Caffeine Boosts Insulin Resistance Regardless of Exercise, Weight Loss

By Anne Harding

NEW YORK (Reuters Health) Mar 18 - Caffeine intake has a negative effect on insulin sensitivity in men with and without type 2 diabetes, and this effect persists even with regular exercise and loss of adiposity, Canadian researchers report.

"Through mechanisms that have yet to be firmly established, caffeine attenuates any of the beneficial effects of exercise or weight loss on insulin resistance," Dr. Robert Ross of Queens University in Kingston, Ontario, told Reuters Health. While the clinical implications remain unclear, Dr. Ross added, the findings are a "red flag" for clinicians and are particularly important for obese patients and those with diabetes, who already are at greater metabolic risk.

Dr. Ross and his team performed hyperinsulemic-euglycemic clamp procedures in 23 men before and after a three-month exercise program. The men were given 5 mg/kg of caffeine or placebo in a double-blind, randomized fashion. Subjects included eight sedentary lean men, seven obese men with type 2 diabetes and eight obese men without diabetes.

Before the exercise program, caffeine reduced insulin sensitivity by 33% in the lean and obese men and 37% in the men with type 2 diabetes compared to placebo. After the exercise program, insulin sensitivity fell 23% after caffeine intake in the lean men, 26% in the obese men, and 36% in the diabetic men. The post-exercise difference was not statistically significant.

The findings, published in the March issue of Diabetes Care, seem to contradict recent reports that coffee intake is associated with a reduction in type 2 diabetes risk, Dr. Ross noted. However, coffee contains several other substances that may affect glucose metabolism, such as antioxidants, potassium and magnesium. "When you give somebody caffeine without all of the other substances that are in coffee you have a very different situation," he added.

"What is clear," he continued, "is that caffeine has a very powerful physiological effect."

Diabetes Care 2005;28:576-572.

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Investigational Diabetes Drug Trials Halted After Health Problems

Two trials of the experimental diabetes drug CS-917 were halted after two patients also taking metformin developed serious health problems, Metabasis announced Wednesday.

Metabasis said it had been informed by Sankyo Co. Ltd., its partner in developing CS-917, that the two patients apparently developed lactic acidosis. The two affected patients were participating in a trial designed to test the safety of using the drugs in combination for type 2 diabetes.

The company said both patients were successfully treated for lactic acidosis, which has previously been associated with metformin, sold by Bristol-Myers Squibb Co. under the name Glucophage.

Metabasis said a second study, involving use of a relatively high dose of CS-917 to evaluate timing of doses, was also stopped, although no similar health problems were seen in that trial.

"These adverse events raise safety concerns for CS-917 that we and our partner need to fully and carefully evaluate," Metabasis said in a release, adding that no patients were currently receiving its drug in any trial.

Investigational Diabetes Drug Trials Halted After Health Problems

Two trials of the experimental diabetes drug CS-917 were halted after two patients also taking metformin developed serious health problems, Metabasis announced Wednesday.

Metabasis said it had been informed by Sankyo Co. Ltd., its partner in developing CS-917, that the two patients apparently developed lactic acidosis. The two affected patients were participating in a trial designed to test the safety of using the drugs in combination for type 2 diabetes.

The company said both patients were successfully treated for lactic acidosis, which has previously been associated with metformin, sold by Bristol-Myers Squibb Co. under the name Glucophage.

Metabasis said a second study, involving use of a relatively high dose of CS-917 to evaluate timing of doses, was also stopped, although no similar health problems were seen in that trial.

"These adverse events raise safety concerns for CS-917 that we and our partner need to fully and carefully evaluate," Metabasis said in a release, adding that no patients were currently receiving its drug in any trial.

Aggressive Lipid-Lowering Therapy Reduces Cardiovascular Events

March 8, 2005 (Orlando) — Aggressive lipid-lowering therapy to achieve low-density lipoprotein (LDL) cholesterol levels of less than 80 mg/dL is associated with a 22% reduction in relative risk of fatal and nonfatal myocardial infarction and stroke and coronary heart disease mortality, according to data reported here Tuesday at the American College of Cardiology 2005 Annual Scientific Session.

Results of the Pfizer-sponsored 10,001 patient study, Treating to New Targets (TNT), were also published online by the New England Journal of Medicine.

In addition to the benefit demonstrated in the combined primary end point, patients in the aggressive treatment group (atorvastatin, 80 mg) had a 25% reduction in risk of stroke compared with patients treated with 10 mg of atorvastatin to a mean LDL cholesterol level of 101 mg/dL (P = .007).

"We have entered a new era in the treatment of established coronary disease from starting at an LDL of 100," said principal investigator John C. LaRosa, MD, from the State University of New York Health Science Center in Brooklyn. Dr. LaRosa presented the findings at an ACC plenary session.

After an eight-week open-label run in treatment with 10 mg of atorvastatin, patients who achieved a mean LDL cholesterol level of less than 130 mg/dL were randomized to 10 mg (n = 5,006) or 80 mg (n = 4,995) of atorvastatin per day. The patients were followed for 4.9 years.

The primary end point was occurrence of fatal or nonfatal stroke or myocardial infarction, resuscitation after cardiac arrest, or death from coronary heart disease.

In the 80-mg group, there were 434 events compared with 558 events in the 10-mg treatment group. This was an absolute risk reduction of 2.2% and a relative risk reduction of 22% (P = .0002), Dr. LaRosa said.

In addition, the risk for a major coronary event was reduced by 20% in the 80-mg group compared with the 10-mg group (P = .002), and the risk of hospitalization for congestive heart failure was reduced by 25% in the high-dose group vs the low-dose group (P = .01).

Moreover, the benefits were achieved without any significant increases in adverse events. There were five cases of rhabdomyolysis (two in the high-dose group). There was, however, no difference in overall mortality between the two groups, but Dr. LaRosa said the study was not powered to show a difference.

Sidney Smith, MD, director of the Center for Cardiovascular Science and Medicine at the University of North Carolina in Chapel Hill and a spokesperson for the American Heart Association, was enthusiastic about the results and not overly concerned about the failure to demonstrate a benefit in overall mortality. As he explained in an interview with Medscape, "Given the choice, I think most people would like to be alive without a stroke than alive with a stroke."

Dr. Smith said that he and other cardiologists have been awaiting the TNT results since last March, when a study from Harvard researchers reported that aggressive LDL cholesterol lowering to less than 70 mg/dL was associated with a 28% reduction in all-cause mortality and a 25% reduction in risk of death from MI or need for urgent revascularization compared with less aggressive treatment. That study compared 80 mg of atorvastatin to 40 mg of pravastatin.

Dr. Smith said, however, that it is probably too soon to change treatment guidelines because two more large studies comparing high-dose statins to lower-dose statins are expected to be reported in the next 12 months.

Christopher P. Cannon, MD, the Harvard cardiologist who was the principal investigator of last year's statin study, is less cautious. "Why wait? This works, is safe, and benefits patients," Dr. Cannon told Medscape. At the very least, he said he thinks that is time to incorporate aggressive statin treatment into clinical practice.

Neither Dr. Smith nor Dr. Cannon was involved in the study.

Speaking at a press conference, Dr. LaRosa said, "I don't think we should change guidelines on the basis of a single study." But he added that he is convinced that treatment with 80 mg of atorvastatin is "absolutely safe."

ACC 2005 Annual Scientific Session: Late-breaking clinical trials. Presented March 8, 2005.

Reviewed by Gary D. Vogin, MD

Diabetes Triples Risk of Liver Cancer

NEW YORK (Reuters Health) Mar 07 - It appears that diabetes is an independent risk factor for hepatocellular carcinoma (HCC), raising the risk two- to three-fold, investigators report in the April issue of Gut.

While previous studies have revealed a relationship between diabetes and HCC (see Reuters Health reports, February 25 and September 7, 2004), results were based on referral samples and selection bias may have occurred.

The current study, using data from the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database, is the first population-based case-control study in the US that adjusted for other major risk factors related to HCC, senior author Dr. Hashem El-Serag, at Baylor College of Medicine in Houston, and colleagues maintain.

The study included 2161 patients aged 65 and older with diagnostic confirmation of HCC between 1994 and 1999. The control group included 6183 randomly selected individuals.

The authors found that 43.3% of HCC patients and 19.4% of control subjects had diabetes diagnosed during the 3 years preceding the date of HCC diagnosis (to exclude the possibility that HCC was the cause of the diabetes).

After adjusting for demographic factors, the odds ratio of HCC associated with diabetes was 3.08 (p < 0.0001). After excluding patients with hepatitis B or C virus, alcoholic liver disease or hemochromatosis, the odds ratio remained 2.87 to 3.11.

Hepatitis C virus alone was associated with an odds ratio of 24.42. In the presence of diabetes, it was increased to 36.88, suggesting a synergistic interaction between the two diseases.

"Diabetes may account for a significant proportion of patients with idiopathic HCC," Dr. El-Serag's group concludes.

Gut 2005;54:533-539.

Infliximab reduces diabetic macular edema

NEW YORK (Reuters Health) - The monoclonal antitumor necrosis factor monoclonal antibody infliximab is showing promise for the treatment of severe macular edema in patients with type 2 diabetes, according to the results of a small prospective study.

"The observed recovery of useful vision in eyes that are in danger of vision loss due to long-standing, severe diabetic macular edema was impressive, especially since the standard treatment with laser photocoagulation had previously failed," lead investigator Dr. Petros P. Sfikakis told Reuters Health,

In the February issue of Diabetes Care, Dr. Sfikakis and colleagues at the University of Athens describe a case series of four women between 52 and 76 years, with diabetes type 2 and sight-threatening refractory diabetic macular edema.

Diabetic macular edema of more than 12 months duration was seen in seven of the eyes, six of which were refractory to laser treatment. The women were given two monthly intravenous infusions of infliximab (5 mg/kg; Remicade).

The therapy was well tolerated. Two patients received one additional infusion and one patient received two additional infusions. Macular thickness decreased in five of the eyes without coexisting epiretinal membranes.

Follow-up ranged from 4 to 7 months after the last infusion. In two eyes, there was a recurrence of diabetic macular edema, but at a less severe level. The effect remained stable in the other three eyes for up to 11 months.

"We are hopeful about this new therapy," continued Dr. Sfikakis, "but long-term effects and safety studies must still be completed. If confirmed, this can be regarded as a significant success... because of the bad prognosis of this condition."

Diabetes Care 2005;28:445-447.

Lifestyle and metformin interventions cost-effective for preventing diabetes

NEW YORK (Reuters Health) - The Diabetes Prevention Program (DPP), which involves lifestyle or metformin interventions, has been shown to delay or prevent the development of type 2 diabetes. Now, new research indicates that the DPP approach is cost-effective.

Meanwhile, in a similar study, lifestyle modifications were found to decrease the risk of diabetes in nonsmokers without impaired glucose tolerance, echoing what was seen previously in patients with impaired tolerance.

Both reports appear in the Annals of Internal Medicine for March 1.

In the first study, Dr. William H. Herman, from the University of Michigan in Ann Arbor, and colleagues used a Markov simulation model to assess the cost-effectiveness of the DPP interventions among subjects 25 years of age or older with impaired glucose tolerance.

The lifestyle intervention of the DPP involved a healthy, low-calorie/low-fat diet and moderate physical activity reinforced on a one-to-one basis and in group sessions. The metformin intervention involved a twice-daily dose of 850 mg with adherence support by a case manager.

The lifestyle and metformin interventions delayed the onset of diabetes by 11 and 3 years, respectively, compared with placebo, the authors note. The corresponding reductions in the absolute incidence of diabetes were 20% and 8%. In addition, both interventions reduced the occurrence of diabetic complications and improved survival.

Compared with placebo, the cost per quality-adjusted life-years (QALYs) for the lifestyle and metformin interventions was $1100 and $31,300, respectively, the researchers found. The corresponding costs per QALY, from a societal perspective, were $8800 and $29,900. In both analyses, the metformin intervention was dominated by the lifestyle intervention.

In the second study, Dr. George Davey Smith, from the University of Bristol in the UK, and colleagues assessed the incidence of diabetes among 11,827 men without impaired glucose tolerance who participated in the Multiple Risk Factor Intervention Trial (MRFIT). As part of the trial, the subjects were randomized to receive a lifestyle intervention, similar to that used in the DPP, or usual care.

In the overall analysis, the rate of diabetes in the intervention group -- 11.5% -- was actually slightly higher than the rate in the usual care group -- 10.8%. Further analysis revealed that the lifestyle intervention raised the risk of diabetes among smokers by 26%, but lowered the risk among nonsmokers by 18% (p = 0.0003).

As to why this occurred, the authors believe that the smoking cessation encouraged by the intervention may have resulted in weight gain among smokers that counterbalanced the beneficial effects seen. By contrast, this would not have occurred in patients who were nonsmokers at baseline.

In a related editorial, Dr. Jaakko Tuomilehto, from the National Public Health Institute in Helsinki, Finland, comments that while these reports show that lifestyle interventions can delay or prevent diabetes and are cost effective, the question remains of "what should be done with smokers?" It is possible that switching from diuretics and beta-blockers to drugs that interfere with the renin-angiotensin system may help cut the risk of diabetes in smokers with hypertension.

Ann Intern Med 2005;142:313-332,381-383.

Toe Pulse Oximetry May Help Detect Lower Extremity Arterial Disease in Type 2 Diabetics

March 2, 2005 — Pulse oximetry of the toes may be as accurate as ankle-brachial index (ABI) for the screening of lower extremity arterial disease (LEAD) in patients with type 2 diabetes, according to the results of a study published in the Feb. 28 issue of the Archives of Internal Medicine.

"LEAD is common and underdiagnosed in patients with diabetes mellitus and is associated with higher total mortality," write G. Iyer Parameswaran, MD, and colleagues from Unity Health System in Rochester, New York. "Early detection of LEAD, before the onset of symptoms in patients with diabetes mellitus, is desirable and can lead to tighter, better control of risk factors for arterial disease."

The investigators compared the accuracy of pulse oximetry, ABI, and both tests combined to diagnose LEAD in 57 consecutive outpatients with type 2 diabetes but with no symptoms of LEAD. Patients younger than 40 years and those with known LEAD or typical symptoms of LEAD were excluded. All patients underwent ABI measurement, which was considered abnormal if it was less than 0.9; pulse oximetry to measure SaO2 of the index fingers and big toes in the supine position and at 12-inch elevation; and Doppler waveform analysis of lower extremity arteries.

Pulse oximetry of the toes was classified as abnormal if the SaO2 was more than 2% lower than in the finger or when the foot was elevated 12 inches. The combination of both tests was classified as positive if either test was positive for LEAD, and negative if both tests were negative.

LEAD, defined as monophasic waveforms on Doppler waveform analysis, was present in 31% of patients. For pulse oximetry, sensitivity was 77% (95% confidence interval [CI], 61% - 88%) and specificity was 97% (95% CI, 91% - 99%). For ABI, sensitivity was 63% (95% CI, 46% - 77%) and specificity was 97% (95% CI, 91% - 99%). Positive likelihood ratios were 30 (95% CI, 7.6 - 121) for pulse oximetry and 24.8 (95% CI, 6.2 - 99.8) for ABI. Negative likelihood ratios were 0.23 (95% CI, 0.12 - 0.43) for pulse oximetry and 0.38 (95% CI, 0.25 - 0.59) for ABI. For both tests combined, sensitivity was 86% (95% CI, 71% - 94%) and specificity was 92% (95% CI, 84% - 96%).

"Pulse oximetry of the toes seems as accurate as ABI to screen for LEAD in patients with type 2 diabetes," the authors write. "Combination of the two tests increases sensitivity."

Study limitations include the small number of patients; performance of the tests by one investigator, precluding measurement of interobserver variability; and the possibility that the sequence of measurements, pulse oximetry followed by ABI, may have influenced the measurements and results.

"These results suggest that pulse oximetry may be a useful additional tool to screen for LEAD in patients with diabetes mellitus," the authors conclude. "Assessment of change in clinical outcomes owing to modification of risk factors for atherosclerosis in asymptomatic patients identified by screening as having LEAD is an area that needs further research."

The authors report no financial conflicts of interest.

Arch Intern Med. 2005;165:442-446

Exercise Inception, Even Late in Life, Cuts Cardiovascular Risks

NEW YORK (Reuters Health) Mar 11 - Adopting a regular exercise routine for the first time later in life, reduces the development of metabolic risk factors for cardiovascular disease, Canadian researchers report in the March issue of Diabetes Care.

"Our next step," lead investigator, Dr. Robert John Petrella, said in an interview with Reuters Health, "is to expand the impact into the broader community."

In particular, Dr Petrella and colleagues at the University of Western Ontario, London examined the effect of chronic exercise training on the development of metabolic markers of cardiovascular disease. Two cohorts of previously sedentary healthy adults between the ages of 55 and 75 years were studied.

One group initiated regular supervised physical exercise training and the other acted as a sedentary control group. Baseline fitness levels were similar between groups.

At 10 years, complete data were available for 161 active and 136 sedentary subjects. Withdrawal was mostly due to failure to adhere to the exercise program in the active group and poor physical health in the sedentary group.

Sedentary patients exhibited significantly more metabolic abnormalities than active patients. Active subjects demonstrated a 3.5% increase in fitness levels versus a 13.8% decrease in sedentary patients.

Sedentary patients were also more likely to have a positive exercise electrocardiogram or symptom (32%) than were active subjects (10%). They also had more comorbidities.

Overall, 11% of active group patients and 28% of sedentary group patients had the metabolic syndrome at 10 years. In the active group, those who moved from low to moderate to high fitness showed significantly fewer metabolic markers compared to those who remained at a low fitness levels or moved to a lower level.

In light of these findings and "since primary care physicians have greatest contact with most of the population at risk for cardiovascular disease," Dr. Petrella concluded, giving such lifestyle intervention to patients "could have the best impact if it were delivered by primary care physicians."

Diabetes Care 2005;28:694-701.

Glucose Tolerance Test, B12 Levels Best to Diagnose Sensory Neuropathy

May 11, 2004 — Patients with sensory neuropathy should be evaluated with a glucose tolerance test and vitamin B12 levels, while other studies should be based on clinical findings, according to the results of a study published in the May 10 issue of the Archives of Internal Medicine.

"Peripheral neuropathy is a common problem that often prompts a lengthy and expensive diagnostic evaluation," write A. Gordon Smith, MD, and J. Robinson Singleton, MD, from the University of Utah School of Medicine in Salt Lake City. "A rational, evidence-based diagnostic approach to peripheral neuropathy is desirable.... The goal was to develop a focused diagnostic algorithm that can be easily applied in a general medical setting."

Using a standard diagnostic approach, the authors evaluated 138 patients referred with predominantly sensory symptoms and no previously defined etiology for neuropathy.

Family history was positive in 25% of patients, with at least one first-degree relative with symptoms suggesting neuropathy. The two-hour oral glucose tolerance test (OGTT) had the highest diagnostic yield (61%) of all laboratory tests and was more sensitive than other measures of glucose metabolism. Two patients were diagnosed with vitamin B12 deficiency.

Less than 5% of patients had abnormal results of serum protein electrophoresis, immunofixation, or antinuclear antibody testing, which is comparable to rates found in the general population.

Based on these findings, the authors suggest that patients with sensory-predominant neuropathy should be tested for glucose tolerance and vitamin B12 level, that abnormalities of serum protein electrophoresis and antinuclear antibodies are of uncertain significance, and that other tests should be performed only when the clinical scenario is suggestive.

"Using this approach, only 31% of patients completing the recommended evaluation were found to have an idiopathic neuropathy," the authors write. "Patients with atypical features may benefit from referral to a peripheral neuropathy center."

Study limitations include the tertiary care setting, in which the prevalence of laboratory abnormalities could be biased against common disorders, and the fact that not every patient had every recommended test.

Since the manuscript was accepted for publication, the American Diabetes Association (ADA) revised its criterion for impaired fasting glucose (IFG) as ranging from 100 to 125 mg/dL (5.6 - 6.9 mmol/L). Of an additional 12 patients with IFG using the new criterion, seven had impaired glucose tolerance (IGT) and two had diabetes on the basis of the two-hour plasma glucose test during an OGTT.

"The revised criterion has not substantially altered the diagnostic yield of the fasting plasma glucose test (either alone or as part of the OGTT) in this patient population," the authors write.

The authors report no relevant financial interest in this article.

Arch Intern Med. 2004;164:1021-1025

U.S. Group Says Crestor Risk Higher Than Other Statins

WASHINGTON (Reuters) Mar 10 - The rate of serious muscle damage reported in patients who took AstraZeneca Plc's Crestor (rosuvastatin) was six times higher than with other statins, a consumer group said on Thursday.

The findings by consumer group Public Citizen contradicted a statement by the U.S. Food and Drug Administration last week that the risks of muscle injury from Crestor were similar to those of related drugs.

Public Citizen renewed its call for the FDA to immediately ban Crestor.

The group said it had reviewed reports of cases of rhabdomyolysis and compared them with the number of prescriptions filled for each drug. The reports were submitted to the FDA between Oct. 1, 2003, and Sept. 30, 2004.

For Crestor, there were about 13 reports of rhabdomyolysis for every million prescriptions filled, Public Citizen estimated. That rate was 6.2 times higher than the rates for all other statins combined.

The lowest rate among other statins was 0.6 reports per million prescriptions of Bristol-Myers Squibb's Pravachol (pravastatin).

"These data affirm the pre-approval findings from clinical trials of increased muscle damage/rhabdomyolysis for Crestor compared with other statins and refute the FDA statement that the rates are 'similar'," Public Citizen said in a letter to FDA Commissioner Lester Crawford.

Last week, the FDA said it had completed a review of Crestor's safety and concluded risks of muscle injury were similar to those of other statins. To reduce the risk, doctors were advised to consider the lowest possible dose for certain patients.

AstraZeneca has repeatedly defended Crestor as safe and effective when used according to directions.

Public Citizen first petitioned the FDA to ban Crestor in March 2004.

Impact on Medication Use and Adherence of Australian Pharmacists' Diabetes Care Services

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Abstract and Introduction
Abstract

Objective: To assess the effect of a specialized service implemented in community pharmacies for patients with type 2 diabetes on medication use and medication-related problems.
Design: Parallel group, multisite, control versus intervention, repeated measures design, with three different regions in New South Wales, Australia, used as intervention regions, then matched with control regions as much as possible.
Intervention: After initial training, pharmacists followed a clinical protocol for more than 9 months, with patient contact approximately monthly. Each patient received an adherence assessment at the beginning and end of the study, adherence support, and a medication review as part of the intervention.
Main Outcome Measures: Risk of nonadherence using Brief Medication Questionnaire (BMQ) scores and changes to medication regimen.
Results: Compared with 82 control patients, 106 intervention patients with similar demographic and clinical characteristics had significantly improved self-reported nonadherence as reflected in total BMQ scores after 9 months. The mean (± SD) number of medications prescribed at follow-up in intervention participants decreased significantly, from 8.2 ± 3.0 to 7.7 ± 2.7. No reduction was observed among the control patients (7.6 ± 2.4 and 7.3 ± 2.4). The overall prevalence of changes to the regimen was also significantly higher in the intervention group (51%) compared with controls (40%).
Conclusion: Community pharmacists trained in medication review and using protocols in collaboration with providers improved adherence in patients with type 2 diabetes, reduced problems patients had in accessing their medications, and recommended medication regimen changes that improved outcomes.
Introduction

Diabetes mellitus (DM) is a chronic incurable disease whose prevalence is growing worldwide.[1] Approximately 7.5% of Australians older than 25 years have diabetes, and more than one half of them are undiagnosed. In Australia, the direct annual health care costs for treating diabetes and its associated complications were estimated to be AU$1.4 billion in 1995 and may reach AU$2.3 billion by 2010.[2]

Since the publication of evidence......Cont online

Should All Diabetic Patients Receive a Statin? Results From Recent Trials

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Abstract

Diabetes is associated with the development of premature cardiovascular disease. In the three early trials of statin therapy for patients with established coronary heart disease there were many patients with diabetes; subgroup analysis has confirmed the benefits of cholesterol lowering with statin therapy in these patients. In the two early primary prevention trials, however, there were few patients with diabetes and so, initially, there was little evidence supporting the use of statins in diabetic patients without cardiovascular disease. The Heart Protection Study (HPS) and Collaborative AtoRvastatin Diabetes Study (CARDS) have now provided this evidence and firmly established that cholesterol lowering is of benefit in reducing cardiovascular events in patients with type 2 diabetes, regardless of the level of baseline cholesterol, or the presence or absence of cardiovascular disease. A few recent studies have failed to find benefit in diabetic patients but there are explanations for these negative findings. Ideally all patients with diabetes, especially the middle-aged and elderly, should be treated with statins but it remains uncertain at what age therapy should start and how low to reduce the cholesterol for maximum benefit.
Introduction..Cont............

Diabetes Triples Risk of Liver Cancer

NEW YORK (Reuters Health) Mar 07 - It appears that diabetes is an independent risk factor for hepatocellular carcinoma (HCC), raising the risk two- to three-fold, investigators report in the April issue of Gut.

While previous studies have revealed a relationship between diabetes and HCC (see Reuters Health reports, February 25 and September 7, 2004), results were based on referral samples and selection bias may have occurred.

The current study, using data from the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database, is the first population-based case-control study in the US that adjusted for other major risk factors related to HCC, senior author Dr. Hashem El-Serag, at Baylor College of Medicine in Houston, and colleagues maintain.

The study included 2161 patients aged 65 and older with diagnostic confirmation of HCC between 1994 and 1999. The control group included 6183 randomly selected individuals.

The authors found that 43.3% of HCC patients and 19.4% of control subjects had diabetes diagnosed during the 3 years preceding the date of HCC diagnosis (to exclude the possibility that HCC was the cause of the diabetes).

After adjusting for demographic factors, the odds ratio of HCC associated with diabetes was 3.08 (p < 0.0001). After excluding patients with hepatitis B or C virus, alcoholic liver disease or hemochromatosis, the odds ratio remained 2.87 to 3.11.

Hepatitis C virus alone was associated with an odds ratio of 24.42. In the presence of diabetes, it was increased to 36.88, suggesting a synergistic interaction between the two diseases.

"Diabetes may account for a significant proportion of patients with idiopathic HCC," Dr. El-Serag's group concludes.

Gut 2005;54:533-539.



Reuters Health Information 2005. © 2005 Reuters Ltd.
Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.

Lifestyle and metformin interventions cost-effective for preventing diabetes

Last Updated: 2005-02-28 17:00:10 -0400 (Reuters Health)

NEW YORK (Reuters Health) - The Diabetes Prevention Program (DPP), which involves lifestyle or metformin interventions, has been shown to delay or prevent the development of type 2 diabetes. Now, new research indicates that the DPP approach is cost-effective.

Meanwhile, in a similar study, lifestyle modifications were found to decrease the risk of diabetes in nonsmokers without impaired glucose tolerance, echoing what was seen previously in patients with impaired tolerance.

Both reports appear in the Annals of Internal Medicine for March 1.

In the first study, Dr. William H. Herman, from the University of Michigan in Ann Arbor, and colleagues used a Markov simulation model to assess the cost-effectiveness of the DPP interventions among subjects 25 years of age or older with impaired glucose tolerance.

The lifestyle intervention of the DPP involved a healthy, low-calorie/low-fat diet and moderate physical activity reinforced on a one-to-one basis and in group sessions. The metformin intervention involved a twice-daily dose of 850 mg with adherence support by a case manager.

The lifestyle and metformin interventions delayed the onset of diabetes by 11 and 3 years, respectively, compared with placebo, the authors note. The corresponding reductions in the absolute incidence of diabetes were 20% and 8%. In addition, both interventions reduced the occurrence of diabetic complications and improved survival.

Compared with placebo, the cost per quality-adjusted life-years (QALYs) for the lifestyle and metformin interventions was $1100 and $31,300, respectively, the researchers found. The corresponding costs per QALY, from a societal perspective, were $8800 and $29,900. In both analyses, the metformin intervention was dominated by the lifestyle intervention.

In the second study, Dr. George Davey Smith, from the University of Bristol in the UK, and colleagues assessed the incidence of diabetes among 11,827 men without impaired glucose tolerance who participated in the Multiple Risk Factor Intervention Trial (MRFIT). As part of the trial, the subjects were randomized to receive a lifestyle intervention, similar to that used in the DPP, or usual care.

In the overall analysis, the rate of diabetes in the intervention group -- 11.5% -- was actually slightly higher than the rate in the usual care group -- 10.8%. Further analysis revealed that the lifestyle intervention raised the risk of diabetes among smokers by 26%, but lowered the risk among nonsmokers by 18% (p = 0.0003).

As to why this occurred, the authors believe that the smoking cessation encouraged by the intervention may have resulted in weight gain among smokers that counterbalanced the beneficial effects seen. By contrast, this would not have occurred in patients who were nonsmokers at baseline.

In a related editorial, Dr. Jaakko Tuomilehto, from the National Public Health Institute in Helsinki, Finland, comments that while these reports show that lifestyle interventions can delay or prevent diabetes and are cost effective, the question remains of "what should be done with smokers?" It is possible that switching from diuretics and beta-blockers to drugs that interfere with the renin-angiotensin system may help cut the risk of diabetes in smokers with hypertension.

Ann Intern Med 2005;142:313-332,381-383.

Angiotensin receptor blockade improves renal blood flow in diabetics

Last Updated: 2005-02-22 12:25:13 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Chronic angiotensin II receptor blockade with olmesartan improves renal vascular perfusion despite significant blood pressure reductions in patients with type 2 diabetes, according to a report by German researchers in the April issue of the Journal of the American Society of Nephrology.

"Angiotensin II subtype 1 receptor antagonists (AT1-RA) not only lower blood pressure, but at the same time lower intraglomerular pressure and increase renal perfusion," Dr. Danilo Fliser from Medical School Hannover told Reuters Health. "Thus, their use offers a complete prevention of hemodynamically mediated damage to the diabetic kidney."

Dr. Fliser and colleagues examined the effect of 12 weeks of treatment with the AT1-RA olmesartan on renal hemodynamics in 35 patients with type 2 diabetes.

Blood pressure fell significantly with olmesartan treatment, the authors report, but did not change significantly in patients that received placebo.

Olmesartan treatment was associated with a significant increase in effective renal plasma flow and decreases in filtration fraction and renal vascular resistance, but glomerular filtration rate did not change with AT1-RA blockade. In contrast, patients that received placebo experienced a significant increase in filtration fraction and a nonsignificant increase in renal vascular resistance.

Reductions in isoprostane generation in the patients treated with olmesartan suggest that chronic AT1-RA blockade may prevent renal vascular damage not only by direct hemodynamic effects but also by reducing inflammation and/or reactive oxygen species generation, the investigators explain.

"Our results document that the favorable renal hemodynamic action of AT1-RA observed in acute experiments in individuals with type 2 diabetes persists even after prolonged AT1-receptor blockade," the authors conclude. "This effect may contribute to the renoprotective effect of AT1-RA documented in large prospective trials on prevention of progression of diabetic nephropathy."

Dr. Fliser added that "our findings support the routine use of AT1-RA, at least in diabetic patients with hypertension and/or presence of renal involvement."

J Am Soc Nephrol 2005.

Finding type 2 diabetics in primary care

A concern about the obesity epidemic is the increased numbers of people with adult-onset diabetes. Chance finding of frank diabetes or pre-diabetic hyperglycaemia is often a major trigger for lifestyle changes of less but better food, more exercise, and lost weight. Early detection and better control could ameliorate problems associated with diabetes.

This smacks of screening. Screening is a word fraught with danger, because in any set of circumstances there are three camps: the small numbers of enthusiasts who are either for it or against it, and the great mass of normal professionals whose main reaction is profound cynicism about another target. A study that shows that real-world targeted screening can work and might make sense [1] is a welcome relief.

Study

The study was conducted in 16 practices in Somerset and Devon, randomly selected from 42 volunteer practices. They had to have over 3,500 patients and have good (>60%) recording of BMI. Each practice was asked to sample 100 patients, 25 from each of four groups with different entry criteria (Table 1) relating to age and BMI. Selection of patients within the practices was done randomly. Patients could be selected for more than one group. Those with previously diagnosed diabetes were excluded, and only Caucasians were screened.

Trained practice nurses ran the screening clinics. Patients were sent a provisional clinic appointment, followed up by telephone reminder. Weight, height and age were recorded, and a fasting venous blood sample taken for plasma glucose measurement. Those with fasting plasma glucose over 6 mmol/L were invited for repeat testing. Diabetes was defined as plasma glucose of 7 mmol/L or more on both occasions. Impaired fasting glycaemia was defined as levels of 6.1-6.9 mmol/L on both tests.

Results

The response rate to invitation to attend the screening clinic was 61%. That meant 1,287 people attended, and, as some were in more than one group, there were 1,644 data points for analysis. BMI information was available for 77% of the over-50 population, and 20% of these were out of date or inaccurate compared with clinic measured BMI. Self-reported age differed from practice computer in 27/1,287 cases by more than one year. Of the 1,287 who attended for screening:

* 199 (15%) had an abnormal first test
* All of these attended a second time
* 148 (12%) had an abnormal second test
* 55 (4.3%) had type 2 diabetes
* 93 (7.2%) had impaired fasting glycaemia

The numbers of patients needed to be screened to detect one case of type 2 diabetes or impaired fasting glycaemia was low (7-13, Table 1), and reasonably flat across the groups.



Comment

These screening strategies discovered substantial numbers of people with previously undiagnosed type 2 diabetes. Undiagnosed diabetes rates were about 20% of those already diagnosed. For those with impaired fasting glycaemia, a glucose tolerance test might have been appropriate. Better recording of BMI and an expert computer system (they do exist!) could identify people at risk relatively simply. Practices could choose what criteria they might wish to adopt based on perceived workload, and on resources available. Lower age and BMI criteria should identify people early enough for lifestyle changes to be effective, especially in those with impaired glycaemia.

Reference:

1. CJ Greaves et al. A simple pragmatic system for detecting new cases of type 2 diabetes and impaired fasting glycaemia in primary care. Family Practice 2004 21: 57-62.

Internet diabetes monitoring

The setting for this trial was Korean patients with type 2 diabetes and Internet access. Severe concomitant disease was an exclusion criterion, or previous participation in any similar programme. Participants underwent examination and laboratory tests before and after 12 weeks in the study.

Patients consenting to participate were randomised to usual or Internet care. Usual care involved monthly visits with two or three visits with senior staff during a 12 week period. The Internet intervention consisted of a portal in which patients could enter pre- and postprandial blood glucose results, with information on type and dose of glucose lowering drugs, weight, exercise, and any other important changes. There was also an opportunity to ask questions.

Internet diabetes monitoring

The setting for this trial was Korean patients with type 2 diabetes and Internet access. Severe concomitant disease was an exclusion criterion, or previous participation in any similar programme. Participants underwent examination and laboratory tests before and after 12 weeks in the study.

Patients consenting to participate were randomised to usual or Internet care. Usual care involved monthly visits with two or three visits with senior staff during a 12 week period. The Internet intervention consisted of a portal in which patients could enter pre- and postprandial blood glucose results, with information on type and dose of glucose lowering drugs, weight, exercise, and any other important changes. There was also an opportunity to ask questions.