HHAL MEDICAL NEWS JUNE2009

HHAL MEDICAL NEWS JUNE2009

Insulin Glargine(Lantus) Associated with Cancer Risk; ADA Calls Findings "Conflicting and Confusing"

Patients will likely ask about a study in Diabetologia that associates use of insulin glargine (Lantus) with a higher risk for cancer. The journal's editor and the American Diabetes Association both urge caution in interpreting the results.

German researchers first identified the association and submitted their results to Diabetologia. Before agreeing to acceptance, that journal's editors commissioned three additional studies using Swedish and U.K. databases. Two of those studies confirmed an association of insulin glargine with cancer risk, but editorialists judge the evidence "entirely insufficient to bring in a verdict."

On the basis of laboratory studies, the editorial writers conclude: "There is no reason to believe that insulin therapy causes cancer, but there is, nonetheless, reason to suspect that high concentrations of insulin may promote [earlier onset of] its development."

The American Diabetes Association called the data "conflicting and confusing" and urged patients not to change their regimens until more information is available.

Diabetologia articles and press release (Free)

Diabetologia editorial (Free PDF)

ADA statement (Free)

Diabetologia webcast (Free)

Wall Street Journal story (Subscription required)

Leukotriene Modifiers(Singulair) for Asthma Associated with Neuropsychiatric Adverse Events

Reports of neuropsychiatric adverse effects from leukotriene modifiers have prompted the FDA to request label changes for these drugs.

The three drugs, used to treat asthma in adults and children aged 12 and older, are montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo and Zyflo CR). Montelukast is also used to treat allergic rhinitis symptoms.

Montelukast and zafirlukast are leukotriene receptor antagonists, and zileuton is an inhibitor of leukotriene synthesis.

The adverse effects, identified in postmarketing surveillance, include agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor.

The FDA noted that doctors should consider discontinuing the drugs in patients who develop neuropsychiatric symptoms.

FDA announcement (Free)

Poor Sleep in Adulthood Linked to Higher Blood Pressure

Reduced sleep duration and quality are associated with elevated blood pressure, reports Archives of Internal Medicine.

Researchers with the CARDIA study examined associations between sleep behaviors (measured with wrist activity monitors) and BP among more than 500 adults in their 30s and 40s. In cross-sectional analyses, they found that shorter sleep duration and poorer sleep maintenance were each associated with increased systolic and diastolic BP.

In addition, in a longitudinal analysis, BP increased more among blacks than whites over 5 years; for diastolic BP, the race difference was partially mediated by a difference in sleep duration.

The authors say the sleep-BP link is supported by previous research and "laboratory evidence of increased sympathetic nervous activity as a likely mechanism underlying the increase in BP after sleep loss."

Conclusion Reduced sleep duration and consolidation predictedhigher BP levels and adverse changes in BP, suggesting the needfor studies to investigate whether interventions to optimizesleep may reduce BP.

http://archinte.ama-assn.org/cgi/content/abstract/169/11/1055

More Tofu, Please?

In a small randomized, controlled study, a low-carbohydrate, plant-based diet improved lipid measures more than a high-carbohydrate, low-fat diet.

Many tout low-carbohydrate, high-protein diets for reducing weight, but most of these diets have no (or adverse) effects on LDL levels, probably because of the high proportions of animal-based fats they contain. These investigators compared the effects on weight loss and lipid measures of a low-carbohydrate vegetarian diet high in proteins from gluten, soy, nuts, fruits, vegetables, cereals, and vegetable oils and of a high-carbohydrate vegetarian diet based on low-fat dairy products and whole grains. Two of the authors were employed by Solae, LLC, a promoter and developer of soy-based foods that supported the study.

Fifty overweight and hyperlipidemic men and women were randomized to consume either a low-carbohydrate (26% of total calories), high-vegetable protein (31% of total calories), and high-vegetable oil (43% of total calories) diet or a high-carbohydrate, lacto-ovo vegetarian diet (58% carbohydrates, 16% protein, and 25% fat) for 4 weeks. All study food (60% of daily caloric requirements for weight maintenance) was supplied by the investigators.

Diet adherence was nearly 95% in both study arms. Weight loss was similar with either diet. As anticipated, reductions in LDL levels and total cholesterol:HDL and apolipoprotein B:apolipoprotein A-1 ratios were significantly greater in the low-carbohydrate group than in the high-carbohydrate group. Greater improvements in blood pressure were also seen in the low-carbohydrate group, although the between-group difference was of borderline significance.

Comment: The results of this small, single-site study suggest that an "Eco-Atkins" diet of plant-based, low-carbohydrate foods yields better lipid measures than a more-traditional high-carbohydrate, low-fat diet. Larger long-term studies are needed to confirm these findings and to ascertain whether such improvements translate into improved cardiovascular outcomes. In the meantime, clinicians should continue to emphasize the benefits of dietary interventions known to improve cardiovascular risk and mortality, such as the Mediterranean diet.

BP-Lowering Drugs and Prevention of Cardiovascular Disease

All five classes of BP-lowering drugs were effective, regardless of patients’ histories.

Uncertainty exists about which blood pressure (BP)–lowering drugs to use and about whom to treat. U.K. investigators determined the efficacy of different classes of BP-lowering drugs in preventing coronary heart disease (CHD)–related events and stroke by conducting a meta-analysis of 147 randomized trials that involved 464,000 patients. The analysis included both hypertensive patients and patients in whom BP-lowering drugs were used for indications other than hypertension. Key meta-analysis findings include the following:

· Compared with placebo or no treatment, β-blockers resulted in 31% fewer CHD events in patients with recent myocardial infarctions (i.e., during the previous 2 years), 13% fewer CHD events in patients with CHD but without recent MIs, and 15% fewer CHD events in patients without histories of CHD. In the absence of recent MI, other BP-lowering drugs were as effective as β-blockers in preventing CHD events among patients with histories of CHD.

· Compared with placebo or no treatment, BP-lowering drugs led to significantly fewer CHD events and strokes (by 22% and 41%, respectively, when standardized to BP reductions of 10 mm Hg systolic or 5 mm Hg diastolic).

· The five classes of drugs (thiazides, β-blockers, angiotensin-converting–enzyme (ACE) inhibitors, angiotensin-receptor blockers, and calcium-channel blockers) all similarly lowered rates of CHD events. Calcium-channel blockers were more effective in preventing stroke than were the others, although all drugs were more effective than no treatment.

· Relative reductions in CHD events and stroke were similar among people with no histories of vascular disease and among those with prior CHD or stroke.

· Regardless of patients’ pretreatment BP (as low as 110 mm Hg systolic and 70 mm Hg diastolic), BP-lowering drugs significantly lowered risk for CHD events and stroke.

· With the exception of non-cardioselective β-blockers, each class of BP-lowering drugs significantly lessened risk for heart failure.

· Compared with placebo or no treatment, BP-lowering drugs were associated with significantly lower all-cause mortality (by 13%). No changes in cancer incidence or nonvascular-related mortality were noted.

Comment: With the exceptions of the protective effects of β-blockers within 2 years after MI and of calcium-channel blockers in preventing stroke, all BP-lowering drugs similarly affected incidence of CHD events and stroke (for a given BP). Risk was lowered in people with and without histories of vascular disease and pretreatment hypertension. The authors conclude "there is benefit in lowering blood pressure in anyone at sufficient cardiovascular risk whatever their blood pressure."

Bone-Density Monitoring After Starting Bisphosphonates 'Cannot Be Justified'

Routinely monitoring the effect of bisphosphonate therapy on bone mineral density is costly and unwarranted, according to a BMJ study.

In a secondary analysis of FIT trial data, researchers found that density measurements within individual patients varied more than measurements between drug and placebo recipients over the first 3 years of treatment — reflecting the imprecision of bone densitometry, according to an editorialist.

The researchers found that 97.5% of patients showed clinically beneficial increases in hip density (0.019 g per square centimeter or more) after 3 years of treatment.

An editorialist concludes: "Routine monitoring ... during the first few years of antiresorptive treatment cannot be justified because it may ... lead to inappropriate management decisions and waste scarce healthcare resources."

BMJ article (Free)

http://www.bmj.com/cgi/content/full/338/jun23_2/b2266

Midlife Migraines with Aura Related to Late-Life Infarct-Like Brain Lesions?

Women who suffer migraine with aura in middle age face increased risk for infarct-like brain lesions on MRI later in life, according to a population-based cohort study in JAMA.

Nearly 4700 adults in Iceland were interviewed about headache symptoms in midlife (mean age, 51) and then underwent brain MRI some 25 years later. In adjusted analyses, adults who reported migraine with aura at least once a month in midlife were at increased risk for infarct-like lesions later on. The increased risk was due to an excess of cerebellar infarcts among women who had migraine with aura (23%, vs. 14% among women without at least monthly headache).

Migraine without aura and nonmigraine headache were not associated with infarct risk.

Editorialists advise caution when interpreting these results, writing: "In the absence of the source and the nature of infarct-like lesions and the absence of clinical symptoms or consequences, it is premature to conclude that migraine has hazardous effects on the brain."

JAMA article (Free abstract; full text requires subscription)

http://jama.ama-assn.org/cgi/content/abstract/301/24/2563

Long-Term Outcomes in Patients with Prolonged PR Interval

A prolonged PR interval "is not as benign as previously believed," the results of a JAMA study imply.

Using data from the Framingham Heart Study, investigators followed a cohort of some 7500 subjects who underwent ECG. After 20 years' follow-up, subjects with PR intervals longer than 200 msec at baseline showed, in multivariable analysis, a threefold higher risk for having a pacemaker implant, a twofold higher risk for atrial fibrillation, and a 1.4-fold higher risk for all-cause mortality than those with shorter PR intervals.

The authors write that their findings "challenge the longstanding perception that PR interval prolongation or first-degree [atrioventricular block] has a benign prognosis."

Asked to comment, Dr. Harlan Krumholz, editor-in-chief of Journal Watch Cardiology, offered this: "Before raising the level of anxiety in patients ... we need to know if this is truly a robust marker of risk and whether that risk can be mitigated."

JAMA article (Free abstract; full text requires subscription)

http://jama.ama-assn.org/cgi/content/short/301/24/2571

Salubrious Components of Mediterranean Diet Identified

A population-based cohort study in BMJ highlights the individual components of the Mediterranean diet that appear to have the greatest effect on mortality.

Researchers interviewed some 23,000 healthy Greek adults about their dietary habits and followed them for 8.5 years. They found that the following elements of the Mediterranean diet contributed the most to a mortality risk reduction:

· moderate consumption of alcohol;

· low intake of meat;

· high consumption of vegetables, fruits, nuts, monounsaturated fats, and legumes.

In contrast, high intake of cereals, fish, and seafood — and low consumption of dairy products — showed little effect on mortality.

BMJ article (Free)

http://www.bmj.com/cgi/content/full/338/jun23_2/b2337

Treating Diabetes and Coronary Artery Disease

Prompt revascularization or initial medical therapy? Insulin sensitization or provision? From the BARI 2D trial, no strategy emerged a clear winner.

Conclusions Overall, there was no significant difference inthe rates of death and major cardiovascular events between patientsundergoing prompt revascularization and those undergoing medicaltherapy or between strategies of insulin sensitization and insulinprovision.

http://content.nejm.org/cgi/content/full/NEJMoa0805796?query=TOC

http://cardiology.jwatch.org/cgi/content/full/2009/610/1?q=etoc_jwgenmed

http://www.ncbi.nlm.nih.gov/pubmed/19502645?dopt=Abstract

http://cardiology.jwatch.org/cgi/content/full/2007/326/1

Two risk-scoring systems for predicting incident diabetes mellitus in U.S. adults age 45 to 64 years.

CONCLUSION: Basic information identified adults at high risk for diabetes. Additional data from fasting blood tests better identified those at extreme risk.
http://www.ncbi.nlm.nih.gov/pubmed/19487709?dopt=Abstract

http://cardiology.jwatch.org/cgi/content/full/

An Herbal Option for Statin-Intolerant Patients?

A supplement of red yeast rice outperforms placebo in a small randomized trial.

Many patients cannot tolerate statins because of muscle ache. One potential option for these patients is the herbal preparation, red yeast rice, which has been shown to decrease LDL levels. These investigators conducted a randomized, controlled trial in 62 adults withhypercholesterolemia who discontinued statin therapy after experiencing myalgias. Patients were assigned to receive red yeast rice (1800 mg) or placebo twice daily for 24 weeks. All participants were enrolled in a 12-week lifestyle-change program. Mean age was 60.5 in the red yeast rice group and 61.5 in the placebo group; 65% of the patients were women.

In the red yeast rice group, the mean LDL level was reduced from baseline by 27.3% at week 12 and by 21.3% at week 24. The corresponding reductions in the placebo group were 5.7% and 8.7%, respectively. Similar changes were seen in total cholesterol levels.Weight loss and pain scores did not differ significantly between the two groups at either week 12 or week 24. Two patients in the red yeast rice group and one in the placebo group discontinued treatment because of persistent intolerable myalgia. Two additional patients in the red yeast rice group discontinued treatment, one because of dizziness and the other because of loose stools.

http://www.ncbi.nlm.nih.gov/pubmed/19528562?dopt=Abstract

Hormone Therapy in Women With Premature Ovarian Failures: Is Transdermal Safer Than Oral?

Results of a small Scottish trial suggest that the answer is yes.

Conventional treatment for premature ovarian failure consists of oral contraceptives (OCs) or menopausal hormone therapy. In an open-label, randomized, crossover trial, investigators in Scotland compared the effects of an OC (30 μg of ethinyl estradiol and 1.5 mg of norethindrone daily for 21 days, followed by 7 hormone-free days) with those of transdermal estrogen (0.1-mg estradiol patch, week 1; 0.15-mg patch, weeks 2 and 3; no estrogen, week 4) plus cyclical vaginal or oral progesterone.

Participants received one treatment for 12 months and then switched to the alternative treatment (after washout) for 12 months.Blood pressure and renal factors (e.g., plasma angiotensin II levels) were measured at baseline and at 3, 6, and 12 months of each treatment period. Participants (age range, 19–38) had ovarian failure that was idiopathic or associated with cancer therapy, surgery, or Turner syndrome; none were hypertensive at baseline.

Eighteen women completed the trial. Compared with OC therapy, transdermal estrogen therapy was significantly associated with lower systolic and diastolic BPs at all time points. At 12 months, 24-hour mean systolic and diastolic BPs were lower by 7.3 and 7.4 mm Hg, respectively, with transdermal estrogen than with OCs (P<0.01 for both). In addition, transdermal estrogen therapy was associated with significantly lower plasma angiotensin II levels.

Comment: Few researchers have assessed the safety of different HT regimens in young women who lack ovarian function, so this trial is welcome. Clinicians should be aware that the highest-dose estradiol patch that is available in the U.S. releases 0.1 mg of estradiol daily. Furthermore, these investigators used cyclic therapy, which can result in withdrawal bleeding; I find that many of my patients prefer continuous HT. The authors speculate that higher BP associated with OC use reflects greater hepatic exposure to estrogen, leading to excessive angiotensinogen production and subsequent activation of the renin–angiotensin system. In women who experience natural menopause at normal ages, risk for venous thromboembolism is lower with transdermal than with oral estrogen therapy (JW Womens Health Apr 5 2007). The results of this small trial suggest that transdermal estrogen therapy might also have safety benefits over OC therapy for ovarian failure in women who are younger than 50.

No Clear Benefit for Aspirin in Primary Prevention of Cardiovascular Disease

Risks might outweigh benefits in patients who receive other modern preventive therapies.

In patients with histories of symptomatic occlusive vascular disease, aspirin’s ability to prevent future adverse cardiovascular events significantly outweighs its association with elevated risks for major bleeding. However, use of aspirin for primary prevention of occlusive vascular disease remains controversial; prospective trials and meta-analyses have shown no overall net benefit for aspirin and have lacked power to identify subgroups of patients in which aspirin’s benefits might significantly outweigh its risks.

To overcome these limitations, investigators pooled individual patient data from six large prospective primary prevention trials of aspirin, in which 95,000 patients without diabetes and without histories of occlusive vascular disease were randomized to receive aspirin or no aspirin for 2 years.

Compared with patients who received no aspirin, aspirin recipients had a statistically significant but a very small absolute reduction (0.51% vs. 0.57% annually) in serious vascular events — primarily major adverse coronary events and strokes — with no significant differences among patient subgroups and no differences in mortality. Patients who received aspirin suffered significantly fewer ischemic strokes but significantly morehemorrhagic strokes, with no significant net effect on stroke incidence. Patients who received aspirin experienced significantly more major extracranial bleeds (0.10% vs. 0.07% annually).

INTERPRETATION: In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress.

http://www.ncbi.nlm.nih.gov/pubmed/19482214?dopt=Abstract

Let's catch diabetes 6 years before it starts
These authors show that changes in glucose concentrations, insulin sensitivity and insulin secretion occur as much as three to six years before a diagnosis of diabetes (The WHITEHALL II Study). The description of biomarker trajectories leading to diabetes diagnosis could therefore contribute to more accurate risk prediction models that use repeated measures available for patients through regular checkups. (Free registration required)

http://www.lancet.com/journals/lancet/article/PIIS0140-6736(09)60619-X/abstract

Psoriasis sharply raises risk of cardiovascular disease, death
A study found psoriasis patients had a 78% higher incidence of heart disease, a 70% higher incidence of stroke and a 98% higher incidence of peripheral arterial disease than those who did not have psoriasis. The death rate for psoriasis patients was 86% higher than among people who didn't have the disease, the study in the Archives of Dermatology reported.Yahoo!/HealthDay News

Rosiglitazone in combination therapy for diabetes: What's the risk?
Using rosiglitazone (Avandia) in combination with standard diabetes treatments (metformin or a sulfonylurea) to lower blood glucose in Type 2 diabetics does not increase the risk of cardiovascular disease or death. However, the study confirms that using rosiglitazone more than doubles the risks of heart failure and also increases the risk of fractures, mainly in women. The Lancet

Study links form of lipoprotein{LP(a)} to risk of heart attack
Lipoprotein (a), a form of cholesterol, appears to increase the risk of heart attack two- to threefold in people with the highest levels of the protein, Danish researchers reported in the Journal of the American Medical Association. People have little control over the protein, and some patients do not respond to cholesterol-lowering drugs, or statins, because those on the market work by lowering low-density lipoprotein. The study's lead author from Copenhagen University Hospital said he hopes the findings will encourage drug companies to develop medicines that target lipoprotein (a). Reuters

How much exercise protects against diabetes and heart disease?
Good cardiorespiratory fitness has been found to protect against cardiovascular diseases and Type 2 diabetes. This study found that the mean intensity, frequency and duration of conditioning physical activity were associated directly with maximal oxygen uptake (VO2max). However, measures of the function of the pulmonary and cardiovascular systems, carbohydrate intake, and body composition were powerful determinants of cardiorespiratory fitness, especially in older middle-aged men. The American Journal of Cardiology

Zicam Nasal Cold Remedies Linked to Loss of Sense of Smell

Several over-the-counter Zicam intranasal cold remedies are associated with long-lasting or even permanent loss of the sense of smell and should not be used, the FDA announced on Tuesday.

The agency says that consumers should "stop using these products and throw them away."

Since 1999, the FDA has received reports of more than 130 cases of anosmia associated with the following zinc-containing products: Zicam Cold Remedy Nasal Gel, Zicam Cold Remedy Nasal Swabs, and Zicam Cold Remedy Swabs (kid size). Some people reported losing their sense of smell after the first dose. In others, the anosmia occurred after later doses.

In a warning letter to the drugs' marketer, the FDA says there is published evidence that zinc salts can harm olfactory function. In addition, the agency says it is "aware that [the marketer] appears to have more than 800 reports related to loss of sense of smell" associated with the products.

FDA public health advisory (Free)

Antioxidant Supplements Blunt Exercise-Induced Improvement of Insulin Sensitivity

Regardless of their previous exercise patterns, young men did not benefit from vitamin E or C supplementation.

Regular exercise increases insulin sensitivity and decreases risk for type 2 diabetes. One mechanism is known: Exercise stimulates glucose-transporter molecules to proliferate and move to the cell membrane, where they ferry glucose into the cell. Exercise also increases the formation of mitochondria, which give cells more energy but also create more harmful reactive oxygen species (ROS).

An international team randomized 39 young men (19 nonconditioned and 20 with prior physical conditioning) to exercise either with or without having ingested daily antioxidant supplements (1000-mg vitamin C and 400-IU vitamin E). In the groups that did not receive antioxidants, mean insulin sensitivity was higher after exercise among both nonconditioned and conditioned men; exercise raised production of ROS but also activated natural antioxidant systems. However, in both antioxidant groups, researchers noted no improvement in insulin sensitivity, and natural antioxidant systems were blunted.

Comment: Surprisingly, use of antioxidant supplements blunts the beneficial effects of regular exercise on insulin sensitivity, even though diets that are rich in fruits and vegetables (and, thus, contain high concentrations of antioxidants) lower risk for developing type 2 diabetes. Overall, little evidence of benefit from regular use of vitamin C or E supplements exists, and this study offers one reason to discourage their use and to encourage diets that are rich in fruits and vegetables.

Journal Watch General Medicine summary (Free)

http://www.ncbi.nlm.nih.gov/pubmed/19433800?dopt=Abstract

http://www.lancet.com/journals/lancet/article/PIIS0140-6736(09)60619-X/abstract