in tissues known to have SGLT2 receptors, such as the brain, liver, thyroid, muscle, or heart tissue.

The true effects of dapagliflozin on renal disease -- since it appears it may be less effective in these patients -- also are unknown, Smith said.

"After two centuries of study, we remain uncertain of the appropriate use and long-term safety of SGLT2 inhibition in persons with diabetes," Smith concluded.

The study was supported by AstraZeneca and Bristol-Myers Squibb.

Primary source: Annals of Internal Medicine

Source reference:

Wilding JPH, et al "Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin" Ann Intern Med 2012; 156: 405-415.

Additional source: Annals of Internal Medicine

Source reference:

Smith SA "Still uncertain about sodium-glucose cotransporter inhibitors despite two centuries of study" Ann Intern Med 2012; 156: 466-467. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

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03/25/2012 02:00 PM
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Medicare Turns Gimlet Eye on diabetic macular edema, DME, Drugs

By Kristina Fiore, Staff Writer, MedPage Today

Published: March 22, 2012

Vascular endothelial growth factor (VEGF) inhibitors, such as ranibizumab (Lucentis) or bevacizumab (Avastin), may improve vision in patients with diabetic macular edema (DME), but more research on specific risks and benefits is needed, according to a Medicare advisory panel.

Nor is there enough evidence to support use of one of these agents over any other in DME, according to the Medicare Evidence Development and Coverage Advisory Committee (MedCAC), an advisory group to the Centers for Medicare and Medicaid Services (CMS).

The meeting was called to help CMS decide whether to undertake a formal National Coverage Determination for anti-VEGF therapies in DME. One specific object was to advise on future trial designs that would give CMS the information it needs.

"It's not enough to say that these [agents] seem to work," said committee chair Clifford Goodman, PhD, of The Lewin Group, a healthcare consulting firm. "We have a long, long way to go."

Off-Label Use

Although laser photocoagulation of the retina has long been the standard of care for treating DME, clinicians have been using VEGF inhibitors off-label for the condition, researchers told MedPage Today at last year's American Diabetes Association meeting.

At that meeting, the RIDE and RISE trials showed that the VEGF inhibitor ranibizumab (Lucentis) improved vision in DME patients compared with placebo.

However, clinicians there told MedPage Today that another anti-VEGF agent, the cancer drug bevacizumab (Avastin), was equally as effective at a much lower price tag. Though both drugs are manufactured by Genentech, ranibizumab injections can run $1,950 each while bevacizumab costs only $50 per shot.

The National Eye Institute sponsored a 1,161-patient study called CATT, which found that both agents appeared to have similar clinical efficacy in wet age-related macular degeneration -- a condition for which ranibizumab is now approved, and for which bevacizumab is frequently prescribed off-label.

Weight of the Evidence

The CATT study results figured heavily into technology assessment reports created for MedCAC, written by researchers at the University of Alberta and Massachusetts General Hospital under contract with the Agency for Healthcare Research and Quality.

The reports concluded that there appears to be a class effect for VEGF inhibitors in DME. Aside from ranibizumab and bevacizumab, two other treatments -- pegaptanib (Macugen) and aflibercept (Eylea) -- are FDA-approved for other indications and have been used off-label in DME.

But panelists noted that the bulk of the evidence has focused on bevacizumab and ranibizumab.

The review of 15 randomized controlled trials and eight observational studies totaling more than 4,000 patients noted, however, that the side effect profile of bevacizumab relative to ranibizumab and the other agents remains the "greatest element of uncertainty" because it may be linked with more systemic side effects.

Future Trials

Head-to-head trials of VEGF inhibitors in DME are just one type needed for the CMS decision, panelists said.

Another key need is appropriate measures of patient outcomes, particularly improvements in quality of life, that are related to gains in visual acuity. Goodman said that while better visual acuity doesn't inevitably translate to an improvement in quality of life, it does track it closely.

There's also a need for more safety data and longer follow-up on the potential for adverse events, panelists said.

Additionally, Goodman noted a need for evidence on appropriate duration of therapy, thresholds of effectiveness -- when to start therapy and when to withdraw -- which subgroups most benefit, and more data from community rather than hospital settings.

Invited speaker Robert Frank, MD, of Wayne State University, said the agents should also be evaluated in proliferative diabetic retinopathy and neovascular glaucoma.

When the time came to vote, eight of nine MedCAC members indicated that they were fairly or highly confident that adequate evidence exists to determine whether VEGF inhibitors improve DME outcomes. Seven were fairly confident that the drugs actually do improve outcomes, with two less sure.

But asked whether the available evidence would permit conclusions about the relative efficacy of current agents, most panelists said no. 31764?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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03/30/2012 12:55 AM
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03/31/2012 01:02 AM
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Bariatric Surgery Best for Obese Diabetics

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: March 26, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

8 comment(s)

Action Points

These two studies provide evidence that in obese patients with type 2 diabetes, surgery can be more effective that either standard or intensive medical treatment alone.

Point out that in both studies, bariatric surgery (gastric bypass, biliopancreatic diversion or sleeve gastrectomy) induced remission and was associated with a significant improvement in metabolic control over and above medical therapy, whether conventional or intensive.

Bariatric surgery improves glycemic control better than optimal medical therapy alone for obese patients with type 2 diabetes, two randomized trials determined.

Hemoglobin A1c levels normalized to under 6% by 1 year for 42% of patients who got gastric bypass surgery and 37% who got sleeve gastrectomy compared with 12% on intensive medical therapy alone (P=0.002 and P=0.008), Philip R. Schauer, MD, of the Cleveland Clinic, and colleagues reported in the STAMPEDE trial.

After 2 years in a second trial, diabetes went into remission with fasting glucose under 100 mg/dL and A1c under 6.5% off medication in 75% of gastric bypass patients and 95% of biliopancreatic diversion patients compared with none on conventional medical therapy.

Metabolic control also improved more in the surgery groups of both trials, appearing online in the New England Journal of Medicine.

"Although type 2 diabetes has been the domain of physicians, surgeons may now be able to claim greater success in achieving improved metabolic control," an accompanying editorial suggested, calling the results likely practice changing.

Longer term and larger studies are needed to prove a durable benefit and whether the results would be as good in routine practice, noted editorialists Paul Zimmet, MD, PhD, of the Baker IDI Heart and Diabetes Institute, Melbourne, Australia, and K. George M.M. Alberti, DPhil, of King's College Hospital in London.

"Meanwhile, the success of various types of bariatric surgery suggests that they should not be seen as a last resort," they wrote. "Such procedures might well be considered earlier in the treatment of obese patients with type 2 diabetes."

American Experience

The STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) trial was presented at the American College of Cardiology meeting in Chicago in conjunction with NEJM publication.

It included 150 obese patients with a body mass index of 27 to 43 kg/m2 (mean 36, 34% under 35 kg/m2) and uncontrolled diabetes with a hemoglobin A1c over 7.0% (mean 9.2%) randomized to Roux-en-Y surgery or sleeve gastrectomy or medical therapy alone.

All patients got intensive medical therapy according to American Diabetes Association guidelines with lifestyle counseling, weight management (recommended to include Weight Watchers), and newer diabetes drugs, such as the incretin analogues.

Glycosylated hemoglobin levels fell rapidly in the first 3 months after surgery. By 1 year, they reached a mean 6.4% after gastric bypass and 6.6% after sleeve gastrectomy compared with 7.5% with medical therapy alone (P<0.001 and P=0.003).

For the primary endpoint of a glycosylated hemoglobin under 6.0% at 1 year, the two bariatric surgery groups came up equal (P=0.59), though all who achieved that target in the gastric bypass group did so off diabetes medications versus 28% in the sleeve gastrectomy group.

Not surprisingly, weight loss after gastric bypass and sleeve gastrectomy exceeded that of medical therapy alone over 1 year (-64.8 and -55.3 lb versus -11.9 lb, both P<0.001).

Gastric bypass cut weight as well as BMI significantly more than sleeve gastrectomy (P=0.02 and 0.03, respectively).

"Reductions in the use of diabetes medications occurred before achievement of maximal weight loss, which supports the concept that the mechanisms of improvement in diabetes involve physiologic effects in addition to weight loss, probably related to alterations in gut hormones," Shauer's group noted.

Medication use to control glucose, lipids, and blood pressure fell significantly after both surgeries but increased with medical therapy alone.

Metabolic syndrome and insulin resistance also improved more with the bariatric procedures.

No patients died or had a life-threatening complication, though four patients required additional surgical interventions.

The study wasn't powered to look for differences between the surgical arms or for clinical outcomes, though cardiovascular risk factors did improve.

Limitations included the short follow-up and the open-label assessment of patients at a single center.

Italian Experience

The second trial, led by Geltrude Mingrone, MD, of the Catholic University of Rome, was likewise a single-center, unblinded trial randomizing patients to gastric bypass, biliopancreatic diversion, or conventional medical therapy alone by a team comprised of a diabetologist, a dietitian, and a nurse.

The 60 participants had a BMI of at least 35 kg/m2 and diabetes of at least 5-years duration with an hemoglobin A1c of 7.0% or more (mean 9%).

The likelihood of a diabetes remission by 2 years was 7.5 times higher for the gastric bypass group and 9.5 times higher for the biliopancreatic-diversion group even assuming the best case scenario that the two medication-group patients who dropped out had a diabetes remission (both P<0.001).

Average reduction in hemoglobin A1c from baseline was 43% in the biliopancreatic-diversion group and 25% in the gastric-bypass group compared with just 8% in the medical therapy group, with all comparisons statistically significant.

Weight reductions came out similar at 2 years between surgery types at 33% to 34% of body weight from baseline compared with just 5% on medical therapy alone (both P<0.001).

BMI dropped from a mean of 45 down to 29 kg/m2 in both surgery groups but from 46 to 43 kg/m2 in the medical-therapy group.

But the glycemic benefit appeared independent of both weight loss and preoperative BMI, the researchers noted.

Lipids and blood pressure also improved more with bariatric surgery.

No patients died with bariatric surgery, but there was one case of an incisional hernia requiring reoperation 9 months later with biliopancreatic diversion and one intestinal obstruction requiring reoperation 6 months after gastric bypass. Two medical-therapy group patients had persistent diarrhea that resolved with substitution of another drug in place of metformin.

Limitations included the small sample size and lack of power for safety and clinical endpoints.

Bariatric surgery isn't without hazards and remission may not be a cure, but it is gaining recognition in management of diabetes, the editorialists noted.

International Diabetes Federation now calls it appropriate for obese patients with type 2 diabetes not getting to glucose control targets with available medical therapy, especially with concomitant hypertension or other major coexisting illnesses.

"The final question, which is as yet untested, is whether bariatric surgery is suitable for all obese patients with type 2 diabetes, even those with a lower body-mass index," they wrote.

The STAMPEDE trial was supported by a grant from Ethicon Endo-Surgery, a grant from the National Institutes of Health, and LifeScan. Schauer reported receiving payment for board membership from Ethicon Endo-Surgery, Surgiquest, Barosense, RemedyMD, and Stryker; consulting fees from Ethicon Endo-Surgery, Stryker, Gore, and Carefusion; payment for expert testimony from Physicians Review of Surgery; lecture fees from Ethi-con Endo-Surgery, Allergan, Cinemed, and Quadrant Healthcare; a patent for a medical device to enhance weight loss in codevelopment with the Cleveland Clinic; royalties from Springer; an equity interest in Intuitive Surgical, Barosense, Surgiquest, and RemedyMD; and institutional grant support from Ethicon Endo-Surgery and Bard Davol. Mingrone's study was funded by the Catholic University of Rome. Mingrone reported having no conflicts of interest to disclose. Zimmet and Alberti reported having no financial relationships with industry to disclose.

From the American Heart Association:

STAMPEDE Video Interview & Presentation Materials -- AHA Science News from ACC.12

Primary source: New England Journal of Medicine

Source reference:

Schauer PR, et al "Bariatric surgery versus intensive medical therapy in obese patients with diabetes" N Engl J Med 2012; DOI: 10.1056/NEJMoa1200225.

Additional source: New England Journal of Medicine

Source reference:

Mingrone G, et al "Bariatric surgery versus conventional medical therapy for type 2 diabetes" N Engl J Med 2012; DOI: 10.1056/NEJMoa1200111.

Additional source: New England Journal of Medicine

Source reference:

Zimmet P, Alberti KGMM "Surgery or medical therapy for obese patients with type 2 diabetes?" N Engl J Med 2012; DOI: 10.1056/NEJMe1202443. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

© 2012 Everyday Health, Inc. All rights reserved.


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