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Pharmacy Cardiovascular Council Treatment Guidelines for the Management of Type 2 Diabetes Mellitus: Toward Better Patient Outcomes and New Roles for Pharmacists

David Hawkins, Pharm.D., J. Chris Bradberry, Pharm.D., Mark J. Cziraky, Pharm.D., Robert L. Talbert, Pharm.D., David W. Bartels, Pharm.D., and Joli D. Cerveny, Pharm.D.

Pharmacotherapy 22(4):436-444, 2002. © 2002 Pharmacotherapy Publications

Introduction

As health care professionals, we are sensitive to the fact that diabetes and its complications are significant and preventable sources of morbidity and mortality. The burden of type 2 diabetes mellitus is substantial, diminishing the physical and economic well-being of those affected. In the United States, an estimated 15.7 million people are afflicted with diabetes, most of whom (90-95%) have type 2 diabetes mellitus.[1] Alarmingly, approximately one-third (5.4 million) of these people do not know they are ill and at risk for serious complications. Each year more than 798,000 Americans are newly diagnosed with diabetes, amounting to a doubling of prevalence rates over the past 2 decades, and these numbers continue to rise. Type 2 diabetes mellitus affects all age groups; the prevalence of the disease among children, adolescents, and young adults is increasing at a precipitous rate.[1,2]

Type 2 diabetes mellitus is an insidious disease that may emerge and progress silently for years before it is detected, all the while supporting a metabolic environment that fosters long-term microvascular and macrovascular complications. In fact, results of the United Kingdom Prospective Diabetes Study (UKPDS) showed that about 50% of patients presented with complications of diabetes at diagnosis.[3] Diabetes is the leading cause of blindness in patients aged 20-74 years and is associated with as many as 24,000 new cases of blindness each year.[4] Diabetes is also the leading cause of end-stage renal disease, and approximately 60-70% of patients with diabetes develop some degree of neuropathy, including erectile dysfunction.[4]

In addition, 60-70% of all diabetes-related deaths are attributable to the macrovascular manifestations of the disease.[5] Diabetic vascular disease is responsible for a 2- to 4-fold increase in the incidence of coronary heart disease (CHD) and stroke and a 2- to 8-fold increase in the risk for heart failure.[6] Compared with individuals without diabetes, patients with diabetes have a 15- to 40-fold increased risk for lower extremity amputations, accounting for more than 67,000 amputations annually.[5]

Type 2 diabetes mellitus has significant economic consequences as well. In the United States, total direct and indirect costs attributable to diabetes were $98 billion in 1997.[7] This figure includes lost earnings from premature mortality ($17 billion) and disability ($37.1 billion). In a study conducted in 1994 at Kaiser Permanente of Northern California[8] in which the annual costs of medical care were calculated for approximately 85,000 plan members with diabetes and a matched cohort of control subjects without diabetes, the mean per capita medical costs were found to be 2.4 times higher among the patients with diabetes compared with the control subjects.

Poor glycemic control in patients with diabetes also has been correlated directly with increased overall health care costs,[9,10] largely due to the high expense of managing preventable long-term complications.[11,12] However, recent reports[13,14] suggest that the additional medical and pharmacologic costs associated with intensified glycemic control may be offset quickly by other reductions in the utilization of health care. In a large retrospective cohort study,[13] average annual cost savings of $685-$950/patient were realized in health maintenance organizations in just 1-2 years among adult patients with diabetes who sustained a reduction in hemoglobin A1c (HbA1c) of at least 1%. These cost savings were statistically significant only among improved patients with the highest baseline HbA1c values, but measures of health care utilization were consistently lower among the entire group of patients with improved glycemic control.

Although the correlations between hyper-glycemia and long-term complications, decreased quality of life, and increased health care costs are well established -- and the benefits of intensive control are widely known -- the current state of glycemic control remains unsatisfactory. Many patients who are diagnosed with diabetes and who seek treatment do not reach current glycemic goals defined by the American Diabetes Association (ADA) (Table 1).[15] In addition, most patients do not regularly receive all of the recommended services essential for optimal care including, but not limited to, patient education, nutritional counseling, foot examinations, routine measurement of HbA1c, blood pressure screening, ophthalmologic examinations, and cholesterol screening. Even when patients do receive all recommended evaluations, compliance with prescribed therapies is often substandard.

The poor state of glycemic control among patients with type 2 diabetes mellitus necessitates reconsideration of the current treatment paradigm. A compelling and growing body of evidence supports more aggressive, comprehensive management of patients with type 2 diabetes mellitus. Pharmacists are uniquely situated to enhance the state of care effectively for patients with type 2 diabetes mellitus. As medical professionals positioned at the forefront of patient care, it is the pharmacist's obligation to actively seek and judiciously implement the highest standards of care. Pharmacists inherently are aware of the relationship between the specialized and sophisticated body of knowledge they possess and the practical applications necessary to improve the well-being of patients. The multifaceted and dynamic nature of this profession demands the relentless pursuit and utility of the latest data, innovative applications, and evolving practices. Nowhere is this need more apparent than in the treatment of type 2 diabetes mellitus.

Diagnosis, Pathophysiology, and Natural History of Type 2 Diabetes Mellitus

Diagnosis

Three accepted diagnostic criteria exist for diabetes.[15] The most common test evaluates fasting plasma glucose (FPG) concentrations; a value of 126 mg/dl or greater (with no caloric intake for at least 8 hours before the test) indicates diabetes. The oral glucose tolerance test (OGTT) indicates diabetes if the patient's 2-hour postprandial plasma glucose value is 200 mg/dl or greater after intake of a 75-g glucose load. Diabetes also can be diagnosed if a random plasma glucose concentration of 200 mg/dl or greater is found in a patient with symptoms of diabetes (e.g., symptoms of marked hyper-glycemia -- including polyuria, polydipsia, weight loss [sometimes with polyphagia], and blurred vision -- or symptoms of potential complications of diabetes). An initial diagnosis must be confirmed by a second biochemical evaluation. Hemoglobin A1c testing is not an accepted instrument for the diagnosis of diabetes.

Patients with 2-hour plasma glucose concen-trations of 140 mg/dl or greater but lower than the diagnostic threshold for clinical diabetes (200 mg/dl) after an OGTT have impaired glucose tolerance (IGT). This is a precursor of type 2 diabetes mellitus that may be modified. Preliminary data from the Diabetes Prevention Program (DPP),[16] among other studies,[17,18] suggest that simple interventions can significantly delay the onset of type 2 diabetes mellitus in patients with IGT.

Pathophysiology

Type 2 diabetes mellitus is a progressive condition characterized by a combination of two fundamental defects: insulin resistance and impaired b-cell function. Insulin resistance in the liver, muscle, and adipose tissue leads to decreased glucose uptake in peripheral tissues, increased hepatic glucose production, and increased lipolysis, respectively. Once estab-lished, insulin resistance remains fairly constant throughout the natural course of type 2 diabetes mellitus; declining b-cell function appears to be the critical factor in the disease's progression. Early in the natural history of this disease, before the emergence of marked hyperglycemia, increased insulin secretion partially compensates for insulin resistance. Eventually, however, as b-cell function deteriorates, insulin secretion no longer can overcome the metabolic burden posed by insulin resistance, and hyperglycemia mani-fests. The presence of dual pathophysiologic defects suggests that optimal antihyperglycemic therapy for patients with type 2 diabetes mellitus (Table 2) should address both sources of metabolic dysregulation.

Although the precise causes of these metabolic failures are unknown, many people with type 2 diabetes mellitus share common traits that may play a role in the genesis of insulin resistance. This constellation of abnormalities -- often referred to as the metabolic syndrome or dys-metabolic syndrome X -- consists of overweight and obesity, high triglycerides, low high-density lipoprotein (HDL) cholesterol levels, hyper-tension, hyperglycemia, and altered fibrinolysis. Active management of these risk factors is imperative for consummate care.

Need for Improved Management of Risk Factors in Type 2 Diabetes Mellitus

Compelling evidence from randomized controlled trials and epidemiologic studies proves that intensive glycemic control significantly reduces the risk of retinopathy, nephropathy, and neuropathy in patients with diabetes mellitus.[19-22] Moreover, in the UKPDS, intensive treatment with metformin reduced the risk of any diabetes-related end point by 32%, diabetes-related death by 42%, and all-cause mortality by 36% in obese individuals.[23] Epidemiologic analysis of the UKPDS data showed that with every 1% reduction in HbA1c, the relative risk for microvascular complications, diabetes-related deaths, and myocardial infarction declined by 37%, 21%, and 14%, respectively.[24]

Hypertension accelerates the progression of atherosclerosis and the development of CHD and renal disease in patients with type 2 diabetes mellitus. In the UKPDS, tight control of blood pressure with either a b-blocker or an angiotensin-converting enzyme (ACE) inhibitor reduced the risks for diabetes-related death (32%), heart failure (56%), stroke (44%), and microvascular disease (37%).[25] Other studies provide additional evidence of the importance of blood pressure control and the benefits of other antihypertensive agents.[26-28] The ADA recom-mends a blood pressure goal of lower than 130/80 mm Hg for adults with diabetes,[15] which is more stringent than the goal of lower than 130/85 mm Hg goal established in the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure report in 1997.[29]

Although no clinical trial specifically has evaluated the effects of lipid-lowering agents on the risk for patients with CHD who also have diabetes, several studies have shown significant reductions in CHD-related morbidity and mortality in subgroups of patients with diabetes receiving either a statin or gemfibrozil.[30,31] Both the ADA and the National Cholesterol Education Program Adult Treatment Panel III recommend a low-density lipoprotein concentration of less than 100 mg/dl.[32,33] In addition, the ADA specifies that triglyceride concentrations should remain below 200 mg/dl and HDL levels should exceed 45 mg/dl in men and 55 mg/dl in women.

Cigarette smoking is an independent risk factor for cardiovascular disease in all patients. However, the cardiovascular risk associated with smoking is doubled in patients with type 2 diabetes mellitus compared with those without diabetes.[34] Smoking cessation should be a key component of an overall management plan for patients with type 2 diabetes mellitus.

The majority of people with type 2 diabetes mellitus are overweight. A 12-year prospective study in approximately 5000 overweight patients with diabetes found that reaching appropriate weight loss targets caused a 25% reduction in total mortality.[35] Both weight reduction and increased physical activity are known to decrease insulin resistance, improve glycemic control, decrease triglyceride concentrations, and raise HDL concentrations.

Overcoming Obstacles to Optimal Glycemic Therapy

Despite ample evidence that intensive control of hyperglycemia and high blood pressure, aggressive management of dyslipidemia, smoking cessation, weight reduction, and increased physical activity substantially reduce the morbidity and mortality associated with type 2 diabetes mellitus, treatment goals are not being met in the majority of patients.[36] One barrier to achieving optimal glycemic control arises, ironically, from the traditional approach to diabetes therapy. The use of conservative, stepwise approaches to glycemic management often means that patients experience unneces-sarily long periods of substandard control as appropriate regimens are tested and adjusted through a prolonged, empiric methodology.

All diabetes treatment guidelines stress the benefits of diet and exercise. Both of these strategies enhance tissue sensitivity to insulin and are important to the overall success of any subsequent pharmacotherapy regimen. Unfortunately, diet and exercise alone are not often successful for extended periods of time at achieving glycemic goals and, all too often, the decision to initiate pharmacotherapy is delayed longer than is necessary to fairly assess the effectiveness of diet and exercise. When the decision to begin drug therapy eventually is made, a single oral antidiabetic agent commonly is prescribed. Such interventions, however, treat only one of the two pathophysiologic defects of type 2 diabetes mellitus, which may explain why only a small proportion of patients are likely to reach glycemic targets. Patients who do not show an adequate response to monotherapy may undergo gradual dosage titrations until the maximal dosage is reached, or a second agent with a different mechanism of action may be added. The patient may be switched from one oral agent to another, although this is less effective than initiating combination therapy using agents with complementary mechanisms of action.

National Pharmacy Cardiovascular Council (NPCC) Treatment Guidelines

A more comprehensive approach to the management of type 2 diabetes mellitus is warranted (Figure 1). As soon as diabetes or IGT is diagnosed, a diet and exercise program for weight loss and improved general fitness should be initiated, along with effective strategies for controlling high blood pressure and dyslipi-demia, cessation of cigarette smoking, and preventive measures such as aspirin therapy. If the fasting blood glucose (FBG) concentration (as determined by fingerstick blood glucose testing) exceeds 100 mg/dl after 4-6 weeks of a diet and exercise program, pharmacotherapy is initiated. (The ease and widespread use of fingerstick glucose testing in the clinic influenced the choice of FBG values as an index of short-term glycemic control. In most situations, adding 10 mg/dl to the fingerstick FBG value gives a useful estimate of the corresponding FPG value.) The decision to start with monotherapy or combination therapy is based on the degree of hyperglycemia and the HbA1c level at baseline. When properly titrated, oral antidiabetic agents generally reduce blood glucose concentrations by 20-60 mg/dl and HbA1c concentrations by 1-2%. Patients requiring larger reductions in blood glucose and HbA1c concentrations are not expected to respond adequately to monotherapy.


Figure 1. National Pharmacy Cardiovascular Council guideline for the treatment of type 2 diabetes mellitus. SMBG = self-monitoring of blood glucose concentration; FBG = fasting blood glucose (to convert to FPG values, add 10 mg/dl); HbA1c = hemoglobin A1c. a, Short-term insulin therapy to reduce glucose toxicity may be indicated in patients with FBG concentrations > 300 mg/dl. b, Monotherapy options are sulfonylurea, repaglinide or nateglinide, metformin, or glitazones. Therapy with an insulin sensitizer (metformin or glitazone) is recommended. c, Combination therapy options include oral and insulin combinations (oral + oral; oral + insulin). Inclusion of an insulin sensitizer is recommended.

In the algorithm presented in Figure 1, subsequent pharmacotherapeutic decisions are made principally on the basis of the HbA1c value. A HbA1c goal of less than 6.5% is consistent with the recent American College of Endocrinology/ American Association of Clinical Endocrinology Consensus Guidelines.[37]

Although there are more than 2 dozen permutations of possible combination therapies (Table 3), there is a particular rationale for combining an insulin secretagogue (sulfonylurea or meglitinide) with an insulin sensitizer (metformin or a glitazone). The rationale is based on the fact that the metabolic defects seen in most patients with type 2 diabetes mellitus result from both decreased insulin secretion and insulin resistance. By combining an insulin secretagogue with an insulin sensitizer, both metabolic defects are targeted. When glycemic goals are not attained or maintained with two antidiabetic agents, a third oral agent with a complementary mechanism of action can be added. Alternatively, an evening or bedtime dose of intermediate-acting insulin can be added to the oral regimen and adjusted to achieve the desired goal.

In summary, more aggressive control of glucose concentrations has been shown to reduce the complications of diabetes. Diet and exercise alone are recommended for patients with IGT but are usually not sufficient once overt type 2 diabetes mellitus develops. As seen in the UKPDS, only 8% of patients allocated to diet and exercise therapy were able to maintain an HbA1c concentration of less than 7% over the study duration.[38] The choice to initiate monotherapy or combination therapy should be based on the level of glycemic control attained with diet and exercise and the blood glucose-lowering efficacy of various pharmacotherapeutic regimens. It is imperative to pursue intensive glycemic control while simultaneously addressing other possible cardiovascular risk factors, including hyper-tension, dyslipidemia, and cigarette smoking. The patient needs to take an active role in setting goals and self-monitoring his or her blood glucose concentration. The pharmacist can make a valuable contribution to the comprehensive care of patients with type 2 diabetes mellitus through patient education, evaluation of treatment outcomes, and pharmacotherapy consultations with patients and their providers.

Challenges in the Management of Type 2 Diabetes Mellitus: A Call to Action for Pharmacists

The most significant global challenges in the management of type 2 diabetes mellitus are underdiagnosis and the need for aggressive follow-up care and support for appropriate patient self-management. According to statistics compiled by the Centers for Disease Control and Prevention,[39] the prevalence of preventive care practices is suboptimal, and compliance with national health recommendations is poor. In 1997, a survey of people with diabetes in 41 states showed that only 61.6% of these individuals reported receiving a dilated-eye examination within the previous year; 54.6% reported receiving a foot examination within the previous year; 39.6% reported self-monitoring their blood glucose at least once/day; and 18.4% reported having their HbA1c levels checked within the previous year.[39]

Once patients are diagnosed, the primary care provider often does not have the time necessary to provide an appropriate self-management education program. Ancillary health care professionals are key in the continued support and education of patients with type 2 diabetes mellitus. However, there are few persons with specialized training to whom patients can be referred for these essential services.

The specific challenges for pharmacists in the management of type 2 diabetes mellitus include obtaining appropriate training, gathering convincing evidence that pharmacists improve patient care outcomes, and securing provider recognition by Medicare, which would allow pharmacists to be reimbursed for their pharmacy care services. Moreover, pharmacists often are not recognized by other health care professionals as a potential referral for patient education and evaluation.

Because of the complex pathophysiology of diabetes and the numerous approaches to therapy for managing diabetes, specialized training is required for pharmacists to become more proficient at providing care to people with diabetes. The most recognized credential in diabetes education is the Certified Diabetes Educator (CDE), which is administered through the National Certification Board for Diabetes Education.[40] Pharmacists make up the fastest-growing group of health professionals becoming CDEs.

The Board Certified-Advanced Diabetes Management (BC-ADM) examination is a jointly sponsored effort between the American Association of Diabetes Educators and the American Nurses Credentialing Center, in collaboration with the ADA, the American Dietetic Association, and the American Pharmaceutical Association. This is the first advanced practice certification in diabetes care that emphasizes clinical assessment and disease-state management in addition to patient education and counseling. This new certification differs from the CDE in that it focuses on advanced management issues; an advanced degree is required before one may sit for the examination.

In addition to the CDE and BC-ADM training programs, numerous certificate programs in diabetes are offered by colleges of pharmacy, state and national pharmacy organizations, and industry. These programs are designed to upgrade the clinical skills and knowledge of practicing pharmacists who are interested in expanding their practice to include patients with diabetes. The National Community Pharmacists Association and the American Pharmaceutical Association offer diabetes certificate programs. Other state- and university-affiliated programs, often in association with industry sponsors, also provide continuing education or certificate programs for pharmacists in the area of diabetes.

People with diabetes see their pharmacists 7 times more often than they see their primary care physician.[41] This frequent contact affords the pharmacist opportunities to increase the level of knowledge and understanding that patients have about their diabetes, reduce complications related to adverse effects of therapy, and work in concert with patients and their physicians to achieve desired therapeutic outcomes. The pharmacy profession must recognize and conduct the necessary studies to demonstrate that appropriately trained pharmacists can improve the long-term clinical outcomes of patients with diabetes. This will enable pharmacists to become one step closer in being recognized as a provider. The reimbursement for pharmacist services is scattered and undependable at best without provider status.

Strategies for Pharmacy Reimbursement of Diabetes Care Services

Historically, pharmacists have been compensated for their services by linking payments to dispensing functions. Clinical or cognitive services that are separate from dispensing a drug generally have not been compensated. Nevertheless, pharmacists are providing patient-care services with increasing frequency.

A growing number of pharmacists practicing in the ambulatory or community setting have developed fiscal relationships with third-party payers that center on compensation for cognitive services. These pharmacists essentially have created an office-type practice similar to the physician model, with billing for nondrug product services including Clinical Laboratories Improvement Act (CLIA)-waived laboratory testing (e.g., lipid level screening, HbA1c testing, and international normalized ratio determination), which most often is done through the insurance company's major medical program. A proposed process for developing compensation for clinical and cognitive services has been described.[42]

Some pharmacists have developed collaborative services with physicians in their office practices. One advantage of this type of arrangement is that the physician's office can bill insurance carriers for the pharmacist's clinical services. In addition, Medicare patients can be billed for the pharmacist's services under the "incident to" guidelines.

More recent progress on compensation for pharmacist services can be seen in diabetes education in some states. For instance, Blue Cross/Blue Shield of Tennessee now credentials pharmacists as providers to offer diabetes and asthma education to patients either individually or in groups. Pharmacists are paid in turn for their cognitive services by billing Blue Cross/Blue Shield on a Form HCFA (Health Care Financing Administration)-1500. This is the same process used to compensate a physician for an office visit. Another pathway for compensation in diabetes is for the pharmacist to participate in an ADA-approved diabetes education program. These approved programs cover Medicare costs for diabetes education. Although pharmacists cannot bill or be compensated directly under this program, they can participate, which will generate revenue.

Currently, pharmacists are not considered providers under Medicare except for a few items such as vaccinations and durable medical equipment. However, there are two bills in the U.S. Congress that, if passed, would amend Title XVIII of the Social Security Act to provide coverage of pharmacist services in the commu-nity or clinic setting under Part B of the Medicare program. The "Medicare Pharmacist Services Coverage Act of 2001" is sponsored in the Senate by Senator Tim Johnson from South Dakota (S. 974) and in the House of Representatives (H.R. 2799) by Representatives Frank Pallone, Jr., from New Jersey and Lynn Rivers from Michigan. These bills would recognize pharmacists as "health care providers" and would allow pharmacists to bill Medicare for providing direct patient care services.

Tables

Table 1. American Diabetes Association Diagnostic Criteria for Diabetes Mellitus[15]


Biochemical Index Normal
Value		 Diagnostic
Criteria
Hemoglobin A1c (%) < 6 NA
Fasting plasma glucose (mg/dl) < 110 >/= 126
Plasma glucose 2 hrs after a 75-g oral glucose tolerance test (mg/dl) < 140 >/= 200


NA = not an acceptable instrument for diagnosing diabetes.


Table 2. Mechanisms of Action of Oral Glucose-Lowering Drugs by Class


  Mechanism of Action
Metformin (immediate or extended release) Decreased insulin resistance, decreased hepatic glucose output, increased peripheral glucose utilization
Sulfonylureas, meglitinides, nateglinide Increased insulin secretion
a-Glucosidase inhibitors Delayed digestion of complex carbohydrates
Glitazones Decreased insulin resistance, decreased hepatic glucose output, increased peripheral glucose utilization



Table 3. Combination Therapy Options


  Sulfonylurea Meglitinide Metformin Glitazone a-Glucosidase
Inhibitor		 Insulin
Sulfonylurea - - + + + +
Meglitinide - - + + + +
Metformin + + - + + +
Glitazone + + + - + +a
a-Glucosidase inhibitor + + + + - +
Insulin + + + +a + -


+ = effective combination; - = inappropriate combination.

a Pioglitazone only.



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Acknowledgements
We would like to acknowledge the technical assistance of Charles Miller, M.A., Director, Scientific Services, ApotheCom Associates, LLC.

Reprint Address
Address reprint requests to David Hawkins, Pharm.D., Southern School of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341; e-mail: Hawkins_dw@mercer.edu.

From the Southern School of Pharmacy, Mercer University, Atlanta, Georgia; the Department of Pharmacy Practice and Pharmacoeconomics, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee; Health Core, Inc., Newark, Delaware; the College of Pharmacy, The University of Texas at Austin, Austin, Texas; the Departments of Medicine and Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; the College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; the College of Medicine, University of Illinois at Rockford, Belvidere, Illinois; and the Department of Pharmacy Practice, Medical University of South Carolina, Charleston, South Carolina; on behalf of the National Pharmacy Cardiovascular Council.


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