Core Defects of Type 2 Diabetes

Core Defects of Type 2 Diabetes
4/20/ :18 AM Core Defects of Type 2 Diabetes Targeting Mechanisms for a Comprehensive Approach Core Defects of Type 2 Diabetes: Targeting Mechanisms for a Comprehensive Approach This presentation will help you understand the regulation of glucose homeostasis, the key pathophysiologic defects in type 2 diabetes mellitus, the rationale for more aggressive approaches to the treatment of type 2 diabetes, and the clinical overview of JANUVIA™ (sitagliptin). We will also provide an overview of the full Prescribing Information for JANUMET™ (sitagliptin/metformin HCl). Note to user: The yellow boxes (boxed text in black-and-white printouts) on the slides are not speaker notes. They have been inserted to emphasize the main concepts of each slide. 1

4/20/ :18 AM Objectives Discuss challenges in treating type 2 diabetes and rationale for earlier and more aggressive treatment approaches Review the physiologic regulation of glucose homeostasis, the role of incretins, and core defects of type 2 diabetes Describe the complementary MOAs of agents used in the treatment of type 2 diabetes to address the 3 core defects Provide a clinical overview of JANUVIA™ (sitagliptin) Provide an overview of the prescribing information for JANUMET™ (sitagliptin/metformin HCl) Objectives Discuss challenges in treating type 2 diabetes and rationale for earlier and more aggressive treatment approaches Review the physiologic regulation of glucose homeostasis, the role of incretins, and core defects of type 2 diabetes Describe the complementary MOAs of agents used in the treatment of type 2 diabetes to address the 3 core defects Provide a clinical overview of JANUVIA™ (sitagliptin) Provide an overview of the prescribing information for JANUMET™ (sitagliptin/metformin HCl)

Genetic abnormalities Obesity and inactivity
Insulin Resistance: An Underlying Cause of Type 2 Diabetes Medications Aging INSULIN RESISTANCE Atherosclerosis Genetic abnormalities Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes Reaven GM. Physiol Rev. 1995;75: Clauser, et al. Horm Res. 1992;38:5-12. Reaven GM. Physiol Rev. 1995;75: Clauser, et al. Horm Res. 1992;38:5-12.

4/20/ :18 AM Development and Progression of Type 2 Diabetes (Conceptual Representation) NGT ® Insulin ® IGT/ IFG ® Type 2 Diabetes Resistance Postprandial glucose Glucose Regulation Fasting glucose –10 –5 5 10 15 20 25 30 Development and Progression of Type 2 Diabetes (Conceptual Representation) Speaker Notes This conceptual diagram shows a recently proposed paradigm on the development and progression of pathophysiology in type 2 diabetes. The horizontal axis in the figure shows the years from diagnosis of diabetes. Insulin resistance rises during disease development and continues to rise during impaired glucose tolerance (IGT). Over time, insulin resistance tends to stabilize in type 2 diabetes.1,2 The insulin secretion rate increases, to compensate for the decrease in insulin effectiveness due to insulin resistance. This increase is often misperceived as an increase in beta-cell function. Beta-cell function can be decreasing even as insulin secretion increases. Over time, beta-cell compensatory function deteriorates and insulin secretion decreases. Beta-cell function progressively fails. Initially, fasting glucose is maintained in near-normal ranges. The pancreatic beta cells compensate by increasing insulin levels, leading to hyperinsulinemia. This compensation keeps glucose levels normalized for a time, but as beta cells progressively fail, IGT develops with mild postprandial hyperglycemia. As the disease further progresses, the beta cells continue to fail, resulting in higher postprandial glucose levels. With further loss of insulin secretory capacity, fasting glucose and hepatic glucose production increase. Once beta cells cannot secrete sufficient insulin to maintain normal glycemia at the fasting or postprandial stage, type 2 diabetes (hyperglycemia) becomes evident. Insulin resistance and beta-cell dysfunction are established well before type 2 diabetes is diagnosed.1,3 Purpose: To address the common misconception that an increase in insulin secretion (hyperinsulinemia) connotes an improvement in beta-cell function. Takeaway: Both insulin resistance and beta-cell dysfunction start early—and well before diabetes is diagnosed—leading to rises in fasting and postprandial glucose levels. Insulin resistance—hepatic and peripheral Metabolic Activity Insulin level Beta-cell function –10 –5 5 10 15 20 25 30 Years From Diabetes Diagnosis NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006. References 1. Ferrannini E. Symposium: When does hyperglycemia become diabetes? Impaired β-cell function. Presentation at ADA th Scientific Sessions in Washington, DC. Available at: Accessed October 2006. 2. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 diabetes. Implications for clinical practice. Prim Care. 1999;26:771–789. 3. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.

UKPDS: -Cell Loss Over Time
4/20/ :18 AM UKPDS: -Cell Loss Over Time Slide 1-24 CORE 100 75 Patients treated with insulin, metformin, sulfonylureas‡ -Cell Function (%)* 50 IGT† Type 2 Diabetes Phase I 25 Postprandial Hyperglycemia Type 2 Diabetes Phase III Type 2 Diabetes Phase II Stages of Type 2 Diabetes Epidemiological studies suggest that the onset of diabetes occurs 10 to 12 years before a clinical diagnosis is made. (Harris 1997) In the UKPDS study of type 2 diabetics, at least 50% of the patients had evidence of diabetic tissue damage when diabetes was first diagnosed. (UKPDS Study 16, 1995) In the earliest phase, when beta-cell function is not impaired, the ability of the beta-cells to hypersecrete insulin masks the impaired glucose tolerance, often for years. During the IGT phase, the FPG will be higher than the normal 110 mg/dL but lower than the 126 mg/dL that is indicative of diabetes. As beta-cell function continues to decline, mild postprandial hyperglycemia develops, reflecting the inability of the beta-cell to hypersecrete enough insulin to overcome insulin resistance. At the end of this prediabetic phase, the first phase of type 2 diabetes typically produces symptoms that lead to a diagnosis. During phase I, in the first 2 years after diagnosis of diabetes, beta-cell function decreases to between 70% and 40% of normal function. -12 -10 -6 -2 2 6 10 14 Years From Diagnosis *Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS. †IGT=impaired glucose testing ‡The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model. Lebovitz HE. Diabetes Rev. 1999;7:

Time From Randomization (years)
Intensive Treatments and Increase in HbA1c Over Time United Kingdom Prospective Diabetes Study (UKPDS) Median HbA1c (%) Conventional Insulin Chlorpropamide Glibenclamide (glyburide) Metformin 3 6 7 8 9 10 Time From Randomization (years) Upper limit of normal range (6.2%) ADA goal ADA action UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:

Guideline Recommendations Are Becoming More Aggressive
4/20/ :18 AM Guideline Recommendations Are Becoming More Aggressive 2007 ADA standards1 “The A1C goal for patients in general is an A1C goal of <7%.” “The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” [boldface added] Guideline Recommendations Are Becoming More Aggressive Speaker Notes Before 2007, the American Diabetes Association (ADA) recommended an A1C goal of <7.0% for patients.1 In 2007, the ADA added a goal for the individual patient of an A1C as close to normal (<6.0%) as possible, specifying the need for this to occur without significant hypoglycemia. This goal for individual patients is further qualified by the following statement: “Less stringent treatment goals may be appropriate for patients with a history of severe hypoglycemia, patients with limited life expectancies, very young children or older adults, and individuals with comorbid conditions.”2 [Advance slide build] In line with the more aggressive goals, the ADA and the European Association for the Study of Diabetes have reached a consensus that advocates more aggressive calls to action and early changes or add-ons to therapy. Their consensus is that “an A1C of ≥7% should serve as a call to action to initiate or change therapy”3 and that “if lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when A1C goal is not achieved.”3 ADA/EASD consensus statement2 “If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when A1C goal is not achieved.” [boldface added] Purpose: To show that the guideline recommendations recently published by the ADA and ADA/EASD are more aggressive. Takeaway: According to recent guidelines, early use of combination therapy is recommended for patients with type 2 diabetes. ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes. 1. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S Nathan DM et al. Diabetes Care. 2006;29:1963–1972. References: 1. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26(suppl 1):S33–S50. 2. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care ;30(suppl 1):S4–S41. 3. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29:1963–1972.

Published Conceptual Approach
4/20/ :18 AM Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment Paradigm Published Conceptual Approach OAD + multiple daily insulin injections Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD + basal insulin Mean A1C of patients 10 A1C, % 9 Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment Paradigm Speaker Notes This slide is a depiction of the conservative, stepwise approach to treating diabetes. The first step is diet and exercise (lifestyle modification), followed by oral monotherapy, up-titration of monotherapy to maximal doses, combination therapy, oral therapy plus basal insulin, and oral therapy plus multiple daily insulin injections.1 This approach has been called “failure oriented,” with progression to the next step occurring after failure to maintain glycemic control becomes apparent.2 A problem with the stepwise approach is that delays often occur between steps even when A1C levels are unacceptably high.1,3 For example, data from the Kaiser Permanente Northwest database between 1994 and 2002 using an action threshold of A1C >8% showed that the mean time after reaching the A1C action point of >8% and moving to the next step in therapy for patients on metformin or sulfonylurea monotherapy was 14.5 and 20.5 months, respectively.3 The authors analyzing the Kaiser data suggest that if, before starting insulin, a hypothetical patient were to progress from nonpharmacologic treatment through sulfonylurea or metformin monotherapy to combination oral therapy, he or she would accumulate nearly 5 A1C-years of excess glycemic burden >8% and about 10 A1C-years of burden >7%.3 Purpose: To show a conceptual view of the stepwise approach to diabetes management. Takeaway: The stepwise approach to treatment, with changes in therapy only after treatment failure, may result in a prolonged glycemic burden. 8 7 6 Duration of Diabetes OAD=oral antihyperglycemic drug. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. References: 1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355. 2. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7:625–631. 3. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535–1540.

Published Conceptual Approach
4/20/ :18 AM Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy Published Conceptual Approach OAD + multiple daily insulin injections Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD + basal insulin 10 A1C, % 9 Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy Speaker Notes The orange line depicts a conceptual view of the conventional stepwise treatment that was discussed earlier. Hypothetically, patients treated with this approach would have a considerable glycemic burden (time spent above A1C goals).1,2 The green line depicts a conceptual view of an aggressive, A1C goal–oriented approach that would initiate changes in therapy earlier—that is, within several months of goals not being met. Hypothetically, patients treated with this approach might be able to achieve A1C results like those depicted in the straight green line. This approach also calls for an earlier use of combination therapy. Moreover, this approach is supported by the ADA/EASD consensus statement. The therapeutic sequence in this approach would be2: 1. Lifestyle change (diet and exercise) 2. Oral monotherapy 3. Oral combination therapy 4. Up-titration of oral therapy 5. Oral therapy plus basal insulin 6. Oral therapy plus multiple daily insulin injections This approach may increase the number of patients with type 2 diabetes who achieve and maintain glycemic goals, thus lowering the glycemic burden over time.2 Purpose: To show conceptually that early, aggressive intervention may reduce the glycemic burden of type 2 diabetes. Takeaway: A treat-to-goal therapeutic approach with aggressive treatment and a low threshold for action (A1C >7%) may reduce the glycemic burden of type 2 diabetes. 8 Mean A1C of patients 7 6 Duration of Diabetes Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. References: 1. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7:625–631. 2. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355.

Challenges in Achieving Glycemic Goals in Diabetes
4/20/ :18 AM Challenges in Achieving Glycemic Goals in Diabetes Less aggressive treat-to-target approach by some clinicians1 Suboptimal use of available therapies1 Inability of any single agent’s MOA to address all core defects of type 2 diabetes2 Potential for increased side effects with use of multiple agents3 Suboptimal adherence to lifestyle measures1 Underuse of medications as a result of Cost4 Complexity of therapy5 Challenges in Achieving Glycemic Goals in Diabetes Speaker Notes Numerous barriers prevent many patients from achieving A1C targets.1 Some of these factors are related to therapeutic decisions that physicians make, and others result from patient attitudes or behavior.2 Many physicians may not aggressively pursue a treat-to-target approach, which involves early initiation of combination therapy and persistent dose titration to achieve treatment goals. In 1 retrospective population-based study, patients continued on monotherapy for 15 to 21 months after their first A1C above 8%, the former ADA “take action” threshold.2 Available treatments may be used suboptimally. For example, oral combination therapy may not be initiated early enough, and insulin therapy may not be initiated because of its perceived complexity.2 The MOAs of the major classes of single oral antihyperglycemic agents do not address the spectrum of core defects of type 2 diabetes when used as monotherapy.3 Many treatment regimens for type 2 diabetes call for multiple medications that have the potential for additional side effects.4 Patient adherence to lifestyle measures is often suboptimal, and patients may be unable to follow their doctors’ recommendations regarding diet and exercise.1 Cost issues may prevent patients from consistently using prescribed medications.5 Similarly, more complex treatment regimens are associated with reduced patient adherence.6 Purpose: To describe some of the factors that prevent patients with type 2 diabetes from reaching glycemic goal. Takeaway: Various factors, including both physician- and patient-related ones, contribute to the inability of many patients to reach A1C goal. 1. Blonde L. Clin Cornerstone. 2005;7(suppl 3):S6–S17. 2. Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44–M50. 3. McDonald HP et al. JAMA. 2002;288:2868–2879. 4. Piette JD et al. Diabetes Care. 2004;27:384–391. 5. Donnan PT et al. Diabet Med. 2002;19:279–284. References: 1. Del Prato S, Felton A-M, Munro N, Nesto R, Zimmet P, Zinman B, on behalf of the Global Partnership for Effective Diabetes Management. Improving glucose management: ten steps to get more patients with type 2 diabetes to glycaemic goal. Int J Clin Pract. 2005;59:1345–1355. 2. Blonde L. Current challenges in diabetes management. Clin Cornerstone. 2005;7(suppl 3):S6–S17. 3. Van Gaal LF, De Leeuw IH. Rationale and options for combination therapy in the treatment of type 2 diabetes. Diabetologia. 2003;46(suppl 1):M44–M50. 4. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA. 2002;288:2868–2879. 5. Piette JD, Heisler M, Wagner TH. Problems paying out-of-pocket medication costs among older adults with diabetes. Diabetes Care. 2004;27:384–391. 6. Donnan PT, MacDonald TM, Morris AD, for the DARTS/MEMO Collaboration. Adherence to prescribed oral hypoglycaemic medication in a population of patients with type 2 diabetes: a retrospective cohort study. Diabet Med. 2002;19:279–284.

Major Pathophysiologic Defects in Type 2 Diabetes
4/20/ :18 AM Major Pathophysiologic Defects in Type 2 Diabetes Islet-cell dysfunction Glucagon (alpha cell) Pancreas Insulin resistance Glucose uptake in muscle and fat Insulin (beta cell) Hepatic glucose output Major Pathophysiologic Defects in Type 2 Diabetes Speaker Notes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis. In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1 Most patients with type 2 diabetes have insulin resistance. Pancreatic beta cells attempt to increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1 By the time diabetes is diagnosed, beta-cell function has already decreased substantially and continues to decline over time.1 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production.1 Likewise, with decreased secretion of insulin, less glucose is taken up by the muscle and adipose tissue.2 Purpose: To explain the 3 core pathophysiologic defects of type 2 diabetes. Takeaway: Insulin resistance, beta-cell dysfunction, and elevated hepatic glucose production each contribute to hyperglycemia in type 2 diabetes. Hyperglycemia Liver Muscle Liver Adipose tissue Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. References: 1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.

Major Targeted Sites of Oral Drug Classes
4/20/ :18 AM Major Targeted Sites of Oral Drug Classes Pancreas The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. Beta-cell dysfunction Sulfonylureas Muscle and fat Meglitinides Liver DPP-4 inhibitors GLP-1 ↓Glucose level Hepatic glucose overproduction Insulin resistance Major Targeted Sites of Various Oral Drug Classes Speaker Notes The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycemia.1,2 Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1 Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells. They are used to control postprandial hyperglycemia.1 TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2 Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1 Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1,3,4 Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product. The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and help regulate insulin production and secretion.5 This glucose-dependent mechanism targets 2 key defects: insulin release and hepatic glucose production. Purpose: To provide a broad overview of the key mechanisms and targeted sites of available antihyperglycemic classes and to introduce the concept that DPP-4 inhibitors have an effect on both the pancreas and the liver. Takeaway: Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve A1C control. The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. Biguanides Gut TZDs TZDs Biguanides Alpha-glucosidase inhibitors DPP-4 inhibitors Glucose absorption Biguanides DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. References: 1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004. 3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. 4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004. 5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.

Alpha-Glucosidase Inhibitors1,2
4/20/ :18 AM No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Alpha-Glucosidase Inhibitors1,2 Meglitinides3 SUs4,5 TZDs6,7 Metformin8 DPP-4 Inhibitors Insulin deficiency Insulin resistance Excess hepatic glucose output      Major Pathophysiologies No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Speaker Notes No single-agent monotherapy has an MOA that addresses all key pathophysiologies of type 2 diabetes. Alpha-glucosidase inhibitors decrease intestinal absorption of glucose.1,2 Meglitinides and sulfonylureas stimulate insulin secretion.3–5 TZDs are insulin sensitizers that also lower hepatic glucose output.6,7 Metformin, a biguanide, lowers hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity.8 DPP-4 inhibitors improve insulin synthesis and release and lower hepatic glucose production, both through suppressing glucagon production and release, and by improving insulin synthesis and release. Each class of oral antihyperglycemic agent does not address at least 1 key pathophysiology of type 2 diabetes. Purpose: To examine the key pathophysiologies targeted by each class of oral antihyperglycemic agent. Takeaway: No one class targets all key pathophysiologies of type 2 diabetes.    Intestinal glucose absorption   1. Glyset [package insert]. New York, NY: Pfizer Inc; Precose [package insert]. West Haven, Conn: Bayer; Prandin [package insert]. Princeton, NJ: Novo Nordisk; Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; Glucotrol [package insert]. New York, NY: Pfizer Inc; Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004. References: 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 4. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 5. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

The Role of Incretins in Type 2 Diabetes
4/20/ :18 AM The Role of Incretins in Type 2 Diabetes The Role of Incretins in Type 2 Diabetes

The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes
4/20/ :18 AM The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes Control Subjects (n=8) Subjects With Type 2 Diabetes (n=14) Normal Incretin Effect Diminished Incretin Effect 80 60 40 20 80 60 40 20 IR Insulin, mU/L IR Insulin, mU/L The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes Speaker Notes In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the gastrointestinal tract than when glucose was delivered via IV infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion.1,2 The incretin effect implies that nutrient ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the rise in glucose secondary to absorption of digested nutrients.1 Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect,3 stimulating insulin release when glucose levels are elevated.4,5 Although the incretin effect is detectable both in healthy subjects and in those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide.6 In this study, patients with type 2 diabetes and weight-matched, metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load. In those individuals without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect)—that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the gastrointestinal tract. In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished in magnitude. The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone.7,8 Purpose: To introduce the concept of the incretin effect in healthy individuals and the abnormality in patients with type 2 diabetes. Takeaway: Gastrointestinal ingestion of glucose stimulates a greater insulin response than that seen from IV glucose infusion. This effect is significantly decreased in patients with type 2 diabetes. The response is largely attributed to the effect of incretins. 60 120 180 60 120 180 Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. References: 1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85. 2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91. 3. Brubaker PL, Drucker DJ. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659. 4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544. 5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52. 7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes. 2001; 109(suppl 2):S288–S303. 8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

4/20/ :18 AM GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 Diabetes GLP-1 Infusion 250 Placebo GLP-1 Glucose 200 * mg/dL 150 100 *P <0.05 Patients with type 2 diabetes (N=10) 50 GLP-1 Infusion 40 When glucose levels approach normal values, insulin levels decrease. Insulin 30 mU/L * GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 Diabetes Speaker Notes This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic infusion of GLP-1. Ten patients with uncontrolled type 2 diabetes mellitus being treated with diet and oral hypoglycemic agents received an IV infusion of GLP-1 over 240 minutes. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, and glucagon levels. One day later, the procedure was repeated with a placebo infusion.1 Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels in all patients, with significant mean reductions observed at all time points from 60 minutes onward (P<0.05 vs placebo). Initially, during GLP-1 infusion with a starting plasma glucose level of 12.7 mmol/L (228.6 mg/dL), plasma insulin increased and glucagon decreased. However, as plasma glucose approached normal basal levels, insulin and glucagon returned to baseline or near-baseline levels, thus demonstrating the glucose-dependent nature of the effects of GLP-1.1 20 10 Purpose: To show the glucose-dependent effect of GLP-1 infusion on insulin and glucagon release in patients with type 2 diabetes. Takeaway: GLP-1 stimulates insulin secretion and suppresses glucagon release only when glucose levels are elevated (glucose dependent), and the combination of these effects results in lower glucose levels in patients with type 2 diabetes when glucose levels are elevated but not when glucose levels are normal. GLP-1 Infusion 20 Glucagon pmol/L 15 When glucose levels approach normal values, glucagon levels rebound. * 10 5 –30 60 120 180 240 Time, min Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. Reference: 1. Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

Incretins Play an Important Role in Glucose Homeostasis
4/20/ :18 AM Incretins Play an Important Role in Glucose Homeostasis Food ingestion  Insulin from beta cells (GLP-1 and GIP) Glucose Dependent ↑Glucose uptake by peripheral tissue2,4 Release of gut hormones— Incretins1,2 Pancreas2,3 GI tract Beta cells Alpha cells ↓ Blood glucose Active GLP-1 & GIP Incretins Play an Important Role in Glucose Homeostasis Speaker Notes GLP-1 and GIP are the currently identified incretin hormones. An incretin is a hormone with the following characteristics1: It is released from the intestine in response to ingestion of food, particularly glucose. The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin. The release of insulin in response to physiologic levels of the hormone occurs only when glucose levels are elevated (glucose dependent). After food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).2–4 Under normal circumstances, DPP-4 (dipeptidyl peptidase-4) rapidly degrades these incretins to their inactive forms after their release into the circulation.2,3 Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.3,4 The subsequent increase in glucose uptake in muscles4,5 and reduced glucose output from the liver3 help maintain glucose homeostasis. Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.3,4 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.3,6 Purpose: To demonstrate how the incretin pathway is part of the normal physiology of glucose homeostasis. Takeaway: After food ingestion, incretins stimulate insulin release from beta cells and suppress glucagon release from alpha cells in a glucose-dependent manner, resulting in downstream effects that regulate glucose homeostasis. ↓Glucose production by liver Glucose Dependent  Glucagon from alpha cells (GLP-1) DPP-4 enzyme Inactive GLP-1 Inactive GIP 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. References: 1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85. 2. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913. 3. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 4. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. 5. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 6. Nauck MA, Kleine N, Ørskov C, Holst JJ, Wilms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

Tips for Diabetes treatment
Reduced HBA1C as low as possible at least below 6.5% without hypoglycemia Use DM meds that shows benefit beyound glycemic control(Heart , vascular inflamation, microalbuminuria) Medications that showed sustained effect and preservation of B-cell function Use meds that have the least side effect.

Pills available for DM 2 Januvia Galvus TZD(Actos, Avandia)
No hypoglycemia: TZD(Actos, Avandia) Metformin/glucophage) Alpha glucosidase inhibitor(Precose, Glyset) Combo(avandamet, actoplusmet, janumet DPP IV inhibitor: Januvia Galvus Can Cause Hypoglycemia: SU(glyburide,Amaryl) Prandin/Starlix Combo(glucovance, avandaryl, duetact)

Non insulin injection for DM2
GLP-1 analog(byetta) Amylin(Symlin)

+insulin sensitizer Metformin __ ____ ______
Less cardiac event by UKPDS Weight reduction Dm prevention data __ ____ ______ contraindicated in renal failure GI side effect had to be stopped 48 hors before and after contrast

Plus: TZD( actos , Avandia) Insulin Sensitizer
Heart and vascular benefit (Proactive ,Chicago) Preservation of B- cell( dream , Adopt) DM prevention data (-): contraindicated in heart failure Stage 3- 4, or liver failure Edema, weight gain ? Bone density

4/20/ :18 AM ADOPT: A Diabetes Outcome Progression Trial Avandia Sustained A1C Over Time* Treatment Difference at 4 Years RSG vs MET –0.13 (–0.22 to –0.05), P=.002 RSG vs SU –0.42 (–0.50 to –0.33), P<.001 1 2 3 4 5 Time (years) HbA1C% 6.0 8.0 7.0 6.5 7.5 RSG SU MET Number of patients: 4012 3308 2991 2583 2197 822 * Mean A1C values per visit are based on a repeated measures mixed model. Kahn SE et al. N Engl J Med. 2006;355:

Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Primary Outcome: Rosiglitazone HR = 0.40 ( ); P<0.0001 Placebo Cumulative Hazard Rosiglitazone Years No. at Risk Rosiglitazone Placebo 60% risk reduction of development of diabetes or death was seen with rosiglitazone This reduction was additive to standard counseling on healthy eating and exercise The DREAM Trial Investigators. Lancet. 2006;368:

4/20/ :18 AM JANUVIA™ (sitagliptin) Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent Food ingestion  Insulin (GLP-1 and GIP) Glucose dependent Release of active incretins GLP-1 and GIP Glucose uptake by peripheral tissue Pancreas GI tract Beta cells Alpha cells Blood glucose X X JANUVIA™ (sitagliptin) Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent Speaker Notes This illustration demonstrates the MOA of JANUVIA. The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic adenosine monophosphate (cAMP). With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 suppresses excess glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones. DPP-4 enzyme Glucose production by liver Glucose dependent  Glucagon (GLP-1) Purpose: To explain the MOA of JANUVIA. Takeaway: Sitagliptin prolongs the action of the 2 incretin hormones. This leads to glucose-dependent effects on alpha and beta cells, which then leads to enhanced glycemic control through lowering of hepatic glucose production and increasing the uptake of glucose by peripheral tissues. JANUVIA (DPP-4 inhibitor) Inactive GLP-1 Inactive GIP Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal. JANUVIA blocks DPP-4 to enhance the level of active incretins for 24 hours.

JANUVIA™ (sitagliptin): Indications and Usage
4/20/ :18 AM JANUVIA™ (sitagliptin): Indications and Usage Monotherapy JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Combination therapy JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPAR agonist (eg, thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control. Important limitations of use JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JANUVIA™ (sitagliptin): Indications and Usage Speaker Notes JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPAR agonist (eg, thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Purpose: To explain the indications, usage, and limitations of use for JANUVIA. Takeaway: JANUVIA can be used as monotherapy as an adjunct to diet and exercise to improve glycemic control and it can be used in combination with metformin or with a TZD when a single agent alone does not provide adequate glycemic control. PPARγ=peroxisome proliferator-activated receptor gamma.

JANUVIA™ (sitagliptin): Significant A1C Reductions as Monotherapy
4/20/ :18 AM JANUVIA™ (sitagliptin): Significant A1C Reductions as Monotherapy Placebo-adjusted results A1C Inclusion Criteria: 7%–10% Mean Baseline: 8.0% P<0.001* Prespecified Pooled Analysis at 18 Weeks|| Baseline A1C, % Overall < ≥8–< ≥9 0.0 0.0 –0.2 –0.2 –0.4 n=411§ –0.4 –0.6 n=769§ n=239§ JANUVIA™ (sitagliptin): Significant A1C Reductions as Monotherapy Speaker Notes Monotherapy with JANUVIA significantly reduced A1C compared with placebo.1,2 In the 18-week study, the average baseline A1C in the group treated with JANUVIA 100 mg was 8%. At Week 18, patients receiving JANUVIA 100 mg achieved significant (P<0.001) placebo-subtracted A1C reductions (–0.6%) compared with those receiving placebo.1 In the 24-week study, the average baseline A1C in the group treated with JANUVIA 100 mg was 8%. At Week 24, patients receiving JANUVIA 100 mg achieved significant (P<0.001) placebo-subtracted A1C reductions (–0.8%) compared with those receiving placebo.2 For both studies, the A1C-lowering effects of JANUVIA 100 mg were consistent across demographic, anthropometric, and disease characteristics subgroups.1,2 As is typical of agents used to treat type 2 diabetes, the mean response to JANUVIA appears to be related to the degree of A1C elevation at baseline. In a pooled analysis of these monotherapy studies at Week 18, the overall patient population demonstrated a 0.7% drop in mean placebo-subtracted A1C. In a prespecified subgroup analysis, the study showed that when patients were grouped by baseline A1C into those with mildly elevated A1C levels (<8%, n=411), moderately elevated A1C levels (≥8% to <9%, n=239), and the highest elevated A1C levels (≥9%, n=119), mean placebo-subtracted reductions in A1C after 18 weeks were –0.6%, –0.7%, and –1.4%, respectively (P<0.001 overall and for treatment by subgroup interactions). The magnitude of A1C lowering by strata varied by study. –0.6 Mean Change in A1C, % ‡ n=193 –0.8 Purpose: To demonstrate the A1C reductions associated with the 2 trials of JANUVIA monotherapy and in a prespecified subgroup analysis. Takeaway: Monotherapy with JANUVIA significantly reduced A1C compared with placebo, and the mean response appeared to be related to the degree of A1C elevation at baseline. –0.7 –0.7 –0.6 Mean Change in A1C, % –0.6† –1.0 n=229 –0.8 –1.2 –0.8† n=119§ –1.4 –1.0 24-week monotherapy study2 (95% CI: –1.0, –0.6) 18-week monotherapy study1 (95% CI: –0.8, –0.4) –1.4 –1.6 –1.8 CI=confidence interval. *Compared with placebo. †Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡Difference from placebo. §Combined number of patients on JANUVIA or placebo. ||P<0.001 overall and for treatment-by-subgroup interactions. 1. Raz I et al. Diabetologia. 2006;49:2564–2571. 2. Aschner P et al. Diabetes Care. 2006;29:2632–2637. References: 1. Raz I, Hanefeld M, Xu L, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564–2571. 2. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637.

4/20/ :18 AM JANUVIA™ (sitagliptin) Monotherapy Significantly Lowers FPG and PPG Levels 24-week placebo-adjusted results FPG 2-Hour PPG Mean Baseline: 170 mg/dL Mean Baseline: 257 mg/dL P<0.001* P<0.001* –60 –40 –30 –20 –10 –50 –60 –40 –30 –20 –10 –50 n = 234 n = 201 –17† JANUVIA™ (sitagliptin) Monotherapy Significantly Lowers FPG and PPG Levels Speaker Notes In the 24-week study, 741 patients with type 2 diabetes were randomized to evaluate the efficacy and safety of JANUVIA.1 This slide shows FPG (shown on the left) and 2-hour PPG (shown on the right) results from these secondary end points in the 24-week study.1 Treatment with JANUVIA 100 mg daily provided a significant improvement in FPG compared with placebo. The adjusted mean difference from placebo was –17 mg/dL at 24 weeks (P<0.001).1 The graph on the right shows the 2-hour PPG results. In addition to effects on FPG, treatment with JANUVIA 100 mg daily provided a significant improvement in PPG compared with placebo. The adjusted mean difference from placebo was –47 mg/dL at 24 weeks (P<0.001).1 The results of this study indicate that JANUVIA has favorable effects on both FPG and PPG.1 Mean Change in FPG, mg/dL‡ Mean Change in 2-Hour PPG, mg/dL‡ Purpose: To demonstrate the FPG and 2-hour PPG reductions in the 24-week monotherapy study of JANUVIA. Takeaway: JANUVIA provided significant improvements in FPG and 2-hour PPG compared with placebo. (95% CI: –24, –10) –47† (95% CI: –59, –34) *Compared with placebo. †Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡Difference from placebo. CI=confidence interval; FPG=fasting plasma glucose; PPG=postprandial plasma glucose (meal challenge test). Aschner P et al. Diabetes Care. 2006;29:2632–2637. Reference: 1. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637.

4/20/ :18 AM JANUVIA™ (sitagliptin): Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone 24-week change from baseline Add-on to metformin study1 Add-on to pioglitazone study2 Mean Baseline A1C: 8.0% Mean Baseline A1C: 8.0%, 8.1% Metformin + Placebo Metformin + JANUVIA Pioglitazone + Placebo Pioglitazone + JANUVIA n=224 n=453 n=174 n=163 –0.2 –0.0% –0.2 –0.2% JANUVIA™ (sitagliptin): Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone Speaker Notes In patients with type 2 diabetes inadequately controlled with metformin or pioglitazone, adding JANUVIA significantly reduced A1C compared with placebo.1,2 In the add-on to metformin study, the average baseline A1C for all patients was 8.0%. At Week 24, patients receiving metformin plus JANUVIA achieved significant (P<0.001) mean placebo-subtracted A1C reductions (–0.7%) compared with those receiving metformin plus placebo.1 In the add-on to pioglitazone study, the average baseline A1C was 8.1% for patients randomized to JANUVIA and 8.0% for patients randomized to placebo. At Week 24, patients receiving pioglitazone plus JANUVIA achieved significant (P<0.001) mean placebo-subtracted A1C reductions (–0.7%) compared with those receiving pioglitazone plus placebo.2 These data represent mean changes. Treatment with JANUVIA may result in higher or lower changes in A1C in some patients. –0.4 –0.4 Purpose: To demonstrate the A1C reductions at 24 weeks in the add-on to metformin and add-on to pioglitazone studies. Takeaway: JANUVIA provided significant improvements in A1C when added to treatment for patients inadequately controlled on metformin or pioglitazone. Mean Change in A1C From Baseline, % Mean Change in A1C From Baseline, % P<0.001* –0.6 –0.6 –0.7% –0.8 P<0.001* –0.8 0.7% placebo- subtracted result –0.9% –1.0 –1.0 0.7% placebo- subtracted result *Compared with placebo. 1. Charbonnel B et al. Diabetes Care. 2006;29:2638–2643. 2. Rosenstock J et al. Clin Ther. 2006;28:1556–1568. References: 1. Charbonnel B, Karasick A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–2643. 2. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–1568.

JANUVIA™ (sitagliptin): Effect on Body Weight
4/20/ :18 AM JANUVIA™ (sitagliptin): Effect on Body Weight Monotherapy studies No increase in body weight from baseline with JANUVIA compared with a small reduction in the placebo group Add-on to metformin A similar decrease in body weight for both treatment groups Add-on to pioglitazone No significant difference in body weight change between treatment groups JANUVIA™ (sitagliptin): Effect on Body Weight Speaker Notes Body weight did not increase from baseline with JANUVIA in either the 18-week or the 24-week monotherapy study compared with a small reduction in the body weight of patients given placebo. A slight but similar decrease in body weight of patients was observed in both treatment groups of the add-on study with metformin. There was no significant difference between JANUVIA and placebo in body weight change in the add-on study with pioglitazone. Overall, JANUVIA appeared to have a neutral effect on body weight. Purpose: To review the effect of JANUVIA on body weight. Takeaway: JANUVIA has a neutral effect on body weight.

JANUVIA™ (sitagliptin): Adverse Reactions
4/20/ :18 AM JANUVIA™ (sitagliptin): Adverse Reactions Overall: Adverse reactions and discontinuation rates were similar to placebo (both as monotherapy and as combination therapy) Incidence of hypoglycemia with JANUVIA was similar to placebo (1.2% vs 0.9%) The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy or in combination with pioglitazone and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache. Incidence of selected GI adverse reactions in patients treated with JANUVIA vs placebo was as follows: Abdominal pain (2.3%, 2.1%) Nausea (1.4%, 0.6%) Diarrhea (3.0%, 2.3%) JANUVIA™ (sitagliptin): Adverse Reactions Speaker Notes JANUVIA, in controlled clinical studies as both monotherapy and combination therapy, had overall incidence of side effects similar to that reported with placebo. Discontinuation of therapy because of clinical adverse reactions was also similar to that of placebo. The overall incidence of hypoglycemia in patients treated with JANUVIA was similar to that of placebo (1.2% vs 0.9%, respectively). The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy or in combination with pioglitazone and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%). Purpose: To provide an overview of the adverse reaction profile for JANUVIA. Takeaway: JANUVIA had an overall incidence of side effects and discontinuation rate similar to those reported with placebo.

4/20/ :18 AM JANUVIA™ (sitagliptin): Once-Daily Dosing—Proven 24-Hour Glycemic Control Usual Dosing for JANUVIA* The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR agonist. Patients With Renal Insufficiency*,† A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. JANUVIA™ (sitagliptin): Once-Daily Dosing—Proven 24-Hour Glycemic Control Speaker Notes This slide shows the recommended dosage and administration of JANUVIA in patients with type 2 diabetes. The recommended dosage of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR agonist, such as a thiazolidinedione. JANUVIA can be taken with or without food. For patients with mild renal insufficiency (CrCl 50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage adjustment of JANUVIA is required. For patients with moderate renal insufficiency (CrCl 30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the dosage of JANUVIA is 50 mg once daily. For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with ESRD requiring hemodialysis or peritoneal dialysis, the dosage of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis. Because there is a need for dosage adjustment based on renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. 50 mg once daily 25 mg once daily Moderate CrCl 30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.7–≤3.0; Women: >1.5–≤2.5) Severe and ESRD‡ CrCl <30 mL/min Men: >3.0; Women: >2.5) Purpose: To show the recommended dosage and administration of JANUVIA. Takeaway: The recommended dosage of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR agonist. For patients with moderate or severe renal insufficiency, the dose is 50 mg once daily or 25 mg once daily, respectively. Assessment of renal function is recommended prior to JANUVIA initiation and periodically thereafter. *JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily. ‡ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis.

JANUVIA™ (sitagliptin): Contraindications/Warnings and Precautions
4/20/ :18 AM JANUVIA™ (sitagliptin): Contraindications/Warnings and Precautions Contraindications None Warnings and Precautions Use in patients with renal insufficiency: A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Use with medications known to cause hypoglycemia: As monotherapy and as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia were similar to rates in patients taking placebo. The use of JANUVIA in combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not been adequately studied. JANUVIA™ (sitagliptin): Contraindications/Warnings and Precautions Speaker Notes There are no contraindications for JANUVIA. Use in patients with renal insufficiency: A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Use with medications known to cause hypoglycemia: As monotherapy and as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia were similar to rates in patients taking placebo. The use of JANUVIA in combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not been adequately studied. Purpose: To review the contraindications and warnings and precautions for JANUVIA. Takeaway: There are no contraindications for JANUVIA. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Use of JANUVIA in combination with medications known to cause hypoglycemia has not been adequately studied.

Summary of JANUVIA™ (sitagliptin)
4/20/ :18 AM Summary of JANUVIA™ (sitagliptin) JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme Indication: Indicated as monotherapy and in combination with metformin or TZDs Usual recommended dose is 100 mg once daily In clinical studies: JANUVIA significantly improved A1C, FPG, and PPG Mean A1C response with JANUVIA appears to be related to baseline A1C level Overall: Incidence of adverse reactions was similar to that with placebo Overall incidence of hypoglycemia similar to that with placebo A neutral effect on weight relative to that with placebo Before prescribing JANUVIA, please read the full Prescribing Information, available at this presentation. Summary of JANUVIA™ (sitagliptin) Speaker Notes JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme. JANUVIA is indicated as monotherapy and in combination with metformin or TZDs. The usual recommended dose is 100 mg once daily. In clinical studies, JANUVIA significantly improved A1C, FPG, and PPG compared with placebo. The mean A1C response with JANUVIA appears to be related to the baseline A1C level. Overall, the incidence of adverse reactions with JANUVIA, including hypoglycemia, was similar to that with placebo, and a neutral effect on weight was seen relative to that with placebo. Purpose: To summarize the indications and findings for JANUVIA. Takeaway: JANUVIA significantly improves the glycemic parameters of A1C, FPG, and PPG. JANUVIA is associated with an incidence of adverse reactions, including hypoglycemia, similar to that with placebo. JANUVIA has a neutral effect on body weight relative to that with placebo.

Complementary Mechanisms of Action
4/20/ :18 AM Complementary Mechanisms of Action Combining Sitagliptin and Metformin Complementary Mechanisms of Action: Combining Sitagliptin and Metformin

↓Glucose production reduced by1–4:
4/20/ :18 AM Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis ↓Glucose production reduced by1–4: Liver Metformin Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity Speaker Notes The glucose-lowering effects of metformin are primarily a consequence of reduced hepatic glucose output. Metformin also increases insulin sensitivity, which leads to increased insulin-stimulated glucose uptake in skeletal muscle and adipocytes.1 Reduced hepatic glucose production: Primarily a result of decreased gluconeogenesis1,2 Secondarily through the acute inhibition of glycogenolysis1,3 Increased insulin sensitivity Increased glucose disposal (mainly in muscle) has been demonstrated using hyperinsulinemic, euglycemic, and hyperglycemic clamp procedures in patients with type 2 diabetes.4 Blood glucose Purpose: To describe the MOA of metformin. Takeaway: Metformin lowers plasma glucose primarily by reducing hepatic glucose output. It also increases insulin sensitivity, which leads to increased glucose uptake in muscle and adipose tissue. Muscle Adipose tissue Liver ↑Glucose uptake in muscle and fat by increasing insulin sensitivity5 1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25– Setter SM et al. Clin Ther. 2003;25:2991– Hundal RS et al. Diabetes. 2000;49:2063– Chu CA et al. Metabolism. 2000;49:1619– Bailey CJ et al. N Engl J Med. 1996;334:574–579. References: 1. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137:25–33. 2. Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49:2063–2069. 3. Chu CA, Wiernsperger N, Muscato N, et al. The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis. Metabolism. 2000;49:1619–1626. 4. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579.

Sitagliptin Reduces Hyperglycemia
The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner Metformin Reduces Hyperglycemia 4/20/ :18 AM Sitagliptin improves beta-cell function and increases insulin synthesis and release. Metformin has insulin- sensitizing properties. Beta-Cell Dysfunction Insulin Resistance The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner Speaker Notes The combination of sitagliptin and metformin improves glycemic control via complementary MOAs. [Build 1] Mechanism of action of sitagliptin: Sitagliptin improves beta-cell function1 and increases insulin synthesis and release. Sitagliptin indirectly reduces hepatic glucose overproduction through suppression of glucagon from alpha cells. [Build 2] Mechanism of action of metformin: Metformin increases insulin sensitivity by decreasing release of free fatty acids from fat to muscle and liver2 and by increasing insulin receptor activity in muscle.3 By increasing insulin sensitivity, metformin increases glucose uptake and utilization in muscle and fat.3,4 Metformin decreases hepatic glucose overproduction by directly targeting the liver to decrease gluconeogenesis and glycogenolysis.3 [Build 3] In combination, these agents help to improve glycemic control as a result of their complementary MOAs. Sitagliptin addresses beta-cell dysfunction, metformin addresses insulin resistance, and both sitagliptin and metformin address glucose overproduction but in different, complementary ways.1,3 Purpose: To describe how metformin and sitagliptin act differently but in a complementary manner. Takeaway: JANUMETTM (sitagliptin/metformin HCl) addresses the 3 core defects of type 2 diabetes with additive efficacy for glycemic parameters and GLP-1. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis. Sitagliptin reduces HGO through suppression of glucagon from alpha cells. Hepatic Glucose Overproduction (HGO) *Please see corresponding speaker note for references. References: 1. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637. 2. Abbasi F, Carantoni M, Chen YD, Reaven GM. Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care. 1998;21:1301–1305. 3. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med. 2002;137:25–33. 4. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174.

JANUMET™ (sitagliptin/metformin HCl): Indications and Usage
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Indications and Usage Indication JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Important limitations of use JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUMET™ (sitagliptin/metformin HCl): Indications and Usage Speaker Notes JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Purpose: To review the indication and limitations of use for JANUMET. Takeaway: JANUMET is indicated for second-line therapy in patients with type 2 diabetes who are not adequately controlled on metformin or sitagliptin alone.

JANUMET™ (sitagliptin/metformin HCl): Boxed Warning: Lactic Acidosis
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Boxed Warning: Lactic Acidosis The labeling for JANUMET contains a boxed warning for lactic acidosis, a rare,* but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET. The risk of lactic acidosis increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately. See the full Prescribing Information for the complete Boxed Warning. JANUMET™ (sitagliptin/metformin HCl): Boxed Warning: Lactic Acidosis Speaker Notes The labeling for JANUMET contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET. The risk of lactic acidosis increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately fatal cases/1,000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50% of cases. See the full Prescribing Information for the complete Boxed Warning. Purpose: To inform physicians of an important warning concerning the use of JANUMET. Takeaway: Lactic acidosis can occur rarely during treatment with metformin. It is a serious condition, and physicians should be alert to it. *The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately fatal cases/1,000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50% of cases.

JANUMET™ (sitagliptin/metformin HCl): Pharmacokinetics
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Pharmacokinetics Bioequivalence: A clinical bioequivalence study has demonstrated that JANUMET is bioequivalent to corresponding doses of sitagliptin plus metformin as individual tablets Bioavailability: Sitagliptin ~87% Metformin ~50–60% Metabolism: both sitagliptin and metformin are predominantly excreted unchanged in the urine Pharmacokinetics: no meaningful changes in either sitagliptin or metformin with co-administration JANUMET™ (sitagliptin/metformin HCl): Pharmacokinetics Speaker Notes The results of a bioequivalence study in healthy subjects demonstrated that the JANUMET 50 mg/500 mg and 50 mg/1,000 mg combination tablets are bioequivalent to coadministration of corresponding doses of sitagliptin (JANUVIATM) and metformin hydrochloride as individual tablets. The absolute bioavailability of sitagliptin is approximately 87%. The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. Approximately 79% of sitagliptin is excreted unchanged in the urine, and metformin is excreted unchanged in the urine. No meaningful pharmacokinetic changes occur when sitagliptin and metformin are coadministered as separate tablets. Purpose: To help physicians understand the pharmacokinetics of JANUMET. Takeaway: The pharmacokinetics information further supports physician understanding of the pharmacokinetic profile of JANUMET.

24-week placebo-adjusted results†
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl) Label Data: Sitagliptin Plus Metformin Provided Significant Improvements in Glycemic Control Beyond Metformin Alone* 24-week placebo-adjusted results† n=453 n=454 n=387 JANUMET™ (sitagliptin/metformin HCl) Label Data: Sitagliptin Plus Metformin Provided Significant Improvements in Glycemic Control Beyond Metformin Alone Speaker Notes This slide shows the results of glycemic parameters at 24 weeks for sitagliptin when added to treatment for patients inadequately controlled on metformin monotherapy. In combination with metformin (when added to treatment for patients inadequately controlled on metformin monotherapy), sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared with placebo plus metformin. A1C: 0.7%, P<0.001. FPG: –25 mg/dL, P<0.001 PPG: –51 mg/dL, P<0.001 The percentage of patients achieving A1C goal (<7%) with sitagliptin plus metformin compared with placebo plus metformin was greater than twofold (47% vs 18%, respectively). –25‡ Purpose: To demonstrate the mean A1C, FPG, and 2-hour PPG reductions at 24 weeks in the add-on to metformin study. Takeaway: Sitagliptin provided significant improvements in mean A1C, FPG, and 2-hour PPG vs placebo when added to treatment for patients inadequately controlled on metformin monotherapy. –0.7%‡ –51‡ (95% CI: –0.8, –0.5) (95% CI: –31, –20) (95% CI: –61, –41) *Compared with placebo plus metformin. †In patients inadequately controlled on metformin monotherapy. ‡Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. §Difference from placebo.

Percentage of patients Sitagliptin + metformin
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl) Label Data: Percentage of Patients Achieving A1C <7.0% With the Combination of Sitagliptin and Metformin 24-Week Study P<0.001 47% n=453 JANUMET™ (sitagliptin/metformin HCl) Label Data: Percentage of Patients Achieving A1C <7.0% With the Combination of Sitagliptin and Metformin Speaker Notes In patients who were inadequately controlled on metformin therapy, the effect of adding sitagliptin on the percentage of patients achieving A1C <7.0% was measured. At the start of the 24-week study of combination therapy with sitagliptin plus metformin, the average baseline A1C for all patients was 8.0%. At Week 24, a significantly (P<0.001) higher proportion of patients receiving metformin plus sitagliptin achieved A1C <7% compared with those receiving metformin plus placebo (47% vs 18%, respectively). Purpose: To demonstrate the percentage of patients treated with JANUMET who attained A1C <7.0%. Takeaway: Of the patients treated with JANUMET, 47% achieved A1C <7.0% vs 18% of patients treated with placebo plus metformin. Percentage of patients 18% n=224 Placebo + metformin Sitagliptin + metformin A total of 41 (of 224) patients on placebo plus metformin and 213 (of 453) patients on sitagliptin plus metformin achieved A1C <7.0%. Intent-to-treat population using last observation on study before pioglitzone rescue therapy.

24-Week Add-On Therapy to Metformin Study
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl) Label Data: Weight Change and Hypoglycemia Incidence in Patients Treated With the Combination of Sitagliptin and Metformin 24-Week Add-On Therapy to Metformin Study Weight Change Hypoglycemia JANUMET™ (sitagliptin/metformin HCl) Label Data: Weight Change and Hypoglycemia Incidence in Patients Treated With the Combination of Sitagliptin and Metformin Speaker Notes A similar decrease in body weight was observed for both the sitagliptin plus metformin and the placebo plus metformin groups: –1.3 lb in the placebo plus metformin group and –1.5 lb in the sitagliptin plus metformin group. The incidence of hypoglycemia was similar in both treatment groups: 1.3% in the sitagliptin plus metformin group and 2.1% in the placebo plus metformin group. Hypoglycemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Purpose: To demonstrate the data for weight change and hypoglycemia for JANUMET vs metformin alone. Takeaway: Weight change and hypoglycemia incidence for JANUMET were similar to metformin alone.

4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl) Label Data: Overall Incidence of Selected Adverse Reactions in Patients Treated With the Combination of Sitagliptin and Metformin Overall: The incidence of side effects and discontinuation rates with sitagliptin and metformin were similar to those with placebo and metformin. The incidence of hypoglycemia in patients treated with sitagliptin and metformin was similar to that in patients treated with placebo and metformin (1.3% vs 2.1%). The incidence of gastrointestinal disturbances in patients treated with sitagliptin and metformin was similar to that in patients treated with placebo and metformin (11.6% vs 9.7%). The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis. The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. JANUMET™ (sitagliptin/metformin HCl) Label Data: Overall Incidence of Selected Adverse Reactions in Patients Treated With the Combination of Sitagliptin and Metformin Speaker Notes The overall incidence of side effects reported in patients receiving sitagliptin and metformin was similar to that reported in patients receiving placebo and metformin. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group. The incidence of hypoglycemia in patients treated with sitagliptin and metformin (1.3%) was similar to that in patients treated with placebo and metformin (2.1%). The incidence of gastrointestinal disturbances in patients treated with sitagliptin and metformin was similar to that in patients treated with placebo and metformin (11.6% vs 9.7%). The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis. The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. Purpose: To provide an overview of the adverse reaction profile of JANUMET. Takeaway: It is important for physicians to be aware of the adverse reactions observed in clinical trials.

Sitagliptin and Metformin, % Placebo and Metformin, %
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl) Label Data: Incidence of Selected Gastrointestinal Adverse Reactions in Patients Treated With Sitagliptin and Metformin Incidence in Patients With Sitagliptin or Placebo Added to a Twice-Daily Metformin Regimen Other AEs Sitagliptin and Metformin, % Placebo and Metformin, % Nausea 1.3 0.8 Vomiting 1.1 Abdominal Pain 2.2 3.8 Diarrhea 2.4 2.5 JANUMET™ (sitagliptin/metformin HCl) Label Data: Incidence of Selected Gastrointestinal Adverse Reactions in Patients Treated With Sitagliptin and Metformin Speaker Notes The incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin and metformin was also similar to placebo and metformin: nausea (sitagliptin and metformin, 1.3%; placebo and metformin, 0.8%), vomiting (1.1%, 0.8%), abdominal pain (2.2%, 3.8%), and diarrhea (2.4%, 2.5%). This incidence reflects the occurrence of gastrointestinal adverse reactions in patients in whom sitagliptin 100 mg or placebo administered once daily was added to a twice-daily metformin regimen. Purpose: To discuss the incidence of selected gastrointestinal adverse reactions in patients treated with JANUMET. Takeaway: The incidence of gastrointestinal adverse reactions in patients receiving JANUMET was similar to that reported in patients receiving placebo plus metformin.

JANUMET™ (sitagliptin/metformin HCl): Contraindications
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Contraindications JANUMET is contraindicated in patients with: Renal disease or renal dysfunction, eg, as suggested by serum creatinine levels ≥1.5 mg/dL (males), ≥1.4 mg/dL (females) or abnormal creatinine clearance Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. JANUMET™ (sitagliptin/metformin HCl): Contraindications Speaker Notes JANUMET is contraindicated in patients with: Renal disease or renal dysfunction, eg, as suggested by serum creatinine levels ≥1.5 mg/dL (males), ≥1.4 mg/dL (females) or abnormal creatinine clearance Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. Purpose: To review the contraindications for JANUMET. Takeaway: JANUMET should not be used in patients with renal disease or dysfunction, with known hypersensitivity to metformin, or with acute or chronic metabolic acidosis. JANUMET should be temporarily discontinued as described.

4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution. JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions Speaker Notes Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In patients with advanced age, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly [see Warnings and Precautions (5.1)]. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present. Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution. Purpose: To review selected warnings and precautions for JANUMET. Takeaway: Use JANUMET with caution in patients with renal impairment.

4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET therapy, the drug should be promptly discontinued. Use of JANUMET should be temporarily suspended for periods of stress, trauma, infection, or any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Patients should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET. JANUMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Hematologic parameters should be measured annually. JANUMET™ (sitagliptin/metformin HCl): Selected Warnings and Precautions Speaker Notes Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET therapy, the drug should be promptly discontinued. Use of JANUMET should be temporarily suspended for periods of stress, trauma, infection, or any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET. Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Hematologic parameters should be measured annually. Purpose: To review selected warnings and precautions for JANUMET. Takeaway: Physicians should be aware of the warnings and precautions related to conditions that increase the incidence of lactic acidosis–associated conditions, such as surgery, alcohol, and impaired hepatic function.

JANUMET™ (sitagliptin/metformin HCl): Drug Interactions
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Drug Interactions Drug Interactions Pharmacokinetic drug interaction studies with JANUMET have not been performed; however, such studies have been conducted with the individual components of JANUMET (sitagliptin and metformin hydrochloride). Use cationic drugs with caution. There are no known clinically meaningful drug interactions for sitagliptin. Use of Metformin With Other Drugs When drugs that tend to produce hyperglycemia are administered to a patient receiving JANUMET, the patient should be closely monitored to maintain adequate glycemic control. JANUMET™ (sitagliptin/metformin HCl): Drug Interactions Speaker Notes Pharmacokinetic drug interaction studies with JANUMET have not been performed; however, such studies have been conducted with the individual components of JANUMET (sitagliptin and metformin hydrochloride). Use cationic drugs with caution. There are no known clinically meaningful drug interactions for sitagliptin. When drugs that tend to produce hyperglycemia and may lead to loss of glycemic control are administered to a patient receiving JANUMET, the patient should be closely monitored to maintain adequate glycemic control. These drugs include: Thiazides and other diuretics Corticosteroids Phenothiazines Thyroid products Estrogens Oral contraceptives Phenytoin Nicotinic acid Sympathomimetics Calcium channel blocking drugs Isoniazid Purpose: To help inform physicians about the drug interactions information for JANUMET. Takeaway: The drug interaction information is important for physicians to know in making prescribing decisions.

JANUMET™ (sitagliptin/metformin HCl): Recommended Dosing
4/20/ :18 AM JANUMET™ (sitagliptin/metformin HCl): Recommended Dosing In general: twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal side effects due to metformin Starting dose based on patient’s current regimen Available dosage forms: 50 mg sitagliptin/500 mg metformin 50 mg sitagliptin/1,000 mg metformin Patients inadequately controlled on metformin: Starting dose equal to 100 mg sitagliptin daily plus current metformin dose Patients inadequately controlled on sitagliptin: Starting dose 50 mg sitagliptin/500 mg metformin twice daily Titrated up to 50 mg sitagliptin/1,000 mg metformin twice daily Patients switching from sitagliptin coadministered with metformin: Initiate at current doses of sitagliptin and metformin Tablets not shown at actual size. JANUMET™ (sitagliptin/metformin HCl): Recommended Dosing Speaker Notes JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal side effects due to metformin. The starting dose should be based on the patient’s current regimen. The following dosage forms are available: 50 mg sitagliptin/500 mg metformin hydrochloride 50 mg sitagliptin/1,000 mg metformin hydrochloride Patients inadequately controlled on metformin: The usual starting dose should be equal to 100 mg total daily dose (50 mg twice daily) of sitagliptin plus the dose of metformin already being taken. Patients inadequately controlled on sitagliptin: The usual starting dose is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may be titrated up to 50 mg sitagliptin/1,000 mg metformin hydrochloride twice daily. Patients taking sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to JANUMET. Patients switching from sitagliptin coadministered with metformin: JANUMET may be initiated at the dose of sitagliptin and metformin already being taken. Purpose: To discuss the recommended dosing of JANUMET, including the recommended starting dose based on the patient’s current treatment regimen. Takeaway: JANUMET should generally be given twice daily with meals, with gradual dose escalation. The recommended starting dose depends on the patient’s current treatment regimen.

Case Study: Caroline D. Considerations for next treatment decision:
4/20/ :18 AM Case Study: Caroline D. Patient History: 45-year-old woman, bus driver BMI = 31 kg/m2 Borderline hypertension Type 2 diabetes diagnosed Lab Results: A1C = 7.6% FPG = 150 mg/dL Serum creatinine = 0.9 mg/dL (CrCl = 104 mL/min) Treatment: Diet and exercise recommended Considerations for next treatment decision: Mechanism of action Efficacy Tolerability Lab Results: A1C = 8.0% FPG = 170 mg/dL Serum creatinine = 1.0 mg/dL (CrCl = 100 mL/min) Treatment: Metformin up-titrated to 2,000 mg/day Current Lab Results: A1C = 7.7% FPG = 150 mg/dL Treatment: Metformin initiated A1C, % Case Study: Caroline D. As noted earlier, when making treatment decisions for patients with type 2 diabetes, it is important to consider the MOA of potential therapies as well as their efficacy and tolerability. Based on these criteria, if you were Caroline’s physician, what would be your next step?

4/20/ :18 AM Overall Summary A majority of patients with type 2 diabetes may fail to attain A1C goal with the conventional treatment paradigm The components of JANUMET™ (sitagliptin/metformin HCl) have complementary MOAs and comprehensively address 3 core pathophysiologic defects of type 2 diabetes. Coadministration of sitagliptin and metformin results in: Significant reductions in A1C, FPG, and PPG compared with metformin alone Weight loss comparable to metformin alone Low incidence of hypoglycemia comparable to metformin alone Similar overall incidence of side effects to metformin alone Overall Summary Speaker Notes A majority of patients with type 2 diabetes may fail to attain A1C goal with the conventional treatment paradigm. The components of JANUMET™ (sitagliptin/metformin HCl) have complementary MOAs and comprehensively address 3 core pathophysiologic defects of type 2 diabetes. Coadministration of sitagliptin and metformin results in: Significant reductions in A1C, FPG, and PPG compared with metformin alone Weight loss comparable to metformin alone Low incidence of hypoglycemia comparable to metformin alone Similar overall incidence of side effects to metformin alone Purpose: To summarize the key messages of the presentation. Takeaway: JANUMET contains 2 components with complementary mechanisms of action, and its efficacy and safety profiles make it a good treatment option that may help more patients reach glycemic goal.

Core Defects of Type 2 Diabetes

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Core Defects of Type 2 Diabetes

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