Friday, February 25, 2005

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]

Thursday, February 24, 2005

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

Wednesday, February 23, 2005

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:
* 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%.

Vitamin B12 Status of Patients Treated With Metformin: A Cross-Sectional Cohort Study


Following the results of the United Kingdom Prospective Diabetes Study (UKPDS)[1] metformin is increasingly used in the treatment of type 2 diabetes. Metformin has an excellent safety profile,[2] but malabsorption of vitamin B12 may occur during long-term metformin treatment.[3,4] However, the prevalence and clinical significance of this potential adverse drug reaction is unknown. The recommendation to check serum cobalamin during therapy, e.g. once a year, is not followed strictly in clinical practice. Moreover, serum cobalamin may be insufficient as a marker of vitamin B12 status. Reduced serum cobalamin concentrations have been observed in controlled clinical studies with metformin alone and added to glibenclamide,[5] and with metformin added to insulin.[6] Vitamin B12 deficiency is associated with raised serum HCy and MMA levels. Whereas marginal elevations of HCy have been observed after metformin in diabetic[6] as well as non-diabetic[7] subjects, MMA has not been measured in this context. HCy is an independent cardiovascular risk factor.[8] Vitamin B12 deficiency may have serious consequences such as megaloblastic anaemia, myelopathy and neuropathy, and subnormal cobalamin concentrations have been associated with dementia. Megaloblastic anaemia due to metformin-associated vitamin B12 deficiency has been reported,[9,10] but it can be treated successfully with cyanocobalamin.[11] Symptoms of B12-related neuropathy can be misinterpreted as diabetes neuropathy.

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Sunday, February 20, 2005

Statin Drugs and Coenzyme Q10

Statin drugs are one of the most used pharmaceutical classes of products throughout the world. Lipitor® (atorvastatin) and Zocor® (simvastatin) have been ranked among the top 10 prescription drugs since 1999, with $9.2 billion in sales generated.

Clinical research has documented the benefit of these drugs for the prevention and treatment of heart disease. Other possible indications include reduction of Alzheimer disease, risk of stroke, and osteoporosis. Millions of Americans use these drugs on a daily basis, and are expected to take them for many years in order to manage elevated cholesterol levels...............................

Friday, February 04, 2005

Diabetes Appears to Increase Risk of Sepsis

"Diabetes Appears to Increase Risk of Sepsis"

ALEXANDRIA, VA -- January 27, 2005 -- A new study adds potentially fatal blood infections to the list of health risks from diabetes, a condition that is on the rise in the United States as obesity rates climb, according to the Feb. 15 issue of Clinical Infectious Diseases, now available online. Researchers have known for years that obesity and diabetes are linked. Most diabetics have type 2 diabetes--and most people with type 2 diabetes are obese. Diabetes can cause a host of health troubles, including kidney problems, damage to nerves and blood vessels and blindness. A heightened risk of infections in diabetic people has also been suggested. The condition known as sepsis can be brought on by bloodstream infection, and may lead to fever and septic shock, a potentially fatal drop in blood pressure. Diabetic people are more vulnerable to bacterial blood infections called bacteremia, particularly if they develop other bacterial infections, such as urinary tract infections (UTIs). Danish researchers studied more than 1,300 patients with bacteremia caused by E. coli and related bacteria and found that about 17 percent had diabetes, compared with only 6 percent among the controls, who were matched for age and sex from the general population. Compared with non-diabetics, diabetic patients were more likely to have bacteremia caused by urinary tract infection, rather than abdominal infection. Death after bacteremia also occurred more often in diabetics than in non-diabetics. So, with type 2 diabetes becoming increasingly common as Americans gain weight, the risk for serious infectious complications is a real one, according to Reimar Thomsen, M.D., Ph.D., lead author of the study. " a life-threatening infection," he says, "and bacteremia with sepsis is the 10th most common cause of death in the United States." Dr. Thomsen of Aalborg Hospital and Aarhus University Hospital (currently with Vanderbilt University) added that urinary tract infections seem to be a common problem in diabetics, and that the researchers "believe that urinary tract infections are the most important link between diabetes and an increased risk of bacteremias caused by E. coli and related bacteria." To reduce the risk of potentially fatal infection, Dr. Thomsen suggested that diabetics--particularly women, who are more prone to UTIs--try to avoid known risk factors, such as unnecessary catheterization. "Diabetic persons with signs and symptoms of urinary tract infection or bacteremia/sepsis should always seek medical care promptly, and doctors should keep a high level of suspicion for these infections if the patient has got diabetes," Dr. Thomsen added. SOURCE: Infectious Diseases Society of America

Thursday, February 03, 2005

Diabetic Neuropathies: The Nerve Damage of Diabetes: "Diabetic Neuropathies: The Nerve Damage of Diabetes"
Diabetic neuropathies are a family of nerve disorders caused by diabetes. People with diabetes can, over time, have damage to nerves throughout the body. Neuropathies lead to numbness and sometimes pain and weakness in the hands, arms, feet, and legs. Problems may also occur in every organ system, including the digestive tract, heart, and sex organs. People with diabetes can develop nerve problems at any time, but the longer a person has diabetes, the greater the risk.