Medical Monofilament Sensory Nerve Testers For Diabetics

Monofilaments: History and Importance

The history of the use of various filaments to test for the presence or absence of sensation dates back to the 1800’s when Von Frey used horsehairs for testing patients’ sensation thresholds. In 1960, Dr. Josephine Semmes and Dr. Sidney Weinstein developed a more sophisticated set of medical grade sensory testing monofilaments.1 Their premise was that an increased diameter of a monofilament would be accompanied by a required increased force needed to create a bend in the monofilament when it was applied to the surface to be tested. They created a progressive scale of monofilaments for neurologic sensory testing. Monofilaments are assigned numbers that range from 4.17 to 6.10. The higher the number, the stiffer the filament. The formula utilized is as follows: Marking = (log10 Force(in mg) x 10). The 5.07 monofilament has been accepted as the medical standard for screening of the minimum level of protective sensation in the foot. The reproducible buckling stress force required to bend the 5.07 monofilament is 10 grams of force.2



The problem with the original Semmes - Weinstein monofilaments was primarily related to cost. The same is true of many of the more recent versions of this product with a plastic handle designed to hold the monofilament. These devices have primarily been distributed only to health care professionals. Another clinical tool often used by health care professionals for sensory testing is the 128 C Tuning Fork used for testing vibratory perception. Again, cost, lack of ease of use and limited distribution are problems with this instrument. In fact, a number of studies have shown that the monofilament is a tool equal to that of the tuning fork as a way to diagnose loss of sensation.
TEST DEMO

Walnuts May Improve Lipid Profile in Type 2 Diabetes

Dec. 1, 2004 — Adding walnuts to a low-fat diet improves lipid profile for patients with type 2 diabetes, according to the results of a randomized study published in the December issue of Diabetes Care.

"Walnuts are distinguished from other nuts by virtue of their higher polyunsaturated fat content (and importantly their ?-linolenic acid [ALA] content) combined with antioxidants in the form of ?-tocopherol," write Linda C. Tapsell, PhD, from the National Centre of Excellence in Functional Foods, University of Wollongong in New South Wales, Australia, and colleagues. "There are mechanistic explanations for the influence of dietary polyunsaturated fatty acid (PUFA) on insulin action and energy metabolism, and cohort studies of women in the U.S. have demonstrated a reduced risk of developing type 2 diabetes with dietary PUFA replacing trans or saturated fatty acids (SFAs)."

In this parallel design trial, 58 adults with type 2 diabetes were randomized to one of three dietary advice groups, each with 30% energy as fat: low fat, modified low fat, and modified low fat inclusive of 30 g of walnuts per day. Mean age was 59.3 ± 8.1 years.

Patients received dietary advice at baseline, with monthly follow-up and telephone calls bimonthly for support. All groups were advised to consume fish and five daily portions of fruits and vegetables. Body weight, percent body fat, blood lipids, glycosylated hemoglobin (HbA1c), total antioxidant capacity, and erythrocyte fatty acid levels were measured at baseline and at three and six months, and analysis was by intent-to-treat.

Erythrocyte biomarkers of dietary intake confirmed higher dietary polyunsaturated fat-to-saturated fat ratio and intakes of ?-3 fatty acids in the walnut group. Compared with the two other treatment groups, the walnut group had a significantly greater increase in high-density lipoprotein (HDL) cholesterol-to-total cholesterol ratio (P = .049) and in HDL (P = .046). The walnut group also had a 10% reduction in low-density lipoprotein (LDL) cholesterol, reflecting a significant effect by group (P = .03) and time (P = .04).

The three groups were similar in changes in body weight, percent body fat, total antioxidant capacity, and HbA1c levels.

Study limitations include open recruitment; participation of only 50% of volunteers, limiting generalizability of the results; and lower baseline cholesterol levels in the walnut group.

"Structured 'whole of diet' advice that included 30 g of walnuts/day delivering substantial amounts of polyunsaturated fatty acid improved the lipid profile of patients with type 2 diabetes," the authors conclude.

The Australian Research Council and the California Walnut Commission funded this study.

Diabetes Care. 2004;27:2777-2783

Measurements in the Diabetic Foot

Abstract and Introduction
Abstract

Diabetic foot syndrome is complex, affects up to 20% of patients with diabetes at least once in their lifetime, and is responsible for the vast majority of amputations in the United States and in Europe. Since its clinical history evolves from an initial nonulcerative phase, to an acute ulcerative phase, an eventual recurrence, and a chronic post-ulcerative phase, measurements related to such a complex condition should explore and exhaustively describe all aspects of the pathology. In the pre-ulcerative phase, evaluation and quantification of risk factors for the development of ulceration are the most important aspects. In this phase, neuropathy and peripheral vascular disease are addressed. In the ulcerative phase, measurements related to the ulcer, including size, location, involvement of deep structures, presence of ischemia, and infection, are all relevant to establish a therapeutic program and a prognosis of the pathologic condition. In the post-ulcerative phase, emphasis should be placed on determining the risk of recurrences and evaluating postural loads and gait imbalances secondary to the outcomes of the acute phase. Such evaluation is important in the prescription of orthesis and shoes that have a protective role with the at-risk foot and thus reduce the risk of recurrences. Measurements in the diabetic foot are of paramount importance to create a quantitative paradigm and reduce empiricism in clinical practice in the management of such a complex pathology.
Introduction

From 4S to FIELD and PROactive: 10 years of CV Trials in People With Diabetes

Abstract and Introduction
Abstract

The last ten years have seen a rapid expansion in the evidence-base for the reduction of cardiovascular risk in people with diabetes. Following the landmark Scandinavian Simvastatin Survival Study (4S), several other studies have shown the benefits of statins in people with diabetes, but much less data are available for the benefit of fibrates, and the main evidence to date comes from subgroup analysis of the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT). The Hypertension in Diabetes Study (HDS), nested within the United Kingdom Prospective Diabetes Study (UKPDS), proved that tight control of hypertension reduced microvascular and macrovascular events in people with diabetes, and the Heart Outcomes Prevention Evaluation (HOPE) and MICRO-HOPE studies suggested a benefit in reducing cardiovascular events with angiotensin-converting enzyme (ACE) inhibition, additional to blood pressure lowering effects. With regards to glycaemic therapy, the UKPDS has shown the benefit of metformin in reducing myocardial infarctions. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) studies will be presented later this year and will give information on the role of fenofibrate and pioglitazone respectively in reducing cardiovascular events in people with diabetes.
Introduction

The brave new world of type 2 diabetes management embarked upon in the last decade has been truly monumental. It is easy to forget the compartmentalisation of care that preceded this with the diabetologist's primary role being the improvement of glycaemic control. The importance of viewing diabetes not so much as a disease of too much sugar associated with microvascular disease to a state of premature cardiovascular death which is associated with hyperglycaemia and microvascular disease was heralded as recently as 1996 when the evidence was still lacking.[1] This review describes some landmark cardiovascular studies over the last 10 years in type 2 diabetic patients in the fields of lipids, hypertension and glycaemic control and discusses the use of specific drugs such as statins and ACE inhibitors.
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Physicians Should Treat All Cardiovascular Risk, Not Just Metabolic Syndrome

Aug. 25, 2005 — A joint statement from the Professional Practice Committee of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), published in the September issue of Diabetes Care, advises physicians not to diagnose or treat the metabolic syndrome. Rather, the statement suggests that they should treat all cardiovascular (CV) risk.

"The term 'metabolic syndrome' refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance," write Richard Kahn, PhD, from the ADA in Alexandria, Virginia, and colleagues. "While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker."

In recent decades, investigators identified clustering of certain CVD risk factors including obesity, type 2 diabetes, hyperlipidemia, and hypertension. Hyperinsulinemia was also linked to hyperlipidemia, obesity, and hypertension; and a cluster of CVD risk factors seemed to underlie type 2 diabetes. In association with insulin resistance, risk factor clustering led to the description of a unique pathophysiologic condition termed the "metabolic" or "insulin resistance" syndrome.

On Jan. 28, 2005, the authors performed a Medline search using the keywords "syndrome X" or "insulin resistance syndrome" or "metabolic syndrome," identifying 4,646 citations, including 3,948 studies performed on human subjects. Definitions for "metabolic syndrome" have been proposed by the World Health Organization (WHO) and the Third Report of the National Cholesterol Education Program's Adult Treatment Panel (ATP III), as well as by other organizations.

This review critically examined the evidence underlying the definition of the metabolic syndrome, as well as its pathogenesis, association with CVD, and impact of treatment. The primary focus was on articles addressing the metabolic syndrome as defined by ATP III, with a view toward answering three main questions: (1) How clear is the existing definition of the metabolic syndrome for diagnostic purposes?; (2) Does the treatment of metabolic syndrome differ from treatment of its individual components?; and (3) What additional research is needed to improve current knowledge of this syndrome?

"Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the 'metabolic syndrome,'" the authors write. "Our analysis indicates that too much critically important information is missing to warrant its designation as a 'syndrome.'"

Until additional studies address unanswered questions, the authors recommend that patients with diabetes or clinical CVD should be excluded from the case definition of metabolic syndrome; that adults with any major CVD risk factor should be evaluated for the presence of other CVD risk factors; that patients with CVD risk variables over normal limits should be counseled regarding lifestyle modification; that those with markers indicating overt disease (such as blood pressure higher than 140/90 mmHg or fasting plasma glucose level at 7.0 mmol/L or more) should be treated according to established guidelines; and that all CVD risk factors should be individually and aggressively treated.

"Providers should avoid labeling patients with the term 'metabolic syndrome,' as this might create the impression that the metabolic syndrome denotes a greater risk than its components, or that it is more serious than other CVD risk factors, or that the underlying pathophysiology is clear," the authors conclude. "Until randomized controlled trials have been completed, there is no appropriate pharmacological treatment for the metabolic syndrome, nor should it be assumed that pharmacological therapy to reduce insulin resistance will be beneficial to patients with the metabolic syndrome."

Diabetes Care. 2005;28:000-000

Canadian Study Demonstrates New Approach To Achieving Diabetes Control

Insight study reveals leading research on the benefits of using insulin earlier HAMILTON, ONTARIO -- June 16, 2005 -- Results of an all-Canadian study announced June 13 at an international diabetes congress demonstrate that patients with type 2 diabetes can safely achieve target blood sugar (glycemic) levels faster and more frequently when insulin glargine (a basal, long-acting insulin) is added to therapy, versus using oral agents alone. In addition to achieving better glycemic control, patients using insulin glargine expressed increased satisfaction with their treatment and experienced improved quality of life. The INSIGHT study (Implementing New Strategies with Insulin Glargine for Hyperglycemia Therapy), presented at the 65th American Diabetes Association Annual Meeting and Scientific Sessions by lead investigator, Dr. Hertzel Gerstein, a professor of medicine and director of endocrinology and metabolism at McMaster University in Hamilton, demonstrated that early addition of insulin glargine therapy (in combination with oral agents or alone) safely achieved better glycemic and metabolic outcomes than adding oral agents. These results were achieved with no increased risk of hypoglycemia (low blood sugar levels) compared to oral medications. "Often, insulin therapy is considered as a last resort during late-stage disease," said Dr. Gerstein. "What INSIGHT has shown is that basal insulin therapy with insulin glargine can be safely and effectively introduced early in the course of diabetes. These results may help change the way that type 2 diabetes is managed in the future." All patients in the study had an A1C (target glycemic level) between seven and 11 per cent. This is above the recommended target of seven per cent or less, established by the Canadian Diabetes Association in the 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. When insulin glargine was added to their treatment, patients were able to achieve lower and steady blood glucose levels more quickly and more often. Diabetes in Canada According to Health Canada, it is estimated that 2.25 million Canadians have either type 1 or type 2 diabetes. Diabetes is the seventh leading cause of death in Canada, and Canadian adults with diabetes are twice as likely to die prematurely, compared to persons without diabetes. The Canadian Diabetes Association states that the aggressive management of diabetes is critical in order to delay or altogether prevent complications such as heart disease, stroke, permanent vision loss, renal disease, damage to the limbs and erectile dysfunction in men. Aggressive treatment is critical, especially for patients with an A1C level of nine per cent or less. Health Canada recognizes that the growth of diabetes is at epidemic levels and estimates that at least 30 per cent of adults with diabetes are unaware they have the condition. Health Canada also states that healthcare costs for managing diabetes and its complications amount to more than $9 billion annually. About Insulin Glargine Insulin glargine is approved for once-daily administration in patients over the age of 17 with type 1 or type 2 diabetes who require basal insulin to control abnormally high blood sugar levels. Insulin glargine can be used with oral diabetes medications and/or short-acting insulin to help control diabetes. About the INSIGHT Study The INSIGHT study is an all-Canadian study comparing the percentage of people who reached a target glycemic level (A1C) of 6.5 per cent or less, in two consecutive readings, when insulin glargine was added to their current therapy, versus those on adjusted oral therapy alone. The study, involving 19 endocrinologists and 34 general practitioners, was conducted at 53 study sites including British Columbia, Alberta, Manitoba, Ontario, Quebec, Prince Edward Island, Nova Scotia and Newfoundland. A total of 405 patients with type 2 diabetes were enrolled to participate in this open-label, randomized, two-arm parallel study that consisted of a two-week screening phase and a 24-week treatment phase. SOURCE: McMaster University

Energy Expenditure Promises Benefits for Diabetics

NEW YORK (Reuters Health) May 25 - Physical activity that expends more than 10 metabolic equivalents (METs) per hour per week will provide health advantages and reduced medical costs for patients with type 2 diabetes, according to Italian researchers. However, full benefits are not achieved unless more than 20 METs per hour per week are expended.

Senior author Dr. Pierpaolo De Feo and colleagues, from the University of Perugia note

that the results confirm that general recommendations of at least 30 minutes of moderate-intensity physical activity on most days are "also valid for type 2 diabetic subjects and demonstrate a significant dose-response relationship."

The findings, which appear in the June issue of Diabetes Care, are based on an analysis of data from 179 type 2 diabetic subjects who participated in a physical activity intervention. The subjects were divided into six groups based on the number of METs expended per hour per week.

The two groups that performed no more than 10 METs of exercise per hour per week experienced no change in HbA1c, blood pressure, total cholesterol, triglycerides, or heart disease risk. By contrast, the other four groups experienced improvements in all of these parameters.

In order to also achieve an improvement in body weight, waist circumference, heart rate, fasting glucose, serum LDL and HDL cholesterol, more than 20 METs per hour per week of activity was needed, the investigators note.

The groups with more than 10 METs per hour per week of exercise experienced a reduction in per capita yearly medication costs. The group with the lowest activity level (no METs) experienced a rise in costs and the group with the next lowest level (1 to 10 METS per hour per week) had no change in costs.

In a related editorial, Dr. James O. Hill, from the University of Colorado, Denver, comments that the results "provide an optimistic message about physical activity and type 2 diabetes. It isn't necessary for your patients to do a lot of strenuous exercise to reap health benefits. Even small increases in physical activity can help, and it seems possible to produce these changes in the majority of your patients."

Diabetes Care 2005;28:1295-1302,1524-1525.

Dairy Products May Lower Risk of Type 2 Diabetes in Men CME

May 10, 2005 — Men who have a high dairy intake have a lower risk of type 2 diabetes mellitus (DM), according to the results of a prospective study published in the May 9 issue of the Archives of Internal Medicine. The editorialist reviews the purported benefits of milk and dairy products.

"Diet and lifestyle modifications can substantially reduce the risk of type 2 diabetes," write Hyon K. Choi, MD, from Massachusetts General Hospital in Boston, and colleagues. "While a strong inverse association has been reported between dairy consumption and the insulin resistance syndrome among young obese adults, the relation between dairy intake and type 2 diabetes is unknown."

The investigators prospectively examined the relationship between dairy intake and incident cases of type 2 DM in 41,254 male participants with no history of DM, cardiovascular disease, and cancer when enrolled in the Health Professionals Follow-up Study.

During 12 years of follow-up, there were 1,243 incident cases of type 2 DM. Dairy intake was associated with a modestly lower risk of type 2 DM. Compared with men in the lowest quintile of dairy intake, the relative risk (RR) for type 2 DM in men in the top quintile of dairy intake was 0.77 (95% confidence interval [CI], 0.62 - 0.95; P for trend = .003), after adjustment for body mass index (BMI), physical activity, dietary factors, and other potential confounders.

For each serving-per-day increase in total dairy intake, there was a 9% lower risk for type 2 DM (multivariate RR, 0.91; 95% CI, 0.85 - 0.97). The corresponding RR was 0.88 (95% CI, 0.81 - 0.94) for low-fat dairy intake and 0.99 (95% CI, 0.91 - 1.07) for high-fat dairy intake. BMI did not affect this association (< 25 vs >/= 25 kg/m2; P for interaction, .57).

"Dietary patterns characterized by higher dairy intake, especially low-fat dairy intake, may lower the risk of type 2 diabetes in men," the authors write.

Study limitations include observational design, potential for unmeasured confounding, self-reporting of DM with possible underdiagnosis, and study population limited to men 40 years old and older with no history of type 2 DM.

The National Institutes of Health supported this study in part. The authors report no financial disclosures.

In an accompanying editorial, Janet C. King, PhD, from Children's Hospital Oakland Research Institute in California, calls this study "a further reminder of the potential importance of dairy intake and the continuing value of research in this area." She notes that milk contains amino acids, vitamins, minerals, and additional bioactive components.

"Many of these components protect individuals from exogenous stresses, toxins, and pathogens; encourage adaptation to the environment; and promote metabolic regulation, while other milk components cause negative effects in susceptible individuals," Dr. King writes. "Research shows that the role of dairy foods in health is very complex and probably varies with the genotype and phenotype of the individual."

Dr. King reports no financial conflicts of interest.

Arch Intern Med. 2005;165:975-976, 997-1003

Pioglitazone Slows Carotid Thickening in Diabetics

NEW YORK (Reuters Health) May 13 - Independent of its ability to improve glycemic control, pioglitazone therapy decreases carotid intima-media thickness (IMT) in patients with type 2 diabetes, according to a report in the May 17th issue of Circulation.

"We are encouraged by these results because the benefits seen with pioglitazone could, theoretically, lead to an overall reduction in the incidence of heart attack and stroke for people with type 2 diabetes," study co-author Dr. Thomas Forst, from the Institute for Clinical Research and Development in Mainz, Germany, said in a statement.

The findings stem from a study funded by Takeda Pharmaceuticals, which markets pioglitazone under the trade name Actos.

The study involved 173 patients with type 2 diabetes who were randomized to receive pioglitazone or glimepiride-based treatment for 24 weeks.

During the study period, patients in each group experienced similar improvements in glycemic control, based on HbA1c levels. However, only pioglitazone-treated subjects showed a significant reduction in carotid IMT at 12 and 24 weeks.

Insulin resistance improved significantly in the pioglitazone group, but not in the glimepiride group.

Further analysis showed that the drop in carotid IMT correlated with the improvement in insulin resistance, but was independent of changes in glycemic control, the authors note.

"Our results support the growing body of evidence for an anti-atherogenic effect of PPAR-gamma activators that reach beyond glycemic control and might imply prognostic benefits for patients treated with this class of drugs and especially for patients with type 2 diabetes," the authors conclude.

Circulation 2005;111:2525-2531.

Danish Study Outlines Risk Factors for Diabetic Maculopathy

By Earl R. Nichols FT. LAUDERDALE, FL -- May 9, 2005 -- According to a large Danish database, there does not appear to be a significant difference in the risk of developing diabetic maculopathy between patients with type 1 or type 2 diabetes, or type 2 patients who are insulin-dependent and who are not insulin-dependent. The risk is more or less similar, at 25.4 cases (a 5--year incidence rate of 11.9%) per thousand patient-years for patients with type 1 diabetes and 31.8 cases (a 5--year incidence rate of 14.7%) per thousand patient-years for those with type 2 diabetes. M. L. Laursen, MD, department of ophthalmology, Odense University Hospital, Odense, Denmark, presented the results in a poster session here at the Association for Research in Vision and Ophthalmology Annual Meeting. The longitudinal observational study was conducted at one diabetes clinic between 1997 and 2001 and examined a total of 1218 patients -- 696 with type 1 diabetes and 522 with type 2 diabetes. Patients had their eyes examined regularly using two-field, non-stereoscopic photography of the fundus. Over the course of the 5-year follow-up period, 47 patients with type 1 diabetes and 39 patients with type 2 diabetes developed maculopathy. Slightly more patients with insulin-dependent type 2 diabetes went on to develop maculopathy, but the difference was not significant when compared with those who were not insulin-dependent. Patients with type 1 diabetes were significantly younger than those with type 2 disease and had had diabetes for longer compared to type 2 diabetics (17.0 years vs. 9 years). When the database began collecting information, the patients were 40.3 years old in the type 1 diabetes group and 57.5 years old in the type 2 group. Those with type 1 disease were more likely to have normal body mass index, while those with type 2 disease were more likely to be overweight or obese. The main factors predicting which patients with type 1 diabetes were most likely to develop maculopathy were elevated triglycerides (risk ratio [RR] 1.29), haemoglobin 1Ac (RR 1.28) and vibration perception threshold, which is a measure of muscle and nerve fiber reactivity (RR 1.21) The factors most likely to be associated with progression to maculopathy among type 2 diabetics were duration of disease (RR 1.08), diastolic blood pressure (RR 1.20) and vibration perception threshold (RR 1.26) Other factors that were associated with a greater risk of developing maculopathy included elevated low-density lipoprotein cholesterol level and elevated total cholesterol level. Men were more likely to develop maculopathy than women (RR 1.61 and 1.44, respectively). Vibration perception threshold may be the most important of all these factors since it is known that mixed sensory autonomic neuropathy is the most common clinical subtype of diabetic neuropathy and that this may in turn reflect abnormalities in choroidal blood flow, which is highly innervated and regulated by the autonomic nervous system, the authors concluded. [Presentation title: Incidence of and Risk Factors for Diabetic Maculopathy in a Danish Photographic Screening Programme. Poster 393/B367]

Intense Insulin Therapy Does Not Improve Outcome After MI

NEW YORK (Reuters Health) May 03 - Intense metabolic control using insulin does not improve mortality and morbidity in type 2 diabetic patients after acute myocardial infarction, according to the results of a multicenter European study.

Insulin does not seem to be the only solution, but tight glucose control by any means is very important." Dr. Lars Ryden from the Karolinska Institute, Stockholm, told Reuters Health. He advises clinicians to "use all available tools to keep blood glucose...down."

Dr. Ryden and colleagues in the Diabetes and Insulin-Glucose Infusion in Acute MI 2 (DIGAMI 2) study compared three glucose management strategies in more than 1200 diabetic patients after suspected acute myocardial infarction.

These included acute insulin-glucose infusion followed by long-term insulin-based treatment; acute insulin-glucose infusion followed by standard glucose control; and routine management according to local practice.

Although blood glucose levels were lower with the first two strategies after the first 24 hours, the authors report, glucose control over time (blood glucose and glycosylated hemoglobin levels) did not differ among the three treatment approaches, Dr. Ryden's group reports in the April issue of the European Heart Journal.

Mortality also did not significantly differ among the three treatment groups. Secondary events (stroke, myocardial reinfarction, etc.) tended to be higher in the most intensive treatment program, but the differences did not reach statistical significance.

Although the three different treatment strategies had similar effects on mortality, "hyperglycemia remained one of the most important prognostic predictors," the investigators note.

"Future development of tools that will allow frequent and precise (non-invasive) measurement of blood glucose levels and, eventually, of an automated system for insulin-titrated tight blood glucose control will be of utmost importance," writes Dr. Greta Van den Berghe from Catholic University of Leuven, Belgium in a related editorial.

"We anxiously await the development and validation of such devices," Dr. Van den Berghe concluded.

Eur Heart J 2005;26:639-641,650-661.

Insulin Identified as Trigger for Type 1 Diabetes

WEDNESDAY, May 11 (HealthDay News) -- Insulin, the hormone most closely linked to diabetes, has turned out to be the cause of the inherited form of the blood sugar disease, researchers report.

For reasons that remain unclear, in patients with type 1 diabetes the body's immune T-cells react against insulin-producing cells in the pancreas -- effectively shutting them down and triggering disease onset.

After eight long years of painstaking----------------------------------------------(read online)

>Diabetic Neuropathies

Introduction

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy.

This statement is based on two recent technical reviews,[1,2] to which the reader is referred for detailed discussion and relevant references to the literature.---- cont online

Impact of MI, Diabetes on Overall Health Differs Between the Sexes

By Megan Rauscher

NEW YORK (Reuters Health) May 02 - In men myocardial infarction increases the risk of death from heart disease more so than diabetes, but in women diabetes is a greater mortality threat, according to results of a Finnish study reported May 3rd in the Journal of the American College of Cardiology.

"In general, diabetes is bad news for women," Dr. Gang Hu from National Public Health Institute and University of Helsinki told Reuters Health. "More aggressive management of diabetes to prevent cardiovascular disease may be needed, particularly in women," the researcher warned.

In the study, the investigators compared the effects of diabetes and MI on the risk of death in two cohorts of patients: a baseline cohort, which included 2416 patients with prior diabetes or MI who were followed for 12 years; and a follow-up cohort, which included 4315 patients who were diagnosed with incident diabetes or MI during follow-up and were further followed for 7.7 years after diagnosis.

Most previous studies only had a "single baseline measurement for the disease status of diabetes and MI," Dr. Hu pointed out.

In the baseline cohort, men with prior MI had a 20% to 80% increased risk of death from CHD or any cause, whereas women with prior MI had a 43% to 45% decreased risk of CHD or total mortality compared with men and women with prior diabetes.

In the follow-up cohort, men and women with incident MI had a greater risk of dying from heart disease, with hazard ratios of 2.15 and 1.65, respectively, compared with men and women with incident diabetes.

Total mortality, however, was similar between subjects with incident diabetes and MI during follow up, Dr. Hu said.

For people with incident MI, CHD is "the major cause of death," Dr. Hu explained, whereas people with incident diabetes may be at increased risk of dying from CHD, stroke, cancer, kidney disease, infection and other causes. Thus, total mortality is similar between subjects with incident diabetes and MI, which highlights the importance of diabetes on overall health, the researcher added.

In a statement, Dr. Christiane E. Angermann, from the University of Wurzburg in Germany said this study provides "yet another strong argument for the necessity to consider gender-related differences between men and women regarding the impact of risk factors, while designing guidelines not only for diagnosis and therapy, but also, and in particular, for the prevention of cardiovascular disease."

J Am Coll Cardiol 2005;45:1413-1418.

FDA OKs Lilly-Amylin Drug for Type 2 Diabetes

Fri Apr 29, 2005 5:38 PM BST

By Toni Clarke

NEW YORK (Reuters) - U.S. regulators have approved a diabetes drug derived from lizard saliva for patients who have not responded to other treatments, the drug's developers, Eli Lilly and Co. and Amylin Pharmaceuticals Inc., said on Friday.

The U.S. Food and Drug Administration approved exenatide, an injectable drug to be sold under the brand name Byetta, as an additional therapy for patients with Type II diabetes -- the most common form -- whose blood sugars are not sufficiently controlled by two oral medications.

Analysts expect the drug could eventually generate sales of about $1 billion to $2 billion.

Shares of Amylin fell 8 percent to $16.73 in midday trade on the Nasdaq, after earlier touching a two-year low of $16.01. Analysts, however, said the news was positive for Amylin.

The companies, which had sought approval only to market Byetta only in combination with other diabetes drugs, said that the FDA also gave conditional approval for Byetta as a stand-alone treatment, subject to further clinical trials.

Jamaison Schuler, a spokesman for Eli Lilly, said the FDA's decision to conditionally approve the drug as a stand-alone treatment is "wonderful news" as the companies had not sought such approval and indicates the agency sees promise in the drug for this use.

Some analysts, as well as Lilly, said that investors may be misinterpreting the conditional approval as a negative move.

Exenatide is Amylin's second product on the commercial market. It already sells Symlin, another diabetes treatment.

Exenatide, which is a synthetic version of saliva of the Gila monster lizard that lives in the Arizona desert, is the first of a new class of drugs known as incretin mimetics. It mimics hormones, released in the human gut in response to food, that help regulate glucose levels.

Trials of 1,446 patients showed about a 1 percent reduction in blood sugar levels in patients who took Byetta along with other oral diabetes medications, including widely used metformin and a class of older drugs called sulfonylureas.

Most patients also experience weight loss. Weight gain is seen as a risk factor for diabetes.

Patients can inject Byetta as an alternative to taking insulin, which can cause hypoglycemia, or worrisome drops in blood sugar levels that can cause fainting.

Because Byetta is not closely linked with hypoglycemia Shao said patients would not have to monitor their blood glucose levels as constantly as insulin users must.

"I'll especially recommend this drug for obese diabetics who are making their best effort to control their diets but are still not losing weight," said Dr. Stuart Weiss, an assistant professor at New York University Medical School.

Shares of Lilly, which has many drugs on the market, were unchanged at $58.00 on the New York Stock Exchange.

More than 15 million people in the United States have type II diabetes. Diabetics are unable to produce enough insulin or cannot process their insulin properly, resulting in dangerously high blood-sugar levels, which can lead to heart disease, blindness and amputations if not treated.

Amylin Chief Operating Officer Daniel Bradbury said the company has not yet set a price for the drug. He said it could face future competition from Danish drug maker Novo Nordisk, which is working on a rival medicine called Liraglutide.

Novartis AG, Merck & Co. Inc. and Bristol-Myers Squibb are also testing diabetes drugs in a different class that try to prolong the gut's natural insulin secretions.

(Additional reporting by Ransdell Pierson in New York and Susan Heavey in Washington.)

© Reuters 2005. All rights reserved

Prevention of Type 2 Diabetes With Troglitazone in the Diabetes Prevention Program

Abstract and Introduction
Abstract

The Diabetes Prevention Program (DPP) was a randomized clinical trial of prevention of type 2 diabetes in high-risk people. Troglitazone, an insulin-sensitizing agent, was used initially but was discontinued during the trial. Troglitazone therapy was compared with other DPP interventions, considering both the short-term "in-trial" results and the longer-term results after troglitazone were discontinued. From 1996 to 1998, participants were randomly assigned to treatment with metformin ( n = 587), troglitazone ( n = 585), double placebo ( n = 582), or intensive lifestyle intervention (ILS) ( n = 589). Because of concern regarding its liver toxicity, the troglitazone arm was discontinued in June 1998, after which follow-up of all participants continued. During the mean 0.9 year (range 0.5-1.5 years) of troglitazone treatment, the diabetes incidence rate was 3.0 cases/100 person-years, compared with 12.0, 6.7, and 5.1 cases/100 person-years in the placebo, metformin, and ILS participants ( P < 0.001, troglitazone vs. placebo; P = 0.02, troglitazone vs. metformin; P = 0.18, troglitazone vs. ILS). This effect of troglitazone was in part due to improved insulin sensitivity with maintenance of insulin secretion. During the 3 years after troglitazone withdrawal, the diabetes incidence rate was almost identical to that of the placebo group. Troglitazone, therefore, markedly reduced the incidence of diabetes during its limited period of use, but this action did not persist. Whether other thiazolidinedione drugs used for longer periods can safely prevent diabetes remains to be determined.
Introduction

The Diabetes Prevention Program (DPP) was a randomized clinical trial of prevention of type 2 diabetes in people at high risk of diabetes.[1] Enrollment began in 1996 with randomization to four treatment groups. Three treatments were standard healthy lifestyle recommendations plus placebo, metformin, or troglitazone. The fourth treatment was intensive lifestyle (ILS), which consisted of no drugs and the same lifestyle recommendations given to the pharmacologic groups, but the lifestyle advice was given with much more behavioral support. The details of these treatments and the results of three of the interventions have been described,[1-3] and the protocol is available at http://www.bsc.gwu.edu/dpp/protocol.htmlvdoc .

In planning the DPP (from 1994 to 1996), the research group considered testing several drugs affecting insulin secretion and sensitivity. Metformin and troglitazone, two drugs of different classes with different actions, were chosen. Metformin had been used worldwide in treating type 2 diabetes for several decades but was not approved in the U.S. until 1994. Troglitazone, an insulin-sensitizing thiazolidinedione, showed promise in improving insulin sensitivity and glucose tolerance.[4] Its use was started in the DPP in 1996 as an investigational drug. It was then approved in the U.S. for diabetes treatment in 1997 but was withdrawn from the DPP in 1998 and from the U.S. market in 2000 because of liver toxicity. In this study, we report the results of troglitazone treatment both before and after its discontinuation during the DPP.
CONTINUED

Diabetic Neuropathies

Introduction

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy.

This statement is based on two recent technical reviews,[1,2] to which the reader is referred for detailed discussion and relevant references to the literature. READ NEXT ONLINE

Metformin May Cut Risk of Cancer in Diabetics

NEW YORK (Reuters Health) Apr 21 - Patients with type 2 diabetes who are prescribed metformin appear to be at lower risk of cancer than those not treated with metformin, according to a pilot observational study reported in the British Medical Journal Online First on April 21.

Lead author Dr. Josie M. M. Evans and colleagues at the University of Dundee in Scotland explain that metformin activates the enzyme AMP activated protein kinase, which in turn is regulated by the tumor suppressor LKB1. They therefore theorized that metformin use may reduce risk of cancer.

To test their hypothesis, they performed a case-control study in which a diabetes clinical information system was linked with a database of dispensed prescriptions.

Between 1993 and 2001, nearly 12,000 patients had been newly diagnosed with type 2 diabetes, including 923 who were later diagnosed with cancer. These were matched to 1846 diabetic subjects without cancer by age, year of diagnosis and gender.

During the year prior to the cancer diagnosis, 36.4% of cases and 39.7% of controls had been given a prescription for metformin (odds ratio 0.86). The odds ratio for any exposure to metformin since 1993 was 0.79.

There appeared to be a dose-response relationship between metformin and cancer, as the odds were further reduced by increasing duration of metformin treatment and total amount of metformin dispensed.

The research team is now in the planning phase of a large cohort study linked to a cancer registration database, they note.

BMJ Online First 2005.

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.

Diabetes Mine

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Monitoring diabetes happenings everywhere in cyberspace,
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This is one of the most informative sites that you will find dealing with diabetes. For a ful index of articles GO HERE

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.
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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.

Genetics of type 2 diabetes mellitus: status and perspectives.

Hansen L, Pedersen O.

Steno Diabetes Center, Copenhagen, Denmark.

Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1-6 according to the mutated genes that by being expressed in the pancreatic beta-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected 'candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects.

PMID: 15715885 [PubMed - in process]

Many Type 2 Diabetics Should Take Statins

April 22, 2004 — Controlling cholesterol is as important as controlling blood sugar for patients with type 2 diabetes, according to new guidelines of the American College of Physicians (ACP) published in the April 20 issue of the Annals of Internal Medicine.

In April 2003, the ACP recommended tight blood pressure control in type 2 diabetes. The new ACP guidelines are the second set of guidelines recommending aggressive management of cardiovascular risk factors in this patient population. Specifically, the guidelines recommend statins for individuals with type 2 diabetes mellitus and coronary artery disease (CAD), and for all people with diabetes and any other risk factor for cardiovascular disease.

"We want both physicians and patients to know that when treating diabetes, controlling cardiovascular risk factors, particularly cholesterol levels and high blood pressure, is as important as controlling blood sugar," lead author Vincenza Snow, MD, FACP, a senior medical associate of scientific policy at the American College of Physicians, says in a news release. "This is life-saving information. In addition to controlling blood sugar levels, people with diabetes may be surprised to know that they must also be vigilant about controlling their blood pressure and cholesterol levels."

According to the American Diabetes Association, approximately 80% of people with type 2 diabetes will develop or die of complications of heart and vascular disease, and approximately 65% of deaths in diabetes are caused by heart disease and stroke. Furthermore, the increase in prevalence of type 2 diabetes has been labeled an epidemic. About 6% of the U.S. population, or 16 million Americans, have type 2 diabetes, and an additional 800,000 Americans older than 20 years are diagnosed with the disease each year.

The ACP evidence-based guidelines offer practical suggestions on all aspects of diabetes treatment for primary care physicians. For patients, the ACP is issuing a video news release to educate those with type 2 diabetes and their families about the importance of controlling cholesterol.

To control cholesterol in individuals with diabetes, specific recommendations are that all adults with type 2 diabetes and known CAD should take statins, regardless of their cholesterol levels. All adults, including premenopausal women, with type 2 diabetes and another CAD risk factor, such as hypertension, hypercholesterolemia, smoking, sedentary lifestyle or obesity, should take statins or the nonstatin drug gemfibrozil, regardless of cholesterol levels.

Having started cholesterol-lowering therapy, patients with type 2 diabetes should remain on at least moderate doses of a statin. Physicians should not delay starting statin treatment until cholesterol exceeds a critical level, nor should they treat only until a target level of cholesterol is reached and then abandon therapy. Except for patients with hepatic dysfunction, muscle pain, or concomitant use of drugs that interact with statins, routine monitoring of liver function or muscle enzymes is probably not necessary.

"Women with diabetes who have not reached menopause may think their female hormones protect them from CAD," Dr. Snow says. "But statistics show that premenopausal women with type 2 diabetes and at least one other cardiovascular risk factor are as likely as men to develop CAD. So ACP says that women with diabetes and other risk factors for CAD should take a statin."

The evidence base for these guidelines is summarized in an accompanying paper by Sandeep Vijan, MD, MS, and Rodney A. Hayward, MD, from Veterans Affairs in Ann Arbor, Michigan. It includes a systematic review of research on cholesterol-lowering drug therapy in people with type 2 diabetes who have CAD or cardiovascular risk factors. Specific issues reviewed include the benefits of tight lipid control in primary prevention, for patients without known CAD, and in secondary prevention, for patients with documented CAD; and the benefit of lowering cholesterol to a target level of low-density lipoprotein (LDL).

The authors concluded that statins are extremely safe, except for patients with hepatic dysfunction or with use of medications interacting with statins. Lipid-lowering medications appear to reduce risk of major cardiovascular events in diabetes by 22% to 24%.

"In patients with type 2 diabetes, treatment with lipid-lowering agents reduces cardiovascular risk," the authors write. "Most patients, including those whose baseline LDL cholesterol levels are below 2.97 mmol/L (< 115 mg/dL), and possibly below 2.59 mmol/L (< 100 mg/dL), benefit from statins. Moderate doses of these drugs suffice in most patients with diabetes."

The authors report no potential financial conflicts of interest.

Ann Intern Med. 2004;140:644-649, 650-658

A Pro-Active Call Center May Improve Glycemic Control in Type 2 Diabetes

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
Feb. 4, 2005 — A Pro-Active Call Center Treatment Support (PACCTS) intervention can improve glycemic control in type 2 diabetes, according to the results of a randomized trial published in the February issue of Diabetes Care. A second article in the same issue established that this intervention, using trained nonmedical telephone operators supported by specially designed software and a diabetes nurse, was well received by the patients.

"Diabetes educator-led PACCTS for diabetes care is well established as a health care delivery vehicle in the US," write Robert J. Young, MD, from Hope Hospital in Salford, U.K., and colleagues. "It seems to offer service delivery characteristics that might enhance effectiveness, such as continuity, convenience, and risk-stratified intervention. However, it has not been subject to rigorous or large-scale clinical trial assessment of its effectiveness or efficiency."

Of 591 randomly selected individuals with type 2 diabetes in Salford, U.K., 197 individuals were randomized to the usual care (control) group and 394 to the PACCTS (intervention) group. Both groups received lifestyle advice and drug treatment according to local guidelines, but only PACCTS patients were telephoned according to a protocol in which the frequency of calls was proportional to the patients' last glycated hemoglobin (HbA1c) level. The primary outcome measure was absolute reduction in HbA1c level, and the secondary outcome was the proportion of patients in whom HbA1c level decreased by at least 1%.

The one-year study was completed by 332 patients (84%) in the PACCTS group and 176 patients (89%) in the control group, and final HbA1c values were available in 374 patients (95%) in the PACCTS group and 180 patients (92%) in the usual care group.

Compared with the usual care group, HbA1c level improved by 0.31% overall (95% confidence interval [CI], 0.11-0.52; P = .003) in the PACCTS group. However, for patients with baseline HbA1c level less than 7%, there was no change, and for patients with baseline HbA1c level of more than 7%, improvement increased to 0.49% (95% CI, 0.21-0.77; P < .001). The difference in the proportions of patients achieving at least a 1% reduction in HbA1c level was 10% overall (95% CI, 4-16; P < .001) and 15% (95% CI, 7-24; P < .001) for patients with baseline HbA1c level of more than 7%, favoring the PACCTS intervention.

"In an urban Caucasian trial population with blood glucose HbA1c > 7%, PACCTS facilitated significant improvement in glycemic control," the authors write. "Further research should extend the validity of findings to rural communities and other ethnic groups, as well as to smoking and lipid and blood pressure control."

GlaxoSmithKline funded the staff, data management, and analysis costs of this study. British Telecom acted as technology partners funding call center equipment, development, and maintenance costs. One of the authors was indirectly funded by GlaxoSmithKline.

An accompanying article by Andrew F. Long, MSc, MPhil, and colleagues from the PACCTS Team describes the results of a questionnaire survey designed to examine patients' views of the acceptability of and satisfaction with PACCTS.

Using the Diabetes Satisfaction and Treatment Questionnaire (DTSQ), the investigators determined satisfaction with care in all 591 patients at baseline and at the end of the study. In addition, 394 intervention patients received an acceptability questionnaire after at least three proactive calls from the call center and at the end of the trial, and a sample of 25 patients participated in in-depth, semistructured interviews.

Response rates were 79% for the DTSQ and 65% for the acceptability questionnaire. Individuals receiving the PACCTS intervention continued to report high levels of satisfaction with their treatment (95% CI, 32.3-33.2 at one year), and more than 90% strongly agreed or agreed that the telecarer approach was acceptable.

Based on qualitative comments, the patients expressed satisfaction with having a personalized service; improved feelings of well-being, such as confidence and self-control; assistance with problem solving; and developing rapport and a strong bond with the telecarers.

"A personalized PACCTS approach is acceptable to patients," the authors conclude. "A service giving priority to the interpersonal dimension leads to increased commitment from patients to improve long-term glycemic control."

Study limitations include potential bias in the measurement of satisfaction; a possible "expectation" effect with behavior change arising from the expectation of a call and the monitoring of glucose control; differences between PACCTS and other telecare systems; and limited one-year follow-up.

"These results suggest that several processes can contribute to a successful patient-centered telephone-supported disease management, [including] listening to and focusing on the concerns of patients, individualized problem solving, and continuity of care over time," the authors conclude. "It may not be the information provision per se that is important (raising awareness and knowledge), but its provision in a context of enablement and support aimed at self-efficacy."

GlaxoSmithKline and British Telecom funded this study, and GlaxoSmithKline indirectly funded some of its authors.

Diabetes Care. 2005;28:278-289
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:

* Describe the PACCTS intervention for diabetes care.
* Evaluate the impact of PACCTS with usual care vs usual care only on diabetic outcomes at one year.

Clinical Context

The U.K. Prospective Diabetes Study demonstrated the effort required to obtain and maintain improved glucose control, and the importance of tight control in preventing long-term adverse outcomes of diabetes. Telephone diabetes education has been advocated and delivered by nurses and dieticians as part of a patient education strategy in chronic disease management. PACCTS was developed as a health care model in the U.S. and offers continuity, convenience, and access to patients as a risk-stratified intervention. However, according to the current authors, the strategy has not been tested for its efficacy in diabetes management in large, rigorous clinical trials.

The current authors conducted a randomized, open controlled trial to compare the outcomes of diabetes control at one year for an unselected group of patients with diabetes who were offered either usual care or usual care with PACCTS intervention modified for that community. The patients were from among 22 group practices in one U.K. community.
Study Highlights

* Patients were from an inner city, and 95% were white. More than 80% were in the lowest 2 socioeconomic strata. 22 practices with 591 patients agreed to participate.
* Exclusion criteria were diabetes duration less than one year, terminal illness, and inability to use the telephone.
* Patients were randomized to receive either usual care (n = 176, control) or usual care and PACCTS (n = 332, PACCTS) stratified by baseline HbA1c level (< 7, good; 7-9, moderate; and > 9%, poor).
* Usual care consisted of following the English National Guidelines for managing glucose control in type 2 diabetes, using a standard stepped-care protocol for patients, continuing medical education to primary care providers, and annual review. The guidelines are available at: http://www.NICE.org.UK.
* PACCTS was delivered by call center operators (telecarers) trained for 3 months by a diabetes specialist nurse with a focus on listening skills, motivational interviewing, and database methodology.
* The PACCTS application consisted of four main domains: knowledge, readiness to change (lifestyle intervention), medication adherence, and blood glucose control (self-testing and clinic follow-up reminders).
* Telecarers (working part-time) made calls once every 3 months if HbA1c level was 7% or less, every 7 weeks if HbA1c level was 7.1% to 9.0%, and monthly if HbA1c level was more than 9%. Each call lasted 20 minutes. If supplemental counseling was required, a referral was made to the specialist nurse.
* Primary outcome was HbA1c level at one year.
* Secondary outcome was proportion of patients reducing HbA1c level by at least 1% at one year.
* The study was powered at 90% to detect a reduction of 1% in HbA1c level in the PACCTS group at a significance level of 5%. Analysis was by intent-to-treat, using last observation carried forward for missing data.
* Mean age was 67 years, 58% were male, mean body mass index was 30.3 kg/m2, and mean duration of diabetes was 6 years. At baseline, a quarter of patients used lifestyle intervention only for control, 30% used one oral hypoglycemic agent (OHA), 25% used two OHAs, and 20% used insulin with or without OHA.
* There were more than 4,000 telephone consultations, with 90% outbound and 10% inbound.
* 10.7% of the control and 15.7% of the PACCTS group withdrew.
* Medication use in the control group increased overall, with no change in 91% and step-up in 9%.
* In the PACCTS group, medication decreased in 3%, did not change in 75%, and increased in 22%.
* Medication use increased more in the PACCTS than in the control group (P = .002).
* Mean HbA1c level improved by 0.3% in the PACCTS vs the control group (P < .003). The improvement was greater for patients with HbA1c level of 7% or more at 0.49% (P < .001), and there was no change in patients with baseline HbA1c level less than 7%.
* Significantly more patients in the PACCTS group had improvement of at least 1% in HbA1c level (overall 10%; P < .001). For patients with baseline HbA1c level of more than 7%, the proportion with improvement of at least 1% in HbA1c level was 15% (P < .001).
* The results were independent of age, sex, or practice (group vs single handed).
* In a separate article, patient surveys with 79% response rate for the PACCTS and 65% response rate for the control group indicated that PACCTS was well accepted by patients and offered increased feelings of well-being, confidence, and self-control.

Pearls for Practice

* The PACCTS intervention for diabetes management consists primarily of trained telecarer-initiated calls to patients focusing on the domains of knowledge, readiness to change (lifestyle intervention), medication adherence, and blood glucose control.
* Compared with usual care, patients with diabetes with a baseline HbA1c level of more than 7% who were offered PACCTS for one year had improved HbA1c control, with a higher proportion showing improvement of at least 1%.