Richard S. Rosenthal, MD
Assistant Professor of Medicine
Department of Endocrinology, Diabetes & Metabolism
The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, Dr. Rosenthal discloses the following: honoria Bristol Myers, GlaxoSmithKline, Aventis, and Pfizer

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 0.25 Category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the activity.

The boards of nursing in many states, including Alabama, recognize Category 1 continuing medical education courses as acceptable activities for the renewal of license to practice nursing.

Cardiovascular disease (CVD) is the leading cause of death among individuals with type 2 diabetes, who are two to four times as likely to die from CVD, compared with those without the disease.

"By 2025, we estimate 27 million Americans will have type 2 diabetes," UAB endocrinologist Richard S. Rosenthal, MD, says. "Combination therapy and strategies to initiate insulin early if needed are key to preserving existing b-cell function and delaying or preventing cardiovascular complications in this growing patient population."

Earlier screening and more aggressive treatments may prevent irreversible damage, including neuropathy, nephropathy, retinopathy, peripheral vascular disease, and stroke, he adds. "Many people are unaware they have diabetes until classic signs and symptoms, such as polyuria, polydipsia, polyphagia, and fatigue, begin to appear. By the time type 2 diabetes is diagnosed, patients typically have had the disease for 5 to 10 years and have lost 50% of their b-cell function."

Earlier Use of Insulin:

The progressive b-cell defect found in type 2 diabetes eventually results in poor glycemic control that, despite lifestyle management and oral therapies, will eventually require insulin. Type 2 diabetes begins with impaired insulin secretion from b cells, progresses to insulin resistance, and results in increased hepatic glucose production. As insulin secretion declines, hyperglycemia develops, ultimately leading to diagnosis.

"Traditionally, insulin has been delayed until oral agents and other therapies have failed. Yet, recent studies suggest earlier use of insulin and combination therapies may result in better disease management and reduced cardiovascular morbidity and mortality," Rosenthal says.

Results from the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study showed that glycemic control (HbA1c approximately 7%) is associated with sustained decreased rates of retinopathy, nephropathy, and neuropathy.

"Lowering hemoglobin A1c just 1% reduces patients' risk of microvascular complications by 30% to 40%," Rosenthal says. The risks and benefits of a HbA1c goal of <6% are currently being tested in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, led by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Researchers will study more than 10,000 participants with type 2 diabetes to determine if tighter glycemic control reduces diabetes-related CVD.

"Less stringent treatment goals may be appropriate to reduce morbidity in patients with severe acute illness, perioperatively, and after myocardial infarction," Rosenthal says.

Attempts to manage glycemic control through lifestyle changes, such as the Diabetes Prevention Program, sponsored by the NIDDK and other agencies, have shown intensive nutrition and weight-loss programs significantly benefit patients. However, such team approaches are costly, and when intervention counseling and strategies are not maintained, participants often regain pounds they lost. Still, the importance of weight loss cannot be overemphasized, he says, adding that adiposity, dyslipidemia, hypertension, and hyperglycemia associated with insulin resistance significantly increase risk for macrovascular complications.

Evidence suggests glucotoxicity and/or lipotoxicity (especially common in obese patients) with type 2 diabetes may contribute to disease progression. "Once type 2 diabetes develops, it typically requires escalating levels of therapy to control worsening hyperglycemia. Within 9 years of diagnosis, the majority of patients require insulin therapy," Rosenthal says.

HbA1c measurements are not useful for diagnosing type 2 diabetes, but quarterly HbA1c evaluations are standard, reflecting glycemic control for the previous 3 months. Historically, initial treatment for patients with HbA1c <8% has been single oral agents, but increasingly, combination oral therapy is prescribed upon diagnosis, Rosenthal says. "Studies show combination therapies introduced earlier result in better glycemic control, compared with adding medications sequentially. Combining oral agents simultaneously attacks different pathophysiological areas: Metfor-min decreases hepatic gluconeogenesis; thiazolidinediones improve insulin sensitivity and have been shown in some studies to induce b-cell rejuvenation; and sulfonylureas, a class of drugs used since the 1950s, stimulate b cells to release more insulin."

When glycemic control cannot be achieved with lifestyle management and oral agents, ADA recommends a single injection of long-acting insulin. Studies show this method of supplementing basal insulin is safe, simple, and less likely to cause weight gain than multiple daily injections with shorter-acting insulins (Am J Med. 2004;116 Suppl 3A:3S-9S). "Continuing oral agents during basal insulin therapy can smooth the transition to insulin and reduce the chance of losing glycemic control," Rosenthal says.

In some cases, however, immediately introducing insulin may provide the best solution for optimal glycemic control. "For severe glucotoxicity, introducing insulin may be necessary. Once glucose levels are restored, patients may be weaned from insulin and converted to oral agents."

Educating Patients:

Many patients fear starting insulin signals a personal failure or end-stage disease. In fact, earlier insulin introduction provides better glucose control and may reduce or prevent vascular consequences, especially coronary artery disease, he says. "Fears about daily injections and self-monitoring can be partially overcome with the newest insulins that require no refrigeration and come in prefilled pens that slip into a purse or pocket. They simplify insulin dosing and improve accuracy of administration and adherence in certain groups, especially neurologically impaired patients and those needing multiple daily injections. Often, symptoms and quality of life improve so dramatically after beginning insulin, patients quickly overcome their phobias. The current flexibility in insulin dosing improves compliance."

Survey findings from the National Lipid Association released in November 2004 found consumers ranked type 2 diabetes sixth on a list of seven medical factors contributing to risk of developing heart disease. Results also demonstrated the public underestimates the impact of dyslipidemia on type 2 diabetes; cholesterol was mentioned last among a list of six conditions Americans think people with diabetes face, ranking behind poor circulation, vision loss, increased risk for stroke, and hypertension.

Despite statistics about type 2 diabetes and CVD, millions of Americans suffer silent symptoms and remain undiagnosed. Rosenthal urges primary care physicians to screen CVD patients for impaired glucose tolerance and impaired fasting glucose and introduce therapy to control this intermediate stage in the potential development of type 2 diabetes.

"By the time type 2 diabetes is diagnosed, patients have typically lived for years with insulin resistance and impaired glucose tolerance, as well as chronic hyperglycemia that is often accompanied by hyperinsulinemia," Rosenthal says.

Impaired glucose tolerance is defined as 2-hour glucose levels of 140 mg/dL to 199 mg/dL on the 75-g oral glucose tolerance test; impaired fasting glucose is defined as glucose levels of 100 mg/dL to 125 mg/dL in fasting patients. These glucose levels are above normal but not high enough to diagnose diabetes.

"Because b cells respond to multiple stimuli, prescribing combination therapies when impaired glucose tolerance is diagnosed may significantly delay progression to type 2 diabetes. Priming insulin-sensitive tissues with dual therapies plays a crucial role in regulating glycemic control and minimizing risk of cardiovascular complications," he says.

"Managing diabetes is a lifetime problem requiring a team approach, involving clinicians, nurses, nutritionists, educators, and family and friends. Educating patients about the benefits of medically managing their type 2 diabetes is vital to preventing vascular complications, but physicians often lack time and resources to do this alone," Rosenthal says. "Patients must be organized and prepared to make good choices when eating, especially when dining out. Educating the family is equally important; enlisting their support is critical to managing a condition that affects the entire household."

For more information:

Dr. Richard Rosenthal
1-800-UAB-MIST
mist@uabmc.edu

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