HYPOGLYCEMIC ORAL THERAPY Dr.Mohamed Farghaly FRCGP(UK),MRCGP(I),DMSc(UK) DIH(I) MBChB (EG)

Pathogenesis Concepts in Type 2 Diabetes Insulin resistance occurs early, before glucose intolerance Genetic cause? Environmental: obesity, aging, lifestyle, etc. Healthy  cells compensate and remain euglycemic “Susceptible”  cells (in predisposed individuals) -cell dysfunction results in imperfect compensation Progress to prediabetes stage Onset of acquired abnormalities leads to worse hyperglycemia=glucotoxicity (a vicious cycle) Pathogenesis Concepts in Type 2 Diabetes Insulin resistance (the impaired effect of insulin to transport glucose into muscle and fat cells and to suppress glucose production in the liver) is a very early abnormality in diabetes. It is often familial, but the exact genetic cause is unknown. Obesity, physical inactivity, and aging are important acquired/environmental causes of insulin resistance. Despite insulin resistance, blood glucose can be kept normal by the increased production of insulin by a healthy pancreas. However, in some predisposed individuals, -cell function declines and then blood glucose declines. This process is further accelerated because glucose, in itself, is toxic to the -cell and worsens insulin resistance, a phenomenon called glucose toxicity. Fortunately, glucose toxicity may be reversible.

Major Metabolic Defects in Type 2 Diabetes Decreased pancreatic insulin secretion Deficient incretin hormones response Peripheral insulin resistance in muscle and fat tissue Increased hepatic glucose output

Decreased incretin effects from GIT Other pathological defect involved in the development of type 2 diabetes Decreased incretin effects from GIT Dysregulated pancreatic α-cell activity Lipotoxicity Maldaptive kidney responses Central neurotransmitter dysfunction

Ominous Octet HYPERGLYCEMIA Decreased Incretin Effect Decreased Insulin Secretion Increased Hepatic Glucose Production Islet– cell Increased Glucagon Secretion Decreased Glucose Uptake Increased Lipolysis Glucose Reabsorption HYPERGLYCEMIA Neurotransmitter Dysfunction Ominous Octet The pathogenesis of type 2 diabetes includes eight identified pathophysiological defects: Decreased insulin secretion Decreased incretin effect Decreased glucose uptake in the muscle Increased glucagon secretion Increased hepatic glucose production Increased lipolysis Increased glucose reabsorption Neurotransmitter dysfunction Reference: Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795. http://www.ncbi.nlm.nih.gov/pubmed/19336687 Reprinted with permission from DeFronzo R et al. Diabetes. 2009;58:773-795. Copyright © 2009 American Diabetes Association. All rights reserved.

Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM Biguanides Increase glucose uptake and decreases hepatic glucose production Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver Sulfonylureas Increase insulin secretion from pancreatic -cells Glinides Increase insulin secretion from pancreatic -cells Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM The number of antihyperglycemic drugs for use either alone, in combination, or with insulin has grown in recent years, and includes agents with widely differing mechanisms of action.1 The major mechanism of action of biguanides (eg, metformin) is to decrease hepatic glucose output primarily by decreasing gluconeogenesis and, to a lesser degree, increasing glucose uptake by skeletal muscle.1 Sulfonylureas (SUs; eg, glimepiride, glyburide) and glinides (eg, nateglinide, repaglinide) stimulate insulin secretion from the β-cell. SUs bind to a specific cell-surface receptor causing metabolic changes that promote exocytosis of insulin-containing vesicles. Glinides also bind to the SU receptor with similar effects, although with a relatively prompt and brief stimulatory effect.1 α-glucosidase inhibitors (eg, acarbose) do not target any specific pathophysiological defect in type 2 diabetes mellitus. Rather, they act by inhibiting α-glucosidase and other intestinal brush-border enzymes responsible for the breakdown of oligosaccharides and disaccharides to monosaccharides suitable for absorption.1 Thiazolidinediones (eg, rosiglitazone, pioglitazone) act as insulin sensitizers, particularly in peripheral tissues. They bind to a specific nuclear receptor active in adipocytes and muscle cells, promoting the expression of various genes involved in carbohydrate and lipid metabolism.1 Glucagon-like peptide (GLP-1) is an incretin hormone released by gut cells in response to food intake, promoting pancreatic islet activity. Unlike the other agents described here, GLP-1 analogs (including exenatide) are not orally available and must be injected.2 By inhibiting dipeptidyl peptidase-4 (DPP-4), DPP-4 inhibitors such as vildagliptin prolong the action of GLP-1 to stimulate insulin secretion and suppress glucagon release in response to glucose.3 References Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005; 172: 213-226. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705. Ahrén B, Foley JE. The islet enhancer vildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract 2008; 62 (Supplement 159): 8-14. -glucosidase inhibitors Delay intestinal carbohydrate absorption Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14. 8

Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM GLP-1 analogues Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake Biguanides Increase glucose uptake and decreases hepatic glucose production Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver Sulfonylureas Increase insulin secretion from pancreatic -cells Glinides Increase insulin secretion from pancreatic -cells Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM The number of antihyperglycemic drugs for use either alone, in combination, or with insulin has grown in recent years, and includes agents with widely differing mechanisms of action.1 The major mechanism of action of biguanides (eg, metformin) is to decrease hepatic glucose output primarily by decreasing gluconeogenesis and, to a lesser degree, increasing glucose uptake by skeletal muscle.1 Sulfonylureas (SUs; eg, glimepiride, glyburide) and glinides (eg, nateglinide, repaglinide) stimulate insulin secretion from the β-cell. SUs bind to a specific cell-surface receptor causing metabolic changes that promote exocytosis of insulin-containing vesicles. Glinides also bind to the SU receptor with similar effects, although with a relatively prompt and brief stimulatory effect.1 α-glucosidase inhibitors (eg, acarbose) do not target any specific pathophysiological defect in type 2 diabetes mellitus. Rather, they act by inhibiting α-glucosidase and other intestinal brush-border enzymes responsible for the breakdown of oligosaccharides and disaccharides to monosaccharides suitable for absorption.1 Thiazolidinediones (eg, rosiglitazone, pioglitazone) act as insulin sensitizers, particularly in peripheral tissues. They bind to a specific nuclear receptor active in adipocytes and muscle cells, promoting the expression of various genes involved in carbohydrate and lipid metabolism.1 Glucagon-like peptide (GLP-1) is an incretin hormone released by gut cells in response to food intake, promoting pancreatic islet activity. Unlike the other agents described here, GLP-1 analogs (including exenatide) are not orally available and must be injected.2 By inhibiting dipeptidyl peptidase-4 (DPP-4), DPP-4 inhibitors such as vildagliptin prolong the action of GLP-1 to stimulate insulin secretion and suppress glucagon release in response to glucose.3 References Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005; 172: 213-226. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705. Ahrén B, Foley JE. The islet enhancer vildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract 2008; 62 (Supplement 159): 8-14. -glucosidase inhibitors Delay intestinal carbohydrate absorption DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14. 9

  Study Microvasc CVD Mortality  Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS   DCCT / EDIC* ACCORD  ADVANCE VADT This slide presents an overview of the microvascular, macrovascular and mortality outcomes from large T1DM and T2DM randomized clinical trials that have focused on the relationship between glycemic control and complications. From these, it is clear, that more intensive glycemic control in both T1DM and T2DM prevents or delays microvascular complications, specifically retinopathy and albuminuria. In contrast the data concerning glucose control and macrovascular complications are more complex. In the context of relatively short clinical trials, more intensive glucose control has an overall neutral effect on cardiovascular events. In longer term follow-up investigations, however, a statistically significant beneficial effect eventually emerged in both the DCCT (Type 1) and the UKPDS (Type 2.) Some have therefore proposed that there may be a ‘legacy effect’ from previous tight glycemic control on these macrovascular outcomes – something that may not be appreciated for several decades. Notably, however, in ACCORD, an increase in mortality was observed in those patients assigned to the most intensive glucose-lowering therapy. This has raised concerns that overly aggressive glycemic targets in older patients at high cardiovascular risk may be problematic. So, HbA1c targets should be individualized to the patient and disease state. Initial Trial Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Long Term Follow-up * in T1DM

Breakdown of Treatments for Diabetes in the United States Among adults with diagnosed diabetes (type 1 or type 2), 12 percent take insulin only, 14 percent take both insulin and oral medication, 58 percent take oral medication only, and 16 percent do not take either insulin or oral medication. Reference: Centers for Disease Control and Prevention. National Diabetes Fact Sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. http://diabetes.niddk.nih.gov/dm/pubs/statistics/DM_Statistics.pdf

ANTI-HYPERGLYCEMIC THERAPY ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors SGLT-2 inhibitors Meglitinides a-glucosidase inhibitors Here are the currently available non-insulin anti-hyperglycemic drug classes. Those on the left are the most popular in the U.S. and Europe. Those on the right are less commonly used and may be considered in certain circumstances. Clinicians should become facile with at least the major glucose-lowering drug classes, including insulin, to optimally manage patients with T2DM. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Major Classes of Medications 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production 2. Drugs that stimulate the pancreas to make more insulin 3. Drugs that slow the absorption of starches Thiazolidinediones Biguanides Sulfonylureas Meglitinides Alpha-glucosidase inhibitors There are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways. Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues. Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin. Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.

Biguanides Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake. Efficacy Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) Reduce A1C 1.0-2.0% Other Effects Diarrhea and abdominal discomfort Lactic acidosis if improperly prescribed Cause small decrease in LDL cholesterol level and triglycerides No specific effect on blood pressure No weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function (Serum Cr > 1.4 mg/dL for women, or 1.5 mg/dL for men) Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glucophage XR) The mechanism of action of metformin is not entirely understood, but it's predominant effect is to suppress hepatic glucose production and to enhance insulin sensitivity in peripheral tissues (primarily muscle). It is unclear if insulin sensitivity occurs by metformin binding to cell receptors,which leads to an increase in glucose transporter expression, or whether insulin sensitivity is simply a secondary effect of the suppressed glucose production. Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas. Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.

Sustained Metformin Release Metformin XR Tablet Sustained metformin release from the Glucophage® XR tablet Here we compare the plasma concentration-time profiles of immediate-release Glucophage® , and Glucophage® XR. The absorption of metformin from Glucophage® XR is slower, smoother and longer, compared with the immediate-release formulation. As a result, the maximal plasma concentration achieved is slightly lower for the same overall metformin dose. In addition, Glucophage® XR does not display the rapid initial rise in plasma metformin concentrations seen with immediate-release metformin, which may help to trigger gastrointestinal side-effects. The overall exposure of the patient to metformin (the area under the plasma concentration-time curve), however, is comparable between the formulations. Marathe P, Turner K. Steady-state pharmacokinetics of the metformin extended-release tablet versus immediate-release metformin in healthy subjects. Diabetes 2002; 51(Suppl 2): A474. Absorption Slower and longer AUCs matched –identical drug exposure for both dosage forms Timmins P. Clin Pharmacokinet 2005; 44: 721-729

Metformin XR – GI Tolerability 3 out of 4 patients tolerate Metformin XR UK Location Liverpool Isle of Wight b Clatterbridge London Patient No 22 24 28 21 Tolerant No (%) 10 12a 15 23 3c 19 (46) (54) (62) (82) (11) (90) Intolerant No (%) - 7 2 (30) (7) (10) a Tolerant < 1.5g/day b 2 patients lost to follow-up c Tolerant with minor symptoms Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8

Thiazolidinediones (TZDs) Thiazolidinediones(TZDs): decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production. Efficacy Decrease fasting plasma glucose ~35-40 mg/dl (1.9-2.2 mmol/L) Reduce A1C ~0.5-1.0% 6 weeks for maximum effect Other Effects Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate insulin release) Contraindicated in patients with abnormal liver function or CHF Improves HDL cholesterol and plasma triglycerides; usually LDL neutral Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia), [troglitazone (Rezulin) - taken off market due to liver toxicity] Thiazolidinediones (TZDs) enhance insulin sensitivity in muscle and adipose tissue by binding to cell receptors,which leads to an increase in glucose transporter expression. TZDs encourage beta cells to respond more efficiently by lowering the amount of glucose and free fatty acids in the bloodstream, both of which are known to be detrimental to insulin secretion. Finally, these drugs reduce glucose production in the liver. Clinical trials indicate that pioglitazone and rosiglitazone are slightly more effective at reducing A1C (1.5-1.6% reduction) than troglitazone (1.1% reduction). Some of the beneficial side effects of thiazolidinediones include an increase in HDL cholesterol and reduction of triglyceride concentrations. This class of drugs has also been shown to lower blood pressure and decrease vascular inflammation in vitro. There are clinical studies underway to further examine the cardiovascular benefit to TZDs. Some adverse effects of TZDs include weight gain, a potential increase in LDL cholesterol levels, and a possible increase in alanine aminotransferase levels (ALT). Because of the risk of weight gain, edema, and increased LDL cholesterol, thiazolidinediones are contraindicated in patients with advanced forms of congestive heart failure. Due to reported cases of liver failure and liver toxicity caused by the increase in ALT levels, TZDs are contraindicated in patients with abnormal liver function. TZDs are the most expensive of the oral antidiabetic agents.

Sulfonylureas Sulfonylureas increase endogenous insulin secretion Efficacy Decrease fasting plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) Reduce A1C by 1.0-2.0% Other Effects Hypoglycemia Weight gain No specific effect on plasma lipids or blood pressure Generally the least expensive class of medication Medications in this Class: First generation sulfonylureas: chlorpropamide (Diabinese), tolazamide, acetohexamide (Dymelor), tolbutamide Second generation sulfonylureas: glyburide (Micronase, Glynase and Glucovance), glimepiride (Amaryl), glipizide (Glucotrol, Glucotrol XL) Sulfonylureas (SUs) increase insulin secretion by binding to receptors on the surface of pancreatic beta cells, triggering a series of reactions which leads to insulin secretion. Because SUs cause circulating insulin levels to increase, there is a risk of hypoglycemia. There is also some concern that increased insulin levels are associated with cardiovascular disease, however the UKPDS did not show a relationship between increased mortality and SU administration. Finally, there is concern that SUs will exhaust beta cell function by increasing insulin secretion. However, the decline in beta cell function is more likely caused by the disease itself, and not the use of SUs. First generation sulfonylureas are just as efficacious as the second generation drugs, however the second generation may be more potent and safer than first. When diet and exercise fail, SUs are an effective monotherapy.

Meglitinides Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose. Efficacy Decreases peak postprandial glucose Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L) Reduce A1C 1.0-2.0% Other Effects Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule) Weight gain No significant effect on plasma lipid levels Safe at higher levels of serum Cr than sulfonylureas Medications in this Class: repaglinide (Prandin), nateglinide (Starlix) The mechanism of action of repaglinide is similar to that of the sulfonylurea drugs: binding to beta cell receptors to stimulate insulin secretion. The major difference between the two drug classes is that meglitinides are shorter-acting, and are most effective when taken after meals in the presence of glucose. Adverse effects include weight gain and hypoglycemia. An additional drawback to this drug is the dosing schedule since it must be taken with meals.

Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine Efficacy Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L) Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L) Decrease A1C 0.5-1.0% Other Effects Flatulence or abdominal discomfort No specific effect on lipids or blood pressure No weight gain Contraindicated in patients with inflammatory bowel disease or cirrhosis Medications in this Class: acarbose (Precose), miglitol (Glyset) Alpha-glucosidase inhibitors (AGIs) work by blocking the enzyme in the small intestine that breaks down complex carbohydrates, alpha-glucosidase. By blocking this enzyme these drugs prevent starches from being absorbed into the bloodstream and in doing so lower blood glucose levels. AGIs are the only drug class used to treat type 2 diabetes that does not specifically target the pathology of the disease. Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas. What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.

UKPDS: Effect of Glibenclamide and Metformin Therapy on HbA1c Conventional Glibenclamide Metformin 9 8 Median HbA1c (%) 7 7 IDF Treatment Goal: <6.5% 6 6 Despite advances in therapy, however, no single antidiabetic agent has been shown to sustain HbA1c levels over time. This slide shows the deterioration in glycemic control that occurred during the UKPDS, which compared conventional with intensive therapy in newly diagnosed patients with type 2 diabetes. At the start of the trial, HbA1c was approximately 7% across all groups. Median follow-up was 10.7 years. A secondary analysis, shown on this slide, compared glucose control among patients receiving metformin (n=342), glibenclamide (n=277), or conventional treatment (primarily diet; n=411). In the first year, HbA1c declined in all groups, with the greatest effect in the metformin and glibenclamide groups. In subsequent years, HbA1c in all groups rose steadily, exceeding 7% within approximately 2 years in the conventional treatment group. Median HbA1c in the glibenclamide and metformin groups exceeded 7% in 5 and 7 years, respectively.   UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865. 3 6 9 12 15 Years UKPDS Group. Lancet. 1998;352:854-865. 21

ANTI-HYPERGLYCEMIC THERAPY ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors SGLT-2 inhibitors Meglitinides a-glucosidase inhibitors Here are the currently available non-insulin anti-hyperglycemic drug classes. Those on the left are the most popular in the U.S. and Europe. Those on the right are less commonly used and may be considered in certain circumstances. Clinicians should become facile with at least the major glucose-lowering drug classes, including insulin, to optimally manage patients with T2DM. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

What is Incretin? Incretins are gut hormones that enhance glucose stimulated insulin secretion Incretin effect designates amplification of insulin secretion following oral glucose load

NATURAL INCRETINS Two types: 1. Glucose dependent insulinotropic polypeptide (GIP) 2. Glucagon like peptides (GLPs) -GLP-1 These two hormones are rapidly degraded by an enzyme DPP-4

21/04/2017 GLP-1: an incretin hormone with multiple direct effects on human physiology β α Pancreas Brain Satiety Intestine β Glucose-dependent insulin secretion GLP-1 Stomach β Insulin synthesis Gastric emptying α Glucose-dependent glucagon secretion ANIMATED SLIDE Heart Cardioprotection Cardiac function Liver Glucose production L-cells secrete GLP-1  degraded by DPP-4 Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57

Incretin System X Glucose dependent  Insulin (GLP-1and GIP) 12, 12.2 Incretin System Glucose dependent  Insulin (GLP-1and GIP)  Glucose uptake by peripheral tissue Ingestion of food Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. 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 AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along 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. X DPP-4 enzyme Glucose- dependent Exenatide  Hepatic glucose production  Glucagon (GLP-1) Inactive GLP-1 Inactive GIP Gliptin GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

THE PROBLEM Because of very short half life (1-2 min) therapeutic efficacy is challenged This led to idea of producing drugs that act as analogue or receptor agonist but longer half life Another idea was to develops drugs that inhibit DPP-4 enzyme responsible for breakdown of GLP-1 or GIP Thus one group of drugs is called incretin mimetics and the other group is known as incretin enhancers

DIPEPTIDYL PEPTIDASE - 4 INHIBITORS Drugs belonging to this class: Sitagliptin (FDA approved 2006) Vildagliptin (EU approved 2008) Saxagliptin (FDA approved 2009) Linagliptin (FDA approved 2011)

Treatment of Type 2 Diabetes: A Sound Approach Based Upon Its Pathophysiology Islet b-cell Impaired Insulin Secretion TZDs GLP-1 analogues DPP-4 Inhibitors Sulfonylureas/ Meglitinides  Increased Lipolysis TZDs Metformin TZDs TZDs Metformin  The soundest approach to developing treatment regimens for patients with type 2 diabetes will be predicated on addressing the disease’s multiple etiologic pathways. Agents that improve insulin resistance, such as TZDs and metformin, help to decrease HGP; these same agents also facilitate increased glucose uptake. Pharmacologic agents such as TZDs that decrease FFA expression may control increased lipolysis. Last, β-cell function and insulin secretion are improved by a variety of agents. TZDs, GLP-1 analogues, and dipeptidyl peptidase-4 (DPP-4) inhibitors have all been shown to improve β-cell function. The latter 2 agents as well as sulfonylureas and meglitinides also directly stimulate insulin secretion. Nevertheless, no single available antidiabetic agent addresses all of the underlying pathophysiologic mechanisms, and no agent has yet been shown to yield sustainable HbA1c reductions, as shown on the next 2 slides. Increased HGP Decreased Glucose Uptake DPP-4=dipeptidyl peptidase-4. 29

Pathophysiology of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP 10 mmol/L In persons with abnormal glucose tolerance, glucose homeostasis is disrupted by the combination of impaired insulin secretion and peripheral insulin resistance, along with increased HGP. These factors lead to increased levels of FPG by the increase from 5 to 10 mmol/L (90 to 180 mg/dL) on the slide.1 A fasting glucose this high is well into the diabetic range (>7.0 mmol/L [126 mg/dL]), but a fasting glucose >5.6 mmol/L (101 mg/dL) indicates impaired fasting glucose, a prediabetic state.2 If rising blood glucose levels remain unchecked, diabetes complications will result in time. In the short term, hyperglycemia results in glucotoxicity, which may occur well before the onset of diabetes. Glucotoxicity worsens the pathophysiologic factors that first led to hyperglycemia, and so begins a vicious circle.1,3 DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37:667-687. World Health Organization/International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Report of a WHO/IDF consultation. Geneva: WHO, 2006. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86:4047-4058. 5 mmol/L Fasting Plasma Glucose 30 30

Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Approximately 180 L of plasma per day pass through the kidney’s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than passed out in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals. With a daily glomerular filtration rate of 180 L, approximately 162 g of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/L (101 mg/dL). As shown on the slide, reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, SGLT1 and SGLT2. SGLT1, which occurs in the straight section of the tubule (S3), is responsible for approximately 10% of glucose reabsorption in the kidney. The other 90% is mediated by SGLT2, which occurs in the convoluted section on the tubule (S1). Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32-43. 10% No Glucose 31 31

Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond Inhibition of SGLT2 is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide. First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity. This approach to therapy is simple and nonspecific and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond. 32 32

Pathophysiology of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP As demonstrated by this animation, if rising blood glucose levels remain unchecked, diabetes complications will result in time. In the short term, hyperglycemia results in glucotoxicity, which may occur well before the onset of diabetes. Glucotoxicity worsens the pathophysiologic factors that first led to hyperglycemia, and so begins a vicious circle.1,2 By increasing glucosuria, SGLT2 inhibition reduces plasma glucose levels toward the normal level of 5 mmol/L. With the reduction in glucotoxicity, insulin secretion improves and insulin sensitivity is enhanced. In turn, these decrease hepatic glucose output. Evidence supporting these actions is described in the following slides. DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37:667-687. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86:4047-4058. 10 mmol/L Glucosuria Fasting Plasma Glucose 33 33

Pathophysiology of Type 2 Diabetes Islet b-cell Impaired Insulin Secretion Insulin Resistance Increased HGP 10 mmol/L By increasing glucosuria, SGLT2 inhibition reduces plasma glucose levels toward the normal level of 5 mmol/L (90 mg/dL). With the reduction in glucotoxicity, insulin secretion improves and insulin sensitivity is enhanced. In turn, these decrease hepatic glucose output. Evidence supporting these actions is described in the following slides. Glucosuria 5 mmol/L Fasting Plasma Glucose 34 34

Unanswered Questions About SGLT2 Inhibition Durability The efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range Safety and tolerability The long-term safety of this class remains to be proven Risk of nocturia and genitourinary infections may limit use in some patients Renal impairment SGLT2 inhibition may not be effective in patients with renal impairment SGLT2 inhibitors are unlikely to be effective in patients with renal insufficiency due to reductions in glomerular filtration rate as well as other reasons under investigation. Studies are also being conducted to identify glomerular filtration rate cut points beyond which SGLT2 inhibitors would be contraindicated. 35

SGLT2 Inhibition: Meeting Unmet Needs in Diabetes Care Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia CVD Risk (Lipid and Hypertension Control) Corrects a Novel Pathophysiologic Defect No Hypoglycemia Complements Action of Other Antidiabetic Agents Promotes Weight Loss Improves Glycemic Control Note: this slide builds, with each unmet need changing to a possible answer with each click. This slide revisits the various unmet needs of type 2 diabetes identified earlier. SGLT2 inhibition may provide solutions to these unresolved issues in the following way: Weight management: SGLT2 inhibitors promote weight loss by increasing glucosuria, which drains glucose from the bloodstream and stimulates breakdown of fat cells for fuel. Multiple defects of type 2 diabetes: Increased renal glucose reabsorption has recently been identified in type 2 diabetes. SGLT2 inhibitors correct this novel defect. Adverse effects of therapy: Among adverse events, hypoglycemia may pose the greatest barrier to optimal glycemic control because of acute safety concerns as well as long-term risk of hypoglycemia unawareness (which develops from repeated episodes of hypoglycemia). Because their function is completely independent of insulin, SGLT2 inhibitors do not increase the risk of hypoglycemia. Hyperglycemia: Treating to HbA1c targets ≤7% in the years immediately following diabetes diagnosis is associated with long-term reduction in the risk of diabetic complications. The unique mechanism of action of SGLT2 inhibitors complements those of other antidiabetic agents, making them extremely suitable for combination therapy. CVD risk (lipid and hypertension control): The improvements in weight and glycemia achieved with SGLT2 inhibition will support treatments that more directly reduce CV risk (eg, statins and antihypertensive agents). Improvements in Glucose and Weight Support Other CVD Interventions 37 37

Treatment of Type 2 Diabetes 1. Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c 2. Will require multiple drugs in combination to correct multiple pathophysiologic defects 3. Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented 38

IDF Treatment Algorithm

Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.

Metformin Dose Response

If the A1c target is not achieved after ~3 months, there is no clearly preferred second agent after metformin. Each drug has its advantages and disadvantages, and what might be best for one patient may not be so for the next. In general, the clinician should consider one of 6 treatment options combined with metformin (i.e., dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, SLGT2 inhibitor, GLP-1 receptor agonist or basal insulin. The major update to this figure from 2012 is the inclusion of the SGLT2 inhibitors. Note that the order in the chart is determined by historical introduction and route of administration and is not meant to imply any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects, especially hypoglycemia. Shared decision-making with the patient may help in the selection of therapeutic options. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider these in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.

If the A1c target is still not achieved after ~3 months and appropriate drug dosage titration, add a third agent (i.e., triple combination therapy), with mechanisms of action should complement each other. Options obviously become more limited as one progresses down the figure. When glucose levels are especially high, a regimen that incorporates basal insulin should be strongly considered, especially if the patient is symptomatic. One important benefit of insulin is its near universal effectiveness when dosed properly. Drug choice is based on patient preferences as well as various patient, disease, and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycemia. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.

Previously, when combinations of multiple oral agents (i. e Previously, when combinations of multiple oral agents (i.e., up to triple combination therapy) were no longer effective at controlling blood glucose, insulin was typically added, initially as a single injection of basal insulin. If this was or became ineffective in controlling HbA1c, post-prandial hyperglycemia was usually to blame. Adding several injections of rapid-acting insulin analogues (‘basal-bolus’ insulin therapy) would be the next step to control meal time glycemic excursions. Over the past several years, there has been increasing evidence that the combination of basal insulin with a GLP-1 receptor agonist may provide equal glucose lowering effect as up to 3 injections of meal time insulin, yet with weight loss instead of weight gain, and with less hypoglycemia. This updated figure therefore underscores the potential value of this specific combination. It should be considered in patients who appear to need more than basal insulin, with or without oral agents. In those patients who do not respond adequately to the addition of a GLP-1 receptor agonist to basal insulin, the “basal–bolus” insulin strategy should be used instead (or twice daily premixed insulin.) In selected patients at this stage of disease, the addition of an SGLT2 inhibitor may further improve control and reduce the amount of insulin required. This is particularly an issue when large doses of insulin are required in obese, highly insulin-resistant patients. Another, older, option, the addition of a TZD (usually pioglitazone), also has an insulin-sparing effect and may also reduce HbA1c, albeit at the expense of weight gain, edema, and increased heart failure risk.

In patients intolerant of, or with contraindications to metformin, consider initial drug from other classes depicted under “Dual therapy” and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations that do not include metformin. Consider starting with 2-drug combinations in patients with very high HbA1c (e.g. ≥9%) to achieve control more rapidly (although a step-wise approach will eventually the patient to target as well.) Insulin has the advantage of being effective where other agents may not be and should be considered a part of any combination regimen when hyperglycemia is severe, especially if the patient is symptomatic or if any catabolic features (weight loss, any ketosis) are evident. Consider initiating combination injectable therapy with insulin when blood glucose is >300–350 mg/dL (>16.7–19.4 mmol/L) and/or HbA1c >10–12%. Potentially, as the patient’s glucose toxicity resolves, the regimen can be subsequently simplified.

What follows are variations of the main treatment recommendations (Figure 2), to help guide the clinician in choosing agents which may be most appropriate under certain common clinical scenarios: to avoid weight gain to avoid hypoglycemia, and to minimize costs. Here is the variation when a major goal is to avoid hypoglycemia. Options are limited to TZDs, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. (Of course, other drugs can be used, but cautiously if the over-riding goal is to avoid hypoglycemia.)

Here is the variation of Figure 2 when a major goal is to avoid weight gain. Options are limited to DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. (Of course, other drugs can be used, but cautiously if the over-riding goal is to avoid weight gain.)

Here is the variation of Figure 2 when a major goal is to minimize cost. Treatment is limited to metformin, sulfonylureas, TZD (mainly pioglitazone) and certain insulins (human insulins.)

Overall Conclusions Understanding of the pathophysiology of type 2 diabetes is an evolving process As new concepts emerge, there is potential for new treatment modalities Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis 50

What to Discuss With Your Patients Establishing a goal for HbA1c and strategies to help accomplish that goal, including weight loss and exercise along with consistent use of medication Strategies to increase adherence include creating a medication schedule, addressing the costs of medications, and reporting adverse events in a timely manner The need for regular glucose testing and routine blood tests for HbA1c What to Discuss With Your Patients Establishing a goal for HbA1c and strategies to help accomplish that goal, including weight loss and exercise along with consistent use of medication. Strategies to increase adherence include creating a medication schedule, addressing the costs of medications, and reporting adverse events in a timely manner. The need for regular glucose testing and routine blood tests for HbA1c. Reference: Bennett WL, Wilson LM, Bolen S, et al. Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 27. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018.) AHRQ Publication No. 11-EHC038-EF. Rockville, MD: Agency for Healthcare Research and Quality. March 2011. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=644. Comparing Medications for Adults With Type 2 Diabetes. Rockville, MD: Agency for Healthcare Research and Quality. AHRQ Pub. No. 11-EHC038-3. June 2011. Available at: www.effectivehealthcare.ahrq.gov. Medicines for Type 2 Diabetes, A Review of the Research for Adults. Rockville, MD: Agency for Healthcare Research and Quality. AHRQ Pub. No. 11-EHC038-A. June 2011. Available at: www.effectivehealthcare.ahrq.gov.

Thank You