New Treatment Considerations for Type 2 Diabetes Mellitus

New Treatment Considerations for Type 2 Diabetes Mellitus Release Date: 11/21/2011 Expiration Date: 11/21/2014 FACULTY: Nicole Van Hoey, PharmD FACULTY AND ACCREDITOR DISCLOSURE STATEMENTS: Nicole Van Hoey has no actual or potential conflict of interest in relation to this program. ACCREDITATION STATEMENT: Pharmacy PharmCon Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Program No.: 0798-0000-11-089-H04-P Credits: 1.5 contact hour, 0.15 CEU Nursing Pharmaceutical Education Consultants, Inc. has been approved as a provider of continuing education for nurses by the Maryland Nurses Association which is accredited as an approver of continuing education in nursing by the American Nurses Credentialing Center s Commission on Accreditation. Program No.: N-713 Credits: 1.5 contact hour, 0.15 CEU

TARGET AUDIENCE: This accredited program is targeted pharmacists and nurses practicing in hospital and community pharmacies. Estimated time to complete this monograph and posttest is 90 minutes. DISCLAIMER: PharmCon, Inc does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. Program Overview: To provide nurses and pharmacists with an understanding of new treatment considerations for type 2 diabetes mellitus. OBJECTIVES: After completing this program, participants will be able to: Describe the morbidity and mortality risks associated with the epidemic of type 2 diabetes mellitus in the United States; Identify goals of treatment and means of monitoring patients to evaluate treatment efficacy; Outline supportive care best practices that can improve quality of life and prevent chronic morbidity; and Compare the mechanisms, dosages, and adverse events of DPP-4 inhibitors, a class of new antidiabetes drugs, with standard treatment options.

Case Presentation G. H. is a 38-year-old father of three who comes to your joint pharmacy-nursing diabetes outpatient clinic at the urging of his wife. She had gestational diabetes during her last pregnancy, and she is concerned about her husband s diabetes risks. G.H. admits to occasional smoking and shortness of breath at rest. He does not have a regular exercise program; his weight has been increasing steadily since the birth of his first child eight years ago. He has a positive family history of the disease.. His father has had a leg amputated as a result of uncontrolled diabetes and suffered from cardiovascular disease as well. At your clinic, G.H. undergoes A1C testing, and the resultant 8.5% score indicates a history of high blood glucose. What questions do you have for G.H. about possible complications or overlapping conditions? What lifestyle and medication treatment regimens should you recommend? How should G.H. be monitored and treated over the long term? Introduction 1-5 Type 2 diabetes mellitus (T2DM or DM) is a chronic disease that causes long-lasting damage to multiple organ systems through endocrine malfunction and resultant hyperglycemia. T2DM is the seventh leading cause of death in the United States and has become a 21 st century health epidemic. Nearly 26 million Americans greater than 8% of the population are living with diabetes, and approximately 2 million new diagnoses are made each year. 2, 4 The striking number of patients in the United States with diabetes is mirrored worldwide, and international organizations, such as WHO and the International Diabetes Federation, have advised proactive prevention and intensive treatment strategies to curb the trend. Minimizing risks and controlling blood sugar levels require monitoring, lifestyle changes, and aggressive treatments. One component of proactive prevention is early identification of risk factors, especially modifiable lifestyle choices. Behavioral risks include poor nutrition (e.g., excessive sugar intake) and low physical activity (e.g., fewer than 15 minutes of moderate exercise each day). Perhaps the most common modifiable risk for diabetes, though, is obesity, defined as a body mass index (BMI) of 25 kg/m 2 or greater. 4 Fat cells, especially abdominal fat cells, retain postprandial glucose longer than muscle and prolong hyperglycemia. A cluster of risk factors known as metabolic syndrome includes visceral fat in particular as a risk for developing cardiovascular disease and diabetes. Waist circumference is a secondary measure of central obesity that reflects these metabolic concerns. 3, 5 Although T2DM was historically considered a disease of older adulthood, patients are now being diagnosed at much younger ages, even as teenagers. Earlier development is associated, at least in part, with the increased rates of obesity and lack of physical activity observed in younger generations. However, advancing age, particularly beyond 45 years, is still a primary diabetes risk factor. Many nonwhite ethnicities are associated with increased diabetes rates as well. African Americans are most at risk, with a 77% greater likelihood of diabetes than whites, followed by Hispanic populations. 2,3 Native Americans and some Asian populations, such as Pacific Islanders, are also more at risk than whites. Other major risk factors include primary relatives with T2DM, a history of gestational diabetes, and delivery of a newborn weighing greater than 9 pounds. Clinical indicators of risk reflect the link between diabetes and cardiovascular health: blood pressure greater than 140/90 mmhg, high-density lipoprotein less than 35 mg/dl, and triglycerides greater than 150 mg/dl. 3, 4 1, 2,4,6,7 Pathophysiology: Disease Development, Progression, and Complications The pancreas controls glucose balance throughout the body by releasing insulin and glucagon from B and A cells, respectively. Blood glucose increases when sugars are absorbed from foods, and this triggers pancreatic insulin secretion to eliminate unused glucose and prevent hyperglycemia. Conversely, when Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 1

blood sugar drops without food intake, pancreatic glucagon initiates glucose formation and release from the liver to prevent hypoglycemia. T2DM occurs when this endocrine balance begins to fail. Although obesity, age, cardiovascular health, and possibly genetics appear to predispose a person to diabetes, the actual cause and timeline of pancreatic dysfunction are unclear. Multiple factors are involved. One component of the disease is reduced insulin secretion, when B cells slowly stop responding to glucose in the blood. As tissue and circulating glucose levels remain high, metabolic communication breaks down even more. To compound the effects of B cell dysfunction, peripheral resistance to insulin develops at organs, so the response to insulin becomes minimal. Insulin resistance, first identified in 1998 by WHO, has become inextricably linked to the development of T2DM. Organ damage from excessive glucose begins even before symptoms manifest; resistance can be present for 3 to 6 years before hyperglycemia is detected. 6,7 High blood glucose concentrations affect fluid volumes to cause polyphagia, polyuria, and polydipsia. When glucose reaches these symptomatic levels, the physical response can be easily identified: dehydration, fatigue, nausea, vomiting, blurred vision, weight loss, and fungal infections are notable. 1 Although these symptoms support a diagnosis of diabetes, up to 50% of people with diabetes are not tested and diagnosed until they experience additional vascular complications. 7 Secondary morbidities of T2DM involve macrovascular and microvascular complications that increase mortality and reduce quality and function of life. Large vessel cardiovascular disease, the primary cause of death in people with diabetes, includes heart attack and stroke. Small vessel damage in the eye, kidney, and lower limbs can increase clot risks and cause nerve damage in up to 70% of patients. 1 Severe impacts of unchecked microvascular damage include blindness, amputation, and kidney failure. Evaluation Tools 1,2,6-10 From a clinical perspective, secondary markers of glucose control are needed to identify diabetes in atrisk populations before hyperglycemic symptoms or vascular problems develop. Evaluation tools quantify blood glucose levels efficiently and can be used in diagnosed patients to monitor treatment efficacy. Fasting plasma glucose (FPG), postprandial glucose (PPG) or oral glucose tolerance testing (OGTT), and A1C are standard laboratory measures for the disease, and the new eag calculation supplements the A1C in a more patient-friendly format. Diagnosis of T2DM can be made when one abnormal result is confirmed by a second measurement, ideally with a different test or on a different day. In practice, a high FPG confirmed on the same day with a high OGTT can diagnose the disease. FPG, measured after at least 8 hours without caloric intake, is considered the gold standard diagnostic tool by the ADA. The test is easy, fast, convenient, low-cost, and reproducible. Normal glucose is < 100 mg/dl; 100 to 125 mg/dl indicates impaired glucose regulation, a warning sign for future disease. Diabetes is present with FPG of 126 mg/dl or greater. Nonfasting plasma glucose is most often measured by the OGTT; this test measures blood glucose 2 hours after an oral 75-gram sugar bolus is ingested. Levels < 140 mg/dl are considered normal; 140 to 199 mg/dl, impaired; and 200 mg/dl or greater, diagnostic. Though sensitive, the test is inconvenient and not preferred by patients. In practice, random nonfasting plasma glucose concentrations greater than 200 mg/dl can support a diagnosis as well. Unlike fasting or postprandial serum glucose, glycosylated hemoglobin (HbA1c or simply A1C) is an indirect measure of plasma glucose, and it reflects a history of long-term (i.e., 8 to 12 weeks), rather than immediate, control problems. An A1C of 4% to 5.6% is normal; greater than 6.5% supports diabetes Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 2

diagnosis according to ADA and international standards. In addition to its diagnostic use, A1C plays an important role in disease monitoring. Increasing A1C is directly proportional to microvascular complications; coronary events and medication costs are greater with higher A1C results also. Thus, consistently high A1C results can dictate treatment changes. Twice yearly A1C monitoring is sufficient for controlled disease, but quarterly A1C testing is recommended during management of complicated disease. A new calculation suggested by the ADA converts the A1C percentage into a more familiar, patientfriendly format of mg/dl. The estimated average glucose (eag) converts percentages into milligrams of glucose per deciliter of blood, the same reporting values used for blood glucose testing and self monitoring. For example, an A1C of 7% converts to an eag of 169 mg/dl, which helps a patient understand that high blood sugar is still present. A free calculator is available at http://professional.diabetes.org/glucosecalculator.aspx. Plasma glucose or A1C testing is suggested for anyone with an overweight BMI (25 kg/m 2 or greater) and age older than 45 years or any one other risk factor. Testing should be repeated every 3 years while results are normal. When testing confirms diagnosis, early medication management helps prevent complications. Intensive control involves sustained lifestyle changes, patient care education, and regular health care monitoring in addition to medication regimens. Treatment Goals and Self-Care 2-4,9-11 As knowledge about prevalence and disease progression increases, integrated care becomes more urgent. Unlike management of most chronic diseases, DM care requires patients to provide 99% of their own disease management. 11 The primary goal of DM care, therefore, is to improve patient self care through continued education and regular follow-up. 3 The CDC Diabetes Prevention Program, together with the National Institutes of Health National Diabetes Education Program, strives to teach patients about the profound benefits of healthy living and regular disease checks. 2 Patients should know the ABC goals of A1C < 7%, blood pressure < 130/80 mmhg, and LDL cholesterol < 100 mg/dl that prevent vascular damage. 3 Blood pressure control alone proportionally reduces cardiovascular risk by approximately 50% and microvascular risk by nearly one third. 2 Implementing a nutrition plan can help patients meet their blood pressure and cholesterol goals: reducing sodium to 1,500 mg/day, lowering potassium and fat intake, and minimizing alcohol use are recommended. 3,4 Similarly the American Association of Diabetes Educators seven self-care behaviors for diabetes (i.e.-, AADE7) encourage long-term patient care through increased physical activity combined with medication, self-monitoring, and proactive psychological care through problem solving, healthy coping, and reducing risks. 11 Weight loss in particular has great demonstrable benefits for disease control and prevention. As little as 4 kg of weight loss decreases blood glucose rapidly, and sustaining a body weight reduction of 7% is effective diabetes prevention in people with existing risk factors. 9 The combination of only moderate physical activity, such as walking daily, and weight loss can reduce the likelihood of DM diagnosis by more than 50% over three years. Benefits from behavior change occur quickly, with protection against morbidities occurring even before weight loss manifests, and the protection can last up to 10 years. 3,9,10 However, maintaining A1C goals is difficult with lifestyle changes alone, as B cell function wanes. Diabetes is a disease of progressive deterioration, often despite behavior change and treatment. Medication management remains integral to patient care; as research about the disease grows, so does the variety of treatment classes. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 3

Standard Treatment Options 3,8,10-13 Drugs in established treatment classes often act either as insulin secretagogues in the pancreas or as insulin sensitizers at peripheral tissue. Some classes provide benefits by reducing glucose absorption or glucagon release, especially in response to meals, and injected insulin is a treatment option for refractory disease. First-Line Treatment 1,9,10,2,14 When diabetes is diagnosed, the consensus for first-line care is oral metformin combined with lifestyle changes. Metformin, the only biguanide approved in the United States to treat diabetes, rapidly lowers blood sugar. Its primary effect is decreasing liver glucose production and release, but the drug is a mild insulin sensitizer as well. Metformin lowers A1C better than most monotherapy, up to 1.5%. 12 The drug causes only mild diarrhea and reduced appetite; hypoglycemia is quite rare. Metformin is not associated with weight gain or loss. Lactic acidosis, though rare, is possible when creatinine clearance is 30 ml/min or less. The initial dosage of metformin 500 mg twice daily should be tapered up to 850 mg twice daily and to a maximally beneficial dosage of 2,500 mg/d if adverse effects are tolerated. As the disease progresses, monotherapy is often not sufficient for long-term care. Addition of a second drug is warranted if A1C remains < 7% after 2 to 3 months of metformin treatment. Combination therapy continues to effectively reduce A1C up to 1.0% over time, but adverse effect risks are compounded. These risks, in addition to high costs and inconvenient administration methods, often limit the drugs preferential use. 9 Algorithms for second-line agents are not clearly defined by the ADA; the actual drug choices are dependent upon patient-specific factors, including side effect tolerance, concomitant diseases (e.g., heart disease), administration method, and cost. 10 Second-Line Oral Antidiabetes Drugs 1,9,10,12-14 Sulfonylureas are typical components of a treatment backbone when metformin is no longer enough; the sulfonylurea class comprises numerous low-cost drug choices supported by well-known long-term safety data. Sulfonylureas, such as glyburide, increase insulin secretion from B cells to reduce blood sugar as quickly as metformin. Unlike metformin, sulfonylurea effects are not sustained enough to be first-line monotherapy. Less-frequent dosage regimens are available with newer, longer-acting agents, such as sustained-release glipizide or glimepiride. Although effective, these extended regimens also have greater rates of adverse effects. The most common secretagogue adverse effects are increased weight (up to 3 kg) and hypoglycemia. Adverse effects are more pronounced in the elderly and when sulfonylureas are combined with insulin or another secretagogue. A broad range of oral agents can be selected as second-tier alternatives to sulfonylureas in combination with metformin or as a third agent. Medications from the thiazolidinedione, glinide, and alphaglucosidase inhibitor classes have beneficial niche uses in the management of diabetes with metformin when patients do not respond to or tolerate sulfonylureas. Selection and dosage titration are at clinician discretion, with an A1C maintenance goal of 7% or less. Two thiazolidinediones, rosaglitazone and pioglitazone, are approved for use in the United States to treat T2DM. The glitazones are insulin sensitizers throughout the body, including in muscle, fat, and the liver. Glitazones can reduce A1C by 0.5% to 1.4% as monotherapy or in combination with another oral agent; they are also approved for combination with insulin to manage severe diabetes. However, both drugs in this class are expensive and have numerous, sometimes serious, adverse effects that limit their usefulness. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 4

When combined with sulfonylureas or insulin, glitazones can exacerbate hypoglycemia, requiring dose reductions in the former agents. Upper respiratory infections, increased liver enzymes, and headache have been noted with both drugs. More recently, increased rates of bone fractures in limbs have been observed, particularly in women. Pioglitazone has been linked to the occurrence of bladder cancer with more than one year of treatment as well, and it is no longer available outside the United States because of this risk. The FDA has recommended a maximum treatment period of one year and close monitoring for bladder adverse effects, such as blood in the urine, for pioglitazone. The most serious adverse effects of thiazolidinediones, however, are congestive heart failure and cardiovascular events. The FDA added black box warnings to both drugs in 2007 because of the documented reports of edema, dyspnea, and other heart failure symptoms; both drugs are contraindicated in people with class III or IV heart failure. Rosaglitazone increases stroke and heart attack risk significantly as well; in 2010, its use was restricted to a manufacturer-controlled access program for patients who have exhausted any other treatment options. 9,10,12-14 Clinicians must use their best judgment when selecting a glitazone for a treatment regimen, especially in patients with existing cardiovascular or fracture risks. Their high toxicities can outweigh any benefits. Similar to sulfonylureas, glinides are second-line secretagogues at pancreatic B cells. Repaglinide and nateglinide, approved in 1997 and 2000 respectively, have short half lives and are given 30 minutes before meals to stimulate postprandial insulin release. They also cause secretagogue-related effects of weight gain and hypoglycemia. In addition, they are costly agents that require three times a day dosing regimen, so glinides are used infrequently. 1,13 Alpha-glucosidase inhibitors are dosed three times daily with meals as well because of their unique mechanism in the gastrointestinal tract. Acarbose and precarbose inhibit digestion of polysaccharides by blocking the enzyme that dissolves carbohydrates in the gut. Although these drugs have a weaker overall benefit on A1C than other second-line agents, they are quite effective at preventing hyperglycemia directly after meals. Alpha-glucosidase inhibitors can be combined with metformin, with metformin and a secretagogue, or with insulin to supplement baseline glucose control. Their safety is well established, as these drugs act quickly and specifically on the intestine. Alpha-glucosidase inhibitors have few adverse effects and do not cause hypoglycemia or weight gain. However, one significant side effect, in the gastrointestinal tract, is substantial: increased gas and diarrhea resulting from excessive carbohydrates retained in the colon. The nearly 80% rate of increased gas is dose proportional and is severe enough to cause up to 45% of patients to discontinue treatment. 1,9,13 Injected Standard Second-Line Treatment Options 1,91,13 A noninsulin injectable treatment for T2DM, pramlintide, was approved by the FDA in 2005. The drug has been studied in combination with insulin alone and with insulin plus oral antidiabetes drug combinations, such as metformin and sulfonylureas. Pramlintide is an agonist of amylin, a hormone that reduces glucagon concentrations. It is best used as a supplemental treatment for postprandial glucose control. Subcutaneous administration after meals slows gastric emptying and increases satiety to provide mild (on average, 0.5%) improvements of A1C. Pramlintide is particularly useful for patients who use insulin, because the drug reduces insulin requirements after meals. However, gastric adverse effects occur frequently, and hypoglycemia is possible. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 5

Insulin 9,13,15 Insulin is the oldest available treatment of diabetes and has a large role in uncontrolled T2DM as the disease progresses. Injected insulin to supplement or replace the body s own supply was once reserved for end-stage DM, when insulin production at B cells had completely failed. Recent consensus for use, endorsed by the ADA, supports more aggressive and earlier use of insulin for uncontrolled T2DM. In severe occurrences, when A1C is 10% or greater, insulin therapy is justified as the first-line treatment at diagnosis. In patients who receive traditional first-line metformin but who continue to have A1C greater than 8.5% after 2 or 3 months, basal (i.e., background or baseline) insulin is a logical second-line additive. Again, insulin should be considered if combination therapy of metformin and a sulfonylurea, for example, fail to reduce A1C to < 8%. Insulin treatment can be progressively intensified to reach the A1C goal of < 7%. 9 Combination of insulin with sulfonylureas, glinides, or thiazolidinediones should be monitored closely, however, to reduce the risk of hypoglycemia. New Mechanistic Approaches to Treatment: The Incretin Effect 7,16,17 Contributing to the classic pathogenesis triad of insulin resistance, B cell dysfunction, and increased glucose storage in fat cells is the incretin effect. Incretins are hormones secreted in response to gastricspecific glucose absorption; the two responsible for most effects are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). After meals, GLP-1 and GIP are released from intestinal L cells to promote insulin release and prevent glucagon release from the pancreas. Because the hormones are quickly broken down by enzymes, including dipeptidyl peptidase-4 (DPP-4), their glucose control efforts are immediate and short lived. Still, this important incretin effect is responsible for up to 70% of insulin secretion after meals. 16 Additional benefits of GLP-1 secretion are reduced gastric emptying and increase satiety, which result in lower food intake. The incretin effect is impaired or absent in T2DM, as GIP effect and GLP-1 concentrations decrease. However, whether incretin malfunction is a cause or result of T2DM pathogenesis is still unknown. Regardless, studies of the incretin effect have opened new avenues of drug development against T2DM. New treatments that promote the incretin effect are not yet preferred agents for first- or second-line treatment because of their high cost and lack of long-term safety and efficacy data. However, drugs in both the GLP-1 agonist and the new DPP-4 inhibitor classes are promising therapeutic options. In particular, these classes might provide similar glucose control benefits as existing treatment options with additional benefits of weight stability and lack of hypoglycemia. GLP Agonists 1,10,16-18 Exenatide (Byetta) is a synthetic GLP-1 agonist that contains an amino acid sequence for resistance to breakdown by DPP-4. This first drug focused on improving the incretin effect was approved by the FDA in 2005 for use alone or with metformin and second-line oral agents; in 2011, the FDA expanded approval to include combination therapy with insulin glargine. Exenatide is an incretin mimetic that is given within 60 minutes before meals to increase insulin production in response to glucose; it can reduce postprandial glucose by as much as 50%. The drug also reduces gastric emptying and food intake, which can result in mild weight loss. Exenatide should not be given without meals or after meals. 17 Unlike endogenous GLP-1, exenatide has a half-life of 2.4 hours, and it remains in the body for approximately 10 hours after subcutaneous injection. The 5- to 10-mcg doses are administered twice daily whether used alone or in combination with oral medications. Each pen is filled with 60 preset doses for a Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 6

1-month supply. Separate needles are required for administration. Exenatide injectable pens should not be used if the normally clear solution turns cloudy or thick. 17 As exenatide improves the body s reaction to glucose intake, the drug contributes to overall B cell health; preservation of B cell function supports long-term diabetes control and delays the need for replacement insulin treatments. Exenatide use for up to 3-1/2 years has shown additional benefits beyond glucose and B cell stability as well. Blood pressure reductions of 2% to 4%, high-density lipoprotein increases of 24%, and low-density lipoprotein reductions of 6% have been documented with continued use. Longacting release (LAR) formulations of exenatide are under investigation for weekly dosing of 0.8 to 2.0 mg. Studies of LAR exenatide so far have demonstrated safety and even greater glucose control than twice-daily treatment for 15 to 30 weeks of treatment. 16 Minor hypoglycemia is possible when exenatide is combined with secretagogues, but the drug causes no hypoglycemia when used alone. The primary adverse effects from exenatide treatment are nausea with vomiting and diarrhea; these complaints are most frequent within the first 2 months of treatment. Pancreatitis, which is three times more likely in all patients with DM, is possible with exenatide. In 2008, the FDA reviewed available adverse effect data of exenatide and determined that the drug does appear associated with occurrences of pancreatitis more than anticipated in a diabetic population; a medication safety guide (though not a black box warning) is required with each prescription. In 2010, a second incretin mimetic, liraglutide (Victoza), received a black box warning because of associations with pancreatitis and the development of thyroid tumors. However, thyroid problems do not appear to cross over to exenatide treatment. Study results support exenatide use in patients who would most benefit from weight loss or who are at risk of hypoglycemia from standard treatments. The ADA considers exenatide a valid treatment option when metformin and sulfonylurea combinations fail to control glucose, for example. As experience with exenatide grows, the best timing and selection of patients will become clearer. 10,17 DPP-4 Inhibitors: A New Approach 1,19-22 The newest mechanism of enhancing the incretin effect is not mimetic. DPP-4 inhibitors comprise a growing class of agents that indirectly increase GLP-1 concentrations to reduce blood glucose. Sitagliptin, saxagliptin, and linagliptin are three DPP-4 inhibitors that have received FDA approval to treat T2DM; more are in the pipeline. DPP-4 inhibitors prevent the normal, rapid DPP-4 enzymatic breakdown of GLP-1 and GIP. These DPP-4 inhibitors block up to 80% of normal enzyme activity and cause a twofold increase in GLP-1 concentrations after meals. Though glycemic control appears less durable than what is seen with GLP agonists, DPP-4 inhibitors have reduced A1C up to 0.7% in clinical trials. 19 Drugs in this class have no hypoglycemia risks as monotherapy and are available as patient-friendly tablet formulations. All four available DPP-4 inhibitors are taken orally once or twice daily. In 2006, sitagliptin (Januvia) was the first DPP-4 inhibitor approved for use in the United States; saxagliptin (Oglynza) was approved in 2009. Both drugs were approved as monotherapy and as combination therapy with other oral antidiabetes drugs. Sitagliptin is available as 25, 50, and 100 mg tablets. Saxagliptin is a potent enzyme inhibitor and is approved for 5 mg and 2.5 mg daily doses. Saxagliptin is also marketed in a combination tablet with metformin 500 or 1,000 mg. Sitagliptin can be taken anytime with or without food; saxagliptin should be taken at the same time every day, likewise without regard to food intake. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 7

The first two approved DPP-4 inhibitors have generally mild adverse effects profiles. Upper respiratory infections are common. Diarrhea has been reported with sitagliptin as well, and slight increases in pancreatitis and pancreatic cancer have been observed in studies. Hypersensitivity reactions to sitagliptin have occurred within the first 3 months of treatment but are unusual. Risks associated with saxagliptin include urinary tract infections, upper respiratory infections, and headache. Saxagliptin combined with glitazones can worsen edema. Neither sitagliptin nor saxagliptin cause hypoglycemia when given without secretagogues, and both are weight neutral and without gastrointestinal side effects. Sitagliptin and saxagliptin are metabolized by the CYP liver enzyme system and are cleared renally. Moderate kidney dysfunction can double sitagliptin blood concentrations. One half of the normal dosage (i.e., 50 mg) of sitagliptin is recommended for creatinine clearances of 30 to less than 50 ml/min, and one quarter of the normal dose (i.e., 25 mg) is recommended for creatinine clearances less than 30 ml/min. Saxagliptin 5 mg daily doses should be reduced as well, to 2.5 mg for moderate kidney disease (defined for this purpose as creatinine clearance of 50 ml/min or less). CYP3A4/5 inhibitors might prevent the breakdown of these DPP-4 inhibitors, particularly saxagliptin, so the lower dosages used for kidney disease also might be required for patients who are taking strong CYP3A4/5 inhibitors, such as macrolide antibiotics or azole antifungal medications. Linagliptin (Tradjenta) is the most recent addition to the DPP-4 inhibitor class, receiving approval in May 2011. Linagliptin also is approved for monotherapy and for combination with metformin, sulfonylureas, and thiazolidinediones. Significant reductions of A1C have been recorded specifically when linagliptin is added to an established treatment regimen of metformin with or without a sulfonylurea. Adverse effects are similar to other DPP-4 inhibitors and include headache, sore throat, muscle pain, and respiratory infections. Linagliptin is dosed as 5 mg daily with or without food; it is the first DPP-4 inhibitor that does not require dosage alterations for kidney disease or CYP interactions. Additional DPP-4 inhibitors in development include alogliptin, in studies as monotherapy and as combination therapy with pioglitazone. No research supports DPP-4 inhibitor combination with insulin for T2DM, in part because proper B cell function and insulin release are required for DPP-4 inhibitors to have an effect. Because DPP-4 inhibitor experience is still primarily from clinical studies, the class effect on other systems, including the immune system, is uncertain. Long-term effects of DPP-4 inhibitor therapy on vascular complications and mortality are also unknown. With easy dosage regimens, tolerable adverse effects, and combination safety, though, DPP-4 inhibitors add substantial variety to existing treatment options for multimodal drug control of T2DM. Conclusion Research about the connections between gastrointestinal, endocrine, and fat storage systems in the body are providing a clearer picture of how diabetes damages the body. Expanding drug classes that focus on the incretin role in disease progression provide treatment mechanisms for recalcitrant disease. GLP-1 agonists and DPP-4 inhibitors present patients and clinicians with growing opportunities for disease control when traditional oral antidiabetes drugs are inadequate. However, long-term risks of these new classes are still unknown compared with established therapies. Diabetes care continues to revolve around patient self-care, regular monitoring, and early, aggressive drug intervention to slow the progressive disease deterioration. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 8

Case Response Although G.H. is not yet 45 years old, he has a high A1C and is overweight, so he should have a second test (fasting or tolerance testing) to confirm a diagnosis of type 2 diabetes mellitus. During a discussion with G.H. about the A1C results, you should obtain his current weight and blood pressure. Hypertension, if present, should be addressed quickly to minimize risks of long-term cardiovascular disease. You also should check his microvascular health by inquiring about vision changes or numbness in the extremities. G.H. should undergo education for diabetes self management, which involves the importance of personal actions to prevent complications. The profound benefits of simple dietary and physical activity changes, such as low-sodium diets and moderate walking, should be emphasize to G.H. as well. Aggressive actions to maintain A1C as close to normal as possible are recommended by the ADA, so G.H. should begin a course of metformin 500 mg twice daily in conjunction with his lifestyle changes. The metformin dosage can be titrated gradually as tolerated. A1C should be monitored quarterly. Additional drug therapy, typically a second oral agent, should be considered if the A1C remains greater than 7% after 3 months of metformin use; initiation of insulin at this point is warranted if the A1C is greater than 8.5%. Second-line oral options to consider include sulfonylureas, although weight gain is a risk that might not be worth the treatment benefit in G.H. Thiazolidinediones are unlikely second-line choices as well because of the existing shortness of breath and risk of heart failure in this patient. The GLP-1 agonist exenatide is a reasonable second-line choice to supplement metformin according to clinical experience, because the drug is weight neutral. DPP-4 inhibitors are possible choices as the disease progresses, especially as more long-term safety data become available. A1C monitoring can be reduced to twice a year when the percentage approaches the goal of 7%. Regular cardiovascular monitoring (e.g., blood pressure and cholesterol checks) and routine visits with allied health providers and specialists (e.g., optometrists and podiatrists) will also contribute to ongoing wellness for G.H. Van Hoey New Treatment for Type 2 Diabetes Mellitus Page 9

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