CONTINUING EDUCATION

The Pharmacists Approach to Primary Care Management of Type 2 Diabetes

By James R. Taylor, PharmD, CDE

pon successful completion of this continuing education activity, the pharmacist should be able to: 1. Discuss benefits of medical nutrition therapy, exercise and weight loss for patients with diabetes 2. Provide general recommendations to patients for medical nutrition therapy, exercise and weight loss 3. Identify goals of therapy for patients with diabetes 4. Discuss impact of pharmacy-managed diabetes programs 5. Discuss role of medications in treating type 2 diabetes INTRODUCTION Both within and outside of the health care environment, there has been an increased awareness of the rising incidence of diabetes in the United States and worldwide. The National Diabetes Fact Sheet from 2007 reports a total prevalence of diabetes in United States for all ages to be 23.6 million, or about 8 percent of the total population. Of that, approximately 6 million people remain undiagnosed. In addition, almost 10 percent of all persons over 20 years of age have diabetes. The majority of the diabetes population (9095 percent) has type 2 diabetes. The focus of this article will be on the primary care prevention and management of type 2 diabetes from a pharmacists perspective. Although these interventions may be appropriately performed by any qualified health care professional, the community pharmacist is in an ideal position to initiate them and help patients maintain a healthy lifestyle.

It has been well docuUseful Websites mented in two landmark www.niddk.nih.gov clinical trials on the prevenNational Institute of Healths (NIH) tion of diabetes that dietary website, focusing on a broad spectrum changes and regular physical of disease states relating to internal activity will prevent or delay medicine. Its helpful if looking for fundthe development of diabetes ing and research opportunities within in high-risk individuals. The this field. Diabetes Prevention Project (DPP), a randomized, con www.nei.nih.gov trolled trial in subjects with The National Eye Institute website prediabetes, showed that a 7 provides free information and educapercent weight loss, achieved tion about proper eye health and eye diseases, including diabetes retinopathy, by a lifestyle modification which includes a prescription bag handprogram, reduced the cumuout for patients. lative incidence of diabetes over four years by 58 percent versus placebo (no formal lifestyle changes). The program incorporated counseling sessions both individually and in a group setting that encouraged a low-fat diet and at least 150 minutes of exercise (brisk walking) per week. The DPP also had a drug treatment arm using metformin, but the 31 percent reduction in cumulative incidence of diabetes, although significant, was smaller than that of the lifestyle intervention arm. The Finnish Diabetes Prevention Study extended the results of the DPP by looking at the reduction in the incidence of diabetes in high risk, middle-aged (mean age 55 years) individuals as much as five years post-intervention. The intervention included personal counseling sessions aimed at moderate (5 percent) weight loss achieved by a low-fat, high-fiber diet and moderate exercise for about 30 minutes per day. The average weight loss at five years was only 4.6 pounds, but still resulted in a much lower incidence of diabetes in this population (23 percent) versus placebo (11 percent). Both studies showed that modest reductions in weight using a

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combination of dietary modifications and exercise result in significant reductions in the incidence of diabetes in high risk individuals. If these non-pharmacological means are effective in preventing diabetes progression, then it only makes sense that they should also be a part of a treatment plan for patients with existing diabetes. Most patients will require pharmacologic therapy in conjunction with lifestyle modifications to achieve optimal control of their diabetes and reduce risk of complications. Numerous medications are now available, each with their own benefits and risks. Table 1 summarizes the goals of therapy for diabetes. MEDICAL NUTRITION THERAPY (MNT) The American Diabetes Association (ADA) advocates initial lifestyle intervention strategies as well as reinforcement of those interventions at each visit. Additionally, medical nutrition therapy (MNT) has become a primary component in the management of type 2 diabetes due to the strong link between obesity and insulin resistance. The main components of MNT are reduced fat and carbohydrate intake, physical activity, maintaining weight loss of 57 percent of body weight, education, and regular patient contact. The nutritional component of MNT is based on the United States Department of Health & Human Services (HHS) Dietary Guidelines for Americans and consists of a diet low in fat (30 percent of total caloric intake) with less than 7 percent of total calories from saturated fat (trans fats should be minimized). Carbohydrate monitoring by exchanges, counting or other methods is recommended, but low carbohydrate diets, especially those that provide fewer than 130 grams per day are discouraged. The ADA does not promote the use of the glycemic index or glycemic load when modifying carbohydrate intake, but these values may give modest additional benefit for those patients with existing diabetes. The glycemic index is defined as the increase in blood glucose above fasting level two hours post-prandially. The amount of each individual food source ingested is equivalent to 50 carbohydrate grams. The resulting blood glucose level is then divided by that produced by a reference food (usually glucose or white bread) to give the glycemic index. The glycemic load is the glycemic index multiplied by the amount of carbohydrate grams. The Institute of Medicines Dietary Reference Intake (DRI) report establishes guidelines for macronutrient intake for all individuals. It is stressed that all dietary measures be

Table 1: ADA Recommended Treatment Goals

A1C (%) Fasting blood glucose (mg/dl) Postprandial blood glucose (mg/dl)* Bedtime blood glucose (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) * 12 h after the beginning of the meal < 7% 70-130 < 180 < 140 < 100 > 40 for men > 50 for women < 150

individualized and recommended by a registered dietician. In keeping consistent with the MNT goal of education and regular follow-up, the ADA goes further to say that all members of the health care team should be familiar with nutrition therapy to provide adequate support to patients. MNT is such an integral component of diabetes care that it can be used as primary prevention in high-risk individuals, secondary prevention in delaying complications in existing diabetics, and in the control of complications once they are present. Since the completion of the Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study (UKPDS) trials, the critical association between uncontrolled hyperglycemia and the increased risk of complications has been recognized, and the goal of drug and non-drug therapy is to achieve and maintain normal to near normal blood glucose levels. It is also known that the elevated blood glucose associated with diabetes is directly related to deficient carbohydrate metabolism; therefore dietary carbohydrate intake has the greatest influence on blood glucose levels. Studies have shown that both the type and source of carbohydrate are important in predicting its effect on blood glucose. It is still controversial whether glycemic index or glycemic load should be used in dietary strategies for the management of diabetes, but it is important to know that foods with a high glycemic index such as bread, potatoes, and pasta induce a more intense, sustained glycemic response than foods like whole grains, beans, legumes, and fruits (fructose). In addition, sugars such as fructose, sucrose, and lactose

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produce a lower glycemic response and fiberrich sources of carbohydrates decrease glucose absorption and therefore lower the glycemic response. It is also believed that whole grain consumption increases insulin sensitivity. Health care providers, including pharmacists, with knowledge of carbohydrate type and source as well as total daily carbohydrate ingestion will demystify the concept of carbohydrate metabolism and assist diabetes patients in making healthy food choices. As mentioned earlier, a total daily intake of less than 130 grams of carbohydrate is not recommended. Because the deficiency in carbohydrate metabolism in diabetes is a result of both insulin secretion abnormalities and insulin resistance, blood glucose may be elevated in both the fasting and postprandial states. Therefore, avoiding carbohydrates completely will not return blood glucose levels to normal range. PHYSICAL ACTIVITY It is well known that regular physical activity is recommended in a number of chronic diseases as both prevention and treatment. The benefits of exercise in diabetes are that glycemic control is improved, cardiovascular risk is reduced, and weight loss is promoted. A systematic review and meta analysis done by Boule and colleagues showed that structured exercise programs in type 2 diabetes patients for at least eight weeks duration showed statistically significant lowering of A1C as compared to control groups. Of note was the fact that these benefits were realized regardless of the reduction in body weight. A subsequent meta analysis by Boule also established a direct relationship between exercise intensity and the degree of A1C lowering, supporting continuation and maximization of physical activity in type 2 diabetics who may already be in a structured exercise program. The Surgeon General has defined physical activity by category. Exercise is considered a structured, planned, repetitive series of movements. Aerobic exercise is rhythmic, repeated activity for at least 10 minutes at a time, and

resistance training involves the use of weights. Authorities on diabetes such as the ADA and American Association of Clinical Endocrinologists (AACE) recommend physical activity as part of a diabetes prevention or treatment program. The ADA promotes least 150 minutes per week of moderately intense aerobic activity and/or at least 90 minutes per week of vigorous aerobic exercise. The addition of resistance training is also advised. The AACE mentions the fact that exercise increases peripheral glucose uptake for up to 48 hours, so the interval between sessions should not exceed two days. In their Dietary Guidelines for Americans (2005) HHS recommends at least 30 minutes of moderate intensity physical activity at 5070 percent of maximum heart rate most days of the week. To promote weight loss, the duration should be increased to 60 minutes per day and the intensity to vigorous aerobic exercise (more than 70 percent maximum heart rate). Likewise, both aerobic and resistance training are considered beneficial. The American College of Sports Medicine cites that resistance training is equivalent to aerobic exercise in improving insulin sensitivity. The health care provider can assist the patient in selecting the type, frequency, and duration of an exercise program based on the current guidelines. The benefits can be justified with current literature, and the mechanisms explained to patients in lay language if necessary. Patients who were previously sedentary, have a high risk of CVD (more than 10 percent), or are prone to hypoglycemia and ketosis should be evaluated by their physician prior to initiating an exercise program. Most patients with diabetes may begin a brisk walking program without consulting with their physician. Based on a patients medication history, a pharmacist may have the information available to determine if a medical evaluation is necessary prior to beginning an exercise program. Patients with uncontrolled hypertension, peripheral neuropathy, autonomic neuropathy or retinopathy should consult a physician prior to initiating any kind of exercise program. A pharmacist may also assist in identifying patients on insulin or insulin secretagogues. Initiating or intensifying an exercise program can increase the risk of hypoglycemia in these patients. WEIGHT LOSS The rapid increase in the prevalence of diabetes in the United States is attributed to the concomitant increase in the percentage of the population that is overweight and

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obese. Likewise, the prevalence of type 2 diabetes is 37 times higher in obese than in normal-weight adults. Overweight is defined as a Body Mass Index (BMI) more than 25 kg/m2, and obese as more than 30 kg/m2. The presence of visceral fat (central obesity) measured by waist circumference (more than 40 in males and more than 35 in females) also predicts the development of the metabolic syndrome. These conditions increase the risk of developing diabetes and complicate the management of diabetes due to increased insulin resistance. In addition, obesity is independently associated with an increased risk for cardiovascular disease, lipid abnormalities, and hypertension. The benefits of weight loss are prevention or delay of type 2 diabetes, increased insulin sensitivity, reduction in the need for medication, improved fasting glucose, and reduction in cardiovascular risk. The ADA, as well as the AACE, HHS, and the National Heart, Lung and Blood Institute (NHLBI) all agree that gradual (12 pounds per week) moderate weight loss (5 percent) can result in significant health benefits, and when combined with physical activity, is more sustainable than rapid weight loss programs. Setting realistic and attainable goals is also more beneficial to the patient in that continuation of the program is supported by small accomplishments. Weight loss can be achieved by the combination of diet (low-calorie, low-fat) and physical activity (see above). Initial goals should be set at 57 percent of total body weight at a rate of 12 pounds per week. The long-term weight loss goal is to achieve a BMI of less than 25 kg/m2. By setting an energy intake goal to achieve a 5001,000 kcal/day energy deficit and reducing total fat to 2530 percent of total calories/day, including no more than 710 percent saturated fat, and exercising at least 30 minutes per day 35 days per week, weight loss is promoted. For most patients, weight loss diets should supply at least 1,0001,200 kcal per day for women, and 1,2001,600 kcal per day for men, but daily caloric requirements may be individualized based on weight (Table 2). Gradual increase of moderate intensity aerobic activity to 6075 minutes per day will support maintenance of weight loss goals. Most importantly, diet and exercise programs must be individualized to meet each patients needs and abilities. Bariatric surgery may be necessary for morbidly obese patients whose BMI exceeds 40 kg/m2 or 35 kg/m2 with other co-morbidities. Studies have shown a return to normal

Table 2: Daily Caloric Requirements Based on Weight

Body Weight in Pounds 150199 200249 250299 300349 >350 Kcal/day 1,0001,200 1,2001,500 1,5001,800 1,8002,000 2,000

blood glucose levels in over two-thirds of obese diabetes patients who underwent this procedure. Frequent patient contact and support is needed for weight loss maintenance at frequencies up to once weekly. The diabetes treatment team, including the pharmacist, must all participate in the patient weight loss program and provide support and encouragement to insure success. Additionally, many weight loss products are available, some of which may not be safe or helpful in promoting sustained weight loss. The community pharmacist may assist in selection of meal replacement products such as bars, shakes, or powders that contain the appropriate amount of macronutrients described previously, and recommend more healthy eating habits. Accommodating obese patients with scales that measure heavier weight, larger blood pressure cuffs, and accessible counseling areas are also measures that can be taken in the ambulatory setting to improve adherence to lifestyle programs and avoid embarrassment. PHARMACY-MANAGED PROGRAMS There have been a number of studies looking at the impact of diabetes education programs that included pharmacists. Morello and his colleagues conducted a retrospective analysis on two pharmacy-managed diabetes care clinics and looked at changes in A1C, fasting glucose, BMI and lipids in 113 patients. Compared to baseline, patients had a mean A1C reduction of 1.3 percent. The mean A1C value at three years post clinic intervention was 7.6 percent, and 55 percent of the patients enrolled met their A1C goals. The interventions included education on lifestyle modification.

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A study by McCord looked at both drug therapy management services and educational services as interventions in 316 diabetes patients (89 percent type 2) and measured changes in A1C. The educational intervention included general diabetes education and counseling on diet and weight loss. The mean A1C reduction was 1.4 percent, and 43.2 percent of patients achieved their A1C goal of under 7 percent (up from 14.8 percent prior to intervention). The diabetes team included two registered nurses, a dietician and a pharmacist who were all certified diabetes educators (CDE). Kiel and McCord conducted a retrospective study of 157 patients receiving clinical practice interventions based on collaborative practice agreements made between pharmacists and providers of diabetes care. The patients were seen on an individual basis and given general diabetes and lifestyle counseling by the pharmacist. Mean A1C reduction was 1.6 percent and an increase from 19 percent to 50 percent of patients postintervention reached an A1C goal of under 7 percent. In addition, an increased percentage of patients adhered to preventive care markers. Scott conducted a study in which 149 patients were randomized to either a control group (standard care) or an intervention group that consisted of pharmacist-managed diabetes care. The primary outcome was A1C reduction, and secondary outcomes were weight loss, decreased BMI, improved lipid profile, and reduction in blood pressure. There was a significant 1 percent difference in A1C decline between the two groups in favor of the intervention arm. This study also showed significant improvement in measurements of quality of life in the intervention group. The Asheville Project looked at the short and long term impact of community-based pharmaceutical care services in diabetes patients. The 12 pharmacies participating in the study had pharmacists certified in diabetes education who conducted lifestyle modification and self-monitoring of blood glucose (SMBG) interventions. Besides measuring overall improvement in A1C and lipids in which 50 percent of the patients showed

improvement over time, the study demonstrated reduced health care costs in the intervention group. A $1,200$1,800 reduction in cost per patient per year was realized as well as a shift in dollars spent from provider to prescription drugs. An estimated $18,000 increase in productivity was measured in one employer group. In a similar study, Campbell et al. demonstrated an improvement in insulin resistance in type 2 diabetes patients receiving lifestyle and medication education in an outpatient setting from pharmacists certified in diabetes education. Marrero identified certain barriers to initiating behavior modifications from previous studies in diabetes patients. Lack of provider experience, patient experience and beliefs, lack of support from the health care system, and minimal community support were all responsible for lack of effective implementation of lifestyle changes. It is proposed that these barriers may be overcome by promoting awareness of the health risks of diabetes, selecting patients that are more receptive to change, setting realistic goals, holding patients accountable, regular follow-up, and positive reinforcement of effort and successes. PHARMACOTHERAPY FOR TYPE 2 DIABETES MELLITUS Sulfonylureas The sulfonylureas work by stimulating insulin secretion from the pancreas. The efficacy of these agents in type 2 diabetes has been well established, providing a decrease in A1C of 1.52 percent. Despite their efficacy, side effects such as weight gain and hypoglycemia, along with decreased efficacy over time may limit the usefulness of sulfonylureas for the chronic treatment of diabetes. Metformin Currently, metformin is considered first line therapy for most patients with type 2 diabetes. Metformin works by decreasing hepatic glucose production and increasing muscle insulin sensitivity. Like sulfonylureas, metformin is very effective, producing a decrease in A1C of 1.52 percent. Gastrointestinal side effects are common with metformin use, occurring in 2030 percent of patients. Lactic acidosis, although rare, is a serious potential side effect associated with metformin therapy and will limit its use in certain populations. Glucosidase Inhibitors Acarbose and miglitol work by inhibiting the enzymes

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responsible for breaking down complex sugars into monosaccharides, thereby slowing the entry of glucose into the systemic circulation. These agents primarily lower postprandial glucose levels and are reported to reduce the A1C by 0.51 percent. The most common adverse effects associated with this class include bloating, abdominal discomfort, diarrhea, and flatulence. The -glucosidase inhibitors are not associated with hypoglycemia or weight gain. Thiazolidinediones (TZDs) By binding to the peroxisome-proliferator-activated receptor (PPAR-), TZDs lower blood glucose by increasing insulin sensitivity in the peripheral tissues. The TZDs are highly effective, demonstrating a decrease in A1C of 11.5 percent. Weight gain and edema are commonly associated with both agents. Despite their effectiveness, recent evidence associated with rosiglitazone suggests that patients taking rosiglitazone may be at an increased risk for myocardial infarction and death from cardiovascular causes. Until this information is further clarified, practitioners should carefully examine the risks versus benefits of using TZDs. Meglitinides Similar to sulfonylureas, the meglitinides work by stimulating insulin release from the pancreas. They are most often used in combination with metformin or the TZDs; as monotherapy they exhibit an A1C reduction of 0.51 percent. Common adverse effects include headache, hypoglycemia, weight gain, and dizziness. In addition to the adverse effects, other disadvantages associated with the meglitinides include cost and drug interactions. These disadvantages, along with minimal efficacy, limit the use of meglitinides in many patients. INCRETIN MIMETICS The single incretin mimetic available at this time functions as a GLP-1 analog slowing gastric emptying, increasing insulin synthesis and release, decreasing appetite, and improving -cell function. Peak plasma concentrations of exenatide are achieved within two hours after subcutaneous injection and the elimination half-life is 2.4 hours. Due to its effects on gastric emptying time, drugs which are rapidly absorbed from the gastrointestinal tract should be administered at least one hour prior to exenatide. Patients should be cautioned regarding ethanol consumption during

the use of exenatide, as the combination can lead to hypoglycemia. Nausea is the most common side effect, with an incidence up to 50 percent, although it is generally transient. Mild to moderate hypoglycemia is possible, especially when used with a sulfonylurea. Other side effects include vomiting and diarrhea. Exenatide use should be avoided in patients with gastroparesis, severe gastrointestinal disease, and severe renal impairment. Postmarketing reports suggest that exenatide may be associated with acute pancreatitis; practitioners should be aware of the signs and symptoms associated with acute pancreatitis and should discontinue therapy if suspected. The use of exenatide has not been evaluated in patients less than 18 years of age or pregnant women. Exenatide is approved as adjunctive therapy in patients with type 2 diabetes. It is dosed at 5 mcg subcutaneously twice daily (60 minutes prior to a meal). After one month, if an optimal response is not achieved, the dose may be increased to 10 mcg twice daily. Exenatide has been studied for up to 82 weeks in patients inadequately controlled on sulfonylureas and/or metformin. Glycosylated hemoglobin (A1C) was reduced 0.40.6 percent in patients on the 5 mcg regimen, and 0.81.3 percent in patients on the 10 mcg regimen. Changes in fasting plasma glucose (FPG) were minimal, however, this is to be expected as exenatide has a greater effect on postprandial glucose levels. Body weight also improved in these patients with a 0.91.6 kg weight loss seen in patients using 5 mcg twice daily and 1.65.3 kg. in patients using 10 mcg twice daily. In a patient weighing 250 pounds, this represents a weight loss of about 14 percent. One placebo-controlled study examined the effect of adding exenatide in patients suboptimally controlled on a thiazolidinedione (TZD) with or without metformin. The addition of exenatide led to a decrease in A1C of 1 percent FPG of 31 mg/dL, and body weight of 1.5 kg. This study provides the first evidence that exenatide is effective when added to a TZD, however, additional studies may be required to support the routine use of this combination.

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The addition of exenatide has been compared to the addition of insulin glargine and insulin aspart in two separate studies. When compared to insulin glargine, both agents decreased A1C by 1 percent. Exenatide demonstrated greater efficacy in reducing postprandial glucose concentrations and body weight. However, insulin glargine produced greater effects on preprandial glucose levels and less adverse events. In the study comparing the addition of exenatide to insulin aspart, both agents decreased A1C as well as fasting serum glucose. Additionally, exenatide led to weight loss and greater improvement in morning and evening postprandial glucose levels. DIPEPTIDYL PEPTIDASE-IV INHIBITORS Dipeptidyl peptidase-IV (DPP-IV) inhibitors function on incretin by slowing inactivation of the hormone, therefore prolonging incretin activity. Sitagliptin Sitagliptin (Januvia) was the first DPP-IV inhibitor to hit the U.S. market, approved in 2006. Sitagliptin has been studied as monotherapy, as well as in combination with sulfonylureas, metformin, and pioglitazone. In one monotherapy trial, 651 patients were randomized to receive: placebo, sitagliptin 5 mg twice daily, sitagliptin 12.5 mg twice daily, sitagliptin 25 mg twice daily, sitagliptin 50 mg twice daily, or glipizide 5 mg (titrated to 20 mg) daily. After 12 weeks of treatment, all doses of sitagliptin yielded a significant reduction in A1C when compared to placebo. The reductions in A1C ranged from 0.380.77 percent (p <0.001) with the greatest reduction seen in the group receiving sitagliptin 50 mg twice daily. Sitagliptin therapy was well tolerated with a low incidence of hypoglycemia or weight gain reported. The authors concluded that sitagliptin was safe and effective as monotherapy for type 2 diabetes, with 50 mg twice daily being the most effective dose. In another trial involving sitagliptin as monotherapy, 495 patients were randomized to receive sitagliptin 100 mg daily, sitagliptin 200

mg daily, or placebo. The results of this trial revealed a significant decrease in A1C of 0.480.6 percent in patients taking sitagliptin (p <0.001). In addition, it was discovered that the incidence of hypoglycemia with sitagliptin was similar to placebo and had a neutral effect on weight. Similar to the previous trial, Aschner and colleagues randomized 711 patients to receive monotherapy with sitagliptin 100 mg once daily, sitagliptin 200 mg once daily, or placebo. As expected, the investigators found that sitagliptin significantly reduced the A1C by 0.790.94 percent (p <0.001) with little hypoglycemia reported and neutral effects on body weight. However, the investigators also found in this study that sitagliptin produced slightly more gastrointestinal disturbances than placebo. A small randomized, double-blind, placebo-controlled, cross-over study involving 28 patients was conducted to examine the effect of adding sitagliptin 50 mg twice daily to metformin therapy. After receiving sitagliptin or placebo for four weeks, patients then received the opposite treatment. Results of this trial showed that adding sitagliptin to ongoing metformin therapy reduced fasting plasma glucose by 20.3 mg/dL (p<0.05 compared to placebo). Additionally, the investigators found that adding sitagliptin to metformin therapy did not produce significantly more GI effects. Two larger trials also examined the effect of adding sitagliptin to ongoing metformin therapy. Both trials found that adding sitagliptin 100 mg once daily to metformin yielded a 0.652.07 percent decrease in A1C. In addition, the incidence of hypoglycemia in all groups was similar to that reported in patients taking placebo. Nauck conducted a non-inferiority trial to determine whether adding sitagliptin to metformin was as effective as adding glipizide to metformin therapy. This was a randomized, parallel-group study with an active-controlled, double-blind treatment period. Both sitagliptin 100 mg once daily and glipizide 5 mg (up to 20 mg) once daily decreased A1C by 0.67 percent. Also, sitagliptin therapy resulted in significantly less hypoglycemia as well as significant weight loss when compared to glipizide. One study has assessed the effect of adding sitagliptin to patients currently uncontrolled on pioglitazone therapy. In this randomized, double-blind, placebocontrolled, parallel-group study, 337 patients received sitagliptin 100 mg once daily or placebo. The addition of sitagliptin resulted in a decrease in A1C of 0.7 percent (p <0.001) and fasting plasma glucose of 17.7mg/dL

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(p <0.001). The incidence of hypoglycemia was similar between groups. However, patients in the sitagliptin group experienced significantly more abdominal pain. SAXAGLIPTIN Saxagliptin (Onglyza) is the newest DPP-IV agent, approved in 2009. Rosenstock researched a saxagliptin dose-ranging study in 423 drug-nave patients with type 2 diabetes. This was a 12-week, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. Patients received 2.5, 5, 10, 20 or 40 mg of saxagliptin once daily or placebo for 12 weeks. In another cohort, patients received 100 mg daily of saxagliptin, or placebo, for six weeks. Saxagliptin reduced A1C by 0.70.9 percent from an average baseline of 7.9 percent. Placebo reduced A1C by 0.3 percent in the low dose cohort. One hour postprandial glucose were reduced 2441 mg/dl as compared to placebo. Saxagliptin did not result in any significant changes in weight and adverse effects were similar across groups. In another randomized, placebo-controlled study, 743 patients with diabetes uncontrolled on metformin received the addition of saxagliptin 2.5 mg, 5 mg, 10 mg or placebo, once daily. Baseline hemoglobin A1C values ranged from 710 percent (mean 8.0 0.9 percent) and metformin doses ranged from 1,500 to 2,550 mg/day. Baseline mean fasting plasma glucose was 176 46 mg/dL. After 24 weeks, patients receiving saxagliptin 2.5 mg, 5 mg, and 10 mg once daily showed significant reductions (p< 0.0001) in A1C compared to placebo (0.73 percent, 0.83 percent and 0.71 percent, respectively). Fasting plasma glucose was also significantly reduced (p < 0.0001) for patients receiving saxagliptin 2.5 mg, 5 mg or 10 mg daily (16 mg/ dL, 24 mg/dL, and 21 mg/dL, respectively). Saxagliptin also decreased post-prandial glucagon and increased post-prandial insulin and c-peptide following oral glucose tolerance tests when compared to placebo. No increase in hypoglycemia was seen with saxagliptin as compared to placebo. Weight changes were similar for all patients (-1.5 kg, -0.9 kg, -0.5 kg, and -1.0 kg for saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo, respectively). The manufacturer also reports that saxagliptin has been studied in combination with pioglitazone and rosiglitazone. A total of 565 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione (TZD)

in patients with inadequate glycemic control (A1C 7 percent to 10.5 percent) on TZD alone. Saxagliptin 2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C (0.7 percent to 0.9 percent) as compared to placebo add-on (0.3 percent). Post-prandial glucose also significantly decreased with addition of saxagliptin (55 to 65 mg/dl) as compared to placebo (15 mg/dl). Saxagliptin is indicated as monotherapy or in combination with other drugs used to treat type 2 diabetes. The recommended dose is 2.55 mg by mouth once daily. Patients with a CrCl less than 50 ml/min or those also receiving a medication that is a strong inhibitor of CYP 3A4/5 (such as ketoconazole) should receive 2.5 mg daily. It has not been studied in combination with insulin. Saxtagliptin is generally well tolerated. The three most commonly reported adverse reactions in clinical trials were upper respiratory tract infection, urinary tract infection, and headache. The overall incidence of hypoglycemia in patients treated with saxagliptin was similar to the incidence in patients taking placebo. Saxagliptin may cause lymphopenia. As compared with data from placebo recipients, the mean decrease in the absolute lymphocyte count was 100 cells/microliter among saxagliptin 5 mg daily recipients. In one trial, a lymphocyte count of 750 cells/microliter or less occurred in 0.5 percent of saxagliptin 2.5 mg recipients, in 1.5 percent of saxagliptin 5 mg recipients, and in 0.4 percent of placebo recipients. No increased risk for cardiovascular disease was seen in trials involving relatively low risk patients. Trials involving those at higher cardiovascular risk are ongoing. INSULIN Insulin is the most effective agent at lowering glucose and plays an integral role in the treatment of type 2 diabetes. While in the past insulin was often reserved as last line therapy, current evidence suggests that aggressive lowering of glucose, especially with insulin, in newly diagnosed diabetes can result in sustained glucose control.

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Holman et al compared three different insulin regimens in 708 patients with type 2 diabetes over a three-year period. Five hundred and seventy-eight patients completed the three years. All patients had a hemoglobin A1C between 710 percent despite receiving maximally tolerated doses of metformin and a sulfonylurea for at least four months. A history of taking a thiazolidinedione or triple oral antidiabetic therapy were exclusion criteria. Patients were randomly assigned to one of three insulin regimens. These regimens were twice daily biphasic insulin aspart/insulin aspart protamine, three times daily prandial insulin aspart, or once or twice daily basal insulin detemir. During the first year of the study, if hemoglobin A1C was greater than 10 percent or greater than or equal to 8 percent two consecutive times after 24 weeks in the study, sulfonylurea therapy was replaced by a second insulin, either prandial or basal, depending on initial insulin use. This was also done in patients whose A1C remained above 6.5 percent further along in the study. The primary outcome of the study was change in hemoglobin A1C. After three years, the median A1c in the biphasic insulin, prandial insulin, and basal insulin groups was 7.1, 6.8, and 6.9 percent, respectively. There was no significant difference in A1C between the three groups. The mean A1C reductions on the three insulin groups was 1.3, 1.4, and 1.2 percent, respectively. The authors identified numerous secondary outcomes, including, but not limited to, those reaching A1C goals, changes in glucose, weight changes, insulin doses, hypoglycemic events, and changes in blood pressure and cholesterol. Significantly more patients in the prandial (67.4 percent) and basal (63.2 percent) groups reached an A1C less than or equal to 7 percent as compared to the biphasic group (49.4 percent). Similar results were seen when comparing those patients who reached an A1C less than or equal to 6.5 percent. The prandial insulin group had the largest mean reduction in all self monitored glucose readings (excluding 3 a.m.

readings) with a mean reduction of 67 mg/dl. No significant differences in fasting glucose readings were observed between the three groups. The prandial group had the largest reduction in postprandial glucose readings, including a significant reduction when compared to the biphasic group. Weight (mean) increased in all three groups as follows: biphasic 5.7 kg, prandial 6.4 kg, and basal 3.6 kg. Insulin doses also increased in all three groups throughout the study, although the biphasic group saw the smallest increase in doses. Overall rates of hypoglycemia were highest in the prandial group and lowest in the basal group. There were no significant changes in blood pressure or cholesterol among the three groups. The biphasic group experienced the highest rates of adverse events (44.7 percent) as compared to 33.1 percent for the prandial group and 33.3 percent for the basal group. The authors pointed out that the basal group had the lowest weight gains and hypoglycemic events. They speculated that the cause of fewer patients in the biphasic group reaching A1C goals may be due to less flexibility with those types of fixed-ratio insulin formulations. The results of this study certainly provide support to current guidelines, which suggest adding basal insulin to oral therapy as a means of introducing insulin in patients not achieving therapeutic goals. Insulin can then be intensified by addition of prandial insulin as was done in this study. Basal insulin is often introduced at a dose of 1020 units once daily or 0.20.3 units/kg once daily. Doses may then be titrated as often as every three days until the desired fasting blood glucose levels are obtained. APPROACH TO THERAPY In 2006 the first consensus treatment algorithm for type 2 diabetes was established by the ADA and the European Association for Study of Diabetes. The algorithm is updated when new evidence supports changes in the clinical role of diabetes interventions. The 2009 version focuses on newer classes of antidiabetes medications and the clinical data that support their role in therapy. In agreement with the ADAs clinical practice guidelines, the consensus algorithm recognizes a general target A1C under 7 percent. It seeks to create a stepwise approach to the treatment of hyperglycemia based on available evidence. The current statement is, except for their differential effects on glycemia, there are insufficient data at this time to support a recommendation of one

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class of glucose-lowering agents, or one combination of medications, over others with regard to effects on complications. The recommendation is to select agents based on the patient-specific level of glucose lowering required, safety profiles, side-effect profiles, expense, tolerability, and ease of use. Treatment options are divided into two therapy tiers and a group of other agents. Tier 1 represents core therapies that are the most validated and cost effective at reaching target glycemic goals. This algorithm is the preferred treatment for most cases of type 2 diabetes. A careful titration of metformin, avoiding GI adverse effects to a dose of 850 mg to 1,000 mg twice daily along with lifestyle modification remains first-line Tier 1 therapy. If glycemic goals are not obtained after lifestyle modifications and titration of metformin to maximal tolerated dose, step 2 of Tier 1 involves the addition of a second medication, either insulin or a sulfonylurea. The amount of A1C reduction required is the determining factor as to which agent is selected. If a patients A1C remains elevated greater than 8.5 percent, insulin is preferred due to its higher efficacy at lowering glycemic levels. If this route is chosen initiate bedtime intermediateacting insulin or long-acting insulin injected in the morning or at bed time. Recommended starting daily dose is 10 units or 0.2 units per kg. FBG levels should be checked by the patient daily, with two-unit increases in basal insulin every three days until fasting levels are consistently at the target range. After two to three months of maintained FBG in the target range, A1C levels should be reevaluated. If A1C levels remain above 7 percent, more intensive insulin regimens should be considered based on blood glucose levels before lunch, dinner, and bedtime. The added agent may be regular, rapid, or mixed insulin depending on glucose levels obtained. Tier 2 therapeutic options include agents that do not have the same level of validation as those in Tier 1. Criteria are slightly more specific for when these agents may be substituted for Tier 1 agents. When assessing patients with particularly resistant hypoglycemia, the use of pioglitazone or exenatide may be considered, but rosiglitazone is not recommended. For patients who are not at ideal weight and for whom weight gain is a concern, exenatide may be considered. The other therapy agents are pramlintide, meglitinide, acarbose, and sitagliptin. These agents are currently not included in the consensus two-tier algorithm

as they are not well established, costly, have inconvenient dosing regimens, and/or undesirable adverse effects. MANAGEMENT OF CARDIOVASCULAR RISK Patients with type 2 diabetes are at an increased risk of cardiovascular disease. Type 2 diabetes is considered a CVD risk equivalent according to NCEP/ATPIII guidelines. The treatment goal for LDL lowering is less than 100 mg/dl with an optional goal of less than 70 mg/dl in a patient at high risk or with concomitant cardiovascular disease. ADA guidelines further recommend initiation of a hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) to achieve a 3040 percent LDL reduction regardless of baseline due to results from the Heart Protection Study and CARDS. It is necessary to acquire baseline fasting lipid levels, LFTs, creatine phosphokinase (CPK). Lipid profiles should be done every four to six weeks, and LFTs twice a year for the first year, then yearly. More frequent LFT monitoring is required at higher dosages (such as simvastatin 80 mg, atorvastatin 80, or rosuvastatin 40 mg). Additional lipid goals include triglyceride levels below 150 mg/dl and HDL greater than or equal to 40 mg/dl in men or greater than or equal to 50 mg/dl in women. Fibrates, niacin, most statins, and cardiovascular exercise reduced triglycerides and increase HDL, whereas fish oil decreases triglycerides. Blood pressure (BP) goals (< 130/80 mmHg) are lower in patients with type 2 diabetes and drug therapy initiated much earlier in therapy. If systolic blood pressure is greater than 140/90 mmHg on two separate occasions, or if BP is 130139 mmHg systole or 8089 mmHg diastole for longer than three months with lifestyle changes, initiation of drug therapy with an inhibitor of the renin-angiotensin-aldosterone system (RAAS) is recommended to not only prevent cardiovascular disease, but to delay the progression to macroalbuminuria and/or nephropathy. RAAS inhibitors include an ACE inhibitor or angtiotensin receptor blocker (ARB). Direct renin inhibitors (aliskiren)

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may be an option in the future. Monitor renal function and potassium levels at baseline, two weeks, and four weeks after initiating therapy and dose titration, and every three to six months thereafter. Agents that maximize blood pressure lowering in combination with RAAS inhibitors (such as thiazide diuretics, dihydropyridine calcium channel blockers) are appropriate additions if further lowering is required. To further reduce cardiovascular risk, aspirin at a dose of 75162 mg/day is recommended in the latest Standards of Medical Care in Diabetes Mellitus by the ADA in men more than 50 years old and women over 60 with at least one major risk factor (smoking, family history of CVD, hypertension, dyslipidemia, or albuminuria). SUMMARY There is a vast amount of information available to patients with diabetes on the lifestyle changes proven to improve glycemic control. These interventions have been supported by a number of clinical trials not only for the treatment of diabetes, but for the prevention or delay of its occurrence in high-risk individuals. The recommendations for diet and exercise made by experts in the field of diabetes and general wellness may be adopted by the public to improve overall health and are essential in the prevention and risk-reduction strategies of other chronic disorders. Health care providers, including pharmacists, can use non-pharmacological strategies to design a treatment program to treat and prevent diabetes, and should become educated in the areas of diet and exercise to properly implement these strategies. The use of pharmacologic agents will be necessary for most patients with diabetes to achieve A1C, LDL, blood pressure, or other clinically relevant therapy goals. Appropriate approaches to therapy can improve outcomes, reduce complications and minimize number of required medications.

CONTINUING EDUCATION QUIZ Select the correct answer. 1. Janice and Bill are both patients with pre-diabetes conditions. Janice is committed to a low-fat diet and 30 minutes of brisk walking five times a week. Bills physician decides to initiate him on metformin 500 mg TID. Applying the findings of the Diabetes Prevention Project, whose cumulative incidence of diabetes over the next four years is higher? a. Janice b. Bill 2. According to the American Diabetes Association, the pre-prandial, or fasting glucose goal (mg/dl) for patients with diabetes is: a. < 200 b. < 180 c. 70130 d. 140180 3. The main components of medical nutrition therapy (MNT) for those with diabetes include all of the following except: a. Dietary protein restriction b. Reduced fat and carbohydrate intake c. Physical activity d. Education 4. Which of the following foods would most likely cause the largest, most significant increase in blood glucose? a. Beans b. Fruits c. Whole grains d. Potatoes 5. A low carbohydrate diet (< 130 g/day) is the best way to reduce blood glucose thru diet. a. True b. False 6. The American Diabetes Associations physical activity recommendations are best summarized as: a. Resistance training only without aerobic activities b. Mild aerobic activity most days of the week c. Moderately intense aerobic activity for 150 minutes per week, or 90 minutes of vigorous aerobic activity d. Vigorous aerobic activity one hour per day, six days per week

James R. Taylor, PharmD, CDE, is a clinical associate professor at the University of Florida College of Pharmacy, Gainesville, Fla.

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7. The potential benefit(s) of exercise in patients with diabetes is/are: a. Improved glycemic control b. Weight loss c. Reduced risk of cardiovascular disease d. All of the above 8. Patients with which of the following conditions should consult a physician before starting an exercise regimen? a. Uncontrolled hypertension b. Retinopathy c. Peripheral neuropathy d. All of the above 9. Generally, a diet designed for weight loss for a patient weighing 100 kg would consist of how many kcal/day? a. 1,0001,200 b. 1,2001,500 c. 1,5001,800 d. 1,8002,000 10. Regarding weight loss, which of the following is false? a. Rapid weight loss programs produce the best longterm results. b. Weight loss programs should consist of dietary modifications and exercise. c. Weight loss can improve insulin sensitivity. d. Dietary recommendations should be individualized. 11. The Asheville Project demonstrated all of the following except: a. Improved A1C in about 50 percent of patients b. $1,200$1,800 increase in health care costs per patient per year c. $18,000 increase in productivity in one employer group d. Improved diabetes knowledge and quality of life among patients 12. Regarding sulfonylureas, which of the following is false? a. Stimulates insulin secretion from pancreas b. Reduces A1C about 1.5 percent c. Weight loss a possible side effect d. Can cause hypoglycemia 13. Which of the following could potentially increase risk for lactic acidosis? a. Glipizide b. Metformin c. Acarbose d. Rosiglitazone

14. By functioning as a GLP-1 analog, exenatide demonstrates which of the following except? a. Stimulates appetite b. Slows gastric emptying c. Increases insulin release d. All of the above 15. Which of the following is the most common side effect of exenatide? a. Hypoglycemia b. Diarrhea c. Nausea d. Headache 16. Exentide has the most prominent effect on reducing: a. Fasting blood glucose b. Midday pre-prandial glucose c. Post-prandial glucose d. Post-prandial glucagon 17. Which medication prolongs the activity of incretin by slowing the inactivation of the hormone? a. Metformin b. Glipizide c. Pioglitazone d. Sitagliptin 18. In one trial, the addition of what dose of Onglyza to metformin resulted in the greatest reduction in A1c levels: a. 2.5 mg b. 5 mg c. 10 mg d. 15 mg 19. Regarding saxagliptin, which of the following is false? a. Recommended dose is 2.55 mg once daily b. Patients with CrCl less than 50 ml/min should receive 2.5 mg daily c. Incidence of hypoglycemia similar to placebo d. Not indicated for use as monotherapy

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20. Based on the study from Holman et al, which of the following insulin regimens (when added to oral therapy) is least likely to allow patients to reach their A1C goal? a. Prandial insulin b. Basal insulin c. Biphasic insulin d. Intensive insulin regimen using four injections per day 21. Which of the following would be the most appropriate starting dose of basal insulin (such as insulin glargine or detemir) when added to oral therapy in a 45-year-old male with type 2 diabetes who weighs 180 pounds and A1C is 9 percent? a. 5 units b. 8 units c. 20 units d. 30 units 22. Which of the following is not considered a tier 1 agent? a. Metformin b. Glipizide c. Pioglitazone d. Insulin 23. Although not a Tier 1 agent, which medication may be considered if weight loss is a major concern? a. Exenatide b. Rosiglitazone c. Acarbose d. Sitagliptin 24. PJ is a 47-year-old patient with type 2 diabetes. On two separate occasions, she has had blood pressure readings of over 140/90 mm Hg. What would be an appropriate anti-hypertensive to initiate at this time? a. Amlodipine b. Lisinopril c. Propanolol d. Aliskiren 25. Regarding cholesterol goals for patients with type 2 diabetes, which of the following is an incorrect goal? a. LDL < 100 mg/dl b. HDL 40 mg/dl in men c. HDL 50 mg/dl in women d. Triglycerides > 150 mg/dl

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