Sulphonylurea A Golden Therapy For Diabetes By Eman Rushdy Prof. Internal Medicine Cairo University

The shoes story Many years ago two salesmen were sent by a British shoe manufacturer to Africa to investigate and report back on market potential. The first salesman reported back, "There is no potential here - nobody wears shoes." The second salesman reported back, "There is massive potential here - nobody wears shoes." You will perhaps have heard this very old story illustrating the difference between positive thinking and negative thinking: This simple short story provides one of the best examples of how a single situation may be viewed in two quite different ways - negatively or positively.

What is your concern about oral hypoglycemic drug ?! B cell exhaution. Less effective Hypoglycemia Expensive

The normal beta-cell 10 µm granules Pancreas consists of 1 million islets of Langerhans Start to develop from week 9-11 gestation 10 µm ~ 10,000 granules Presented by Pr Philippe Halban at the 1st Amsterdam Diabetes Meeting, March 30-April 1, 2006 Micrograph: Lelio Orci, Geneva

Apoptosis is the major mechanism of death Half-life of ~30 days Apoptosis is the major mechanism of death normal apoptotic New beta-cells by: *Replication *Neogenesis

~65% -cell mass (%) Modified from Butler AE, et al. Diabetes 2003;52:102–10.

Factors for progressive loss of B- cell function & mass Glucotoxicity Lipotoxicity l Apoptosis Insulin Secretion Amyloid deposition Inflamatory Cytokines& ROS Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.

Exhaustion is reversible B-cell Exhaustion - A physical depletion of B-cell insulin stores secondary to prolonged chronic stimulation with glucose on non-glucose secretagogues. - No defect in insulin synthesis. - The B-cell function fully recovers as it rests. Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects In normal subjects, with the ingestion of food, gut hormones are released.1 The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2 Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2 Glucose is taken up by adipose and muscle tissue.3 Exhaustion is reversible References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. 3. 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. 8

Glucotoxicity Non physiological and potentially irreversible B-cell damage caused by chronic exposure to supra-physiological glucose concentration with characteristic decreases in insulin synthesis and secretion caused by decreases insulin gene expression. Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects In normal subjects, with the ingestion of food, gut hormones are released.1 The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2 Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2 Glucose is taken up by adipose and muscle tissue.3 Glucotoxicity is irreversible References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. 3. 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. 9

Interplay between B-cell exhaustion & glucotoxicity Hyperglycemia Excess insulin secretion Prolonged hyperglycemia Treatment Insulin depletion from B-cell (Exhaustion) Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects In normal subjects, with the ingestion of food, gut hormones are released.1 The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2 Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2 Glucose is taken up by adipose and muscle tissue.3 More, prolonged hyperglycemia ER Stress ROS Ca++ Cytokines Irreversible B-cell damage &  apoptosis (Glucotoxicity) References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940. 3. 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. 10

Frequently prescribed oral hypoglycemic medications?

Factors to Consider when Choosing Pharmacological Agent(s) for Diabetes Current A1C Duration of diabetes Body weight (BMI, abdominal obesity) Effectiveness Co-morbidities Cradiovascular risk Cost of medication Compliance.

ADA/EASD: Considerations for the Guidelines Use of information from clinical trials that address the efficacy and safety of different modalities of treatment (Evidence based) Clinical judgment of the panel participants (Recognize that beta cell failure is progressive) Extrapolation of UKPDS data that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in complications. Nonglycemic effects of medication, such as effect on CV risk, lipids, hypertension or insulin resistance Safety, side effects, ease of use and expense

AACE/ ACE Criteria Attempts to provide a place and recommendation for all FDA approved drugs Greater emphasis on hypoglycemia avoidance Recognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations

ADA/EASD Management Algorithm Lifestyle intervention and metformin If HbA1c ≥7%* Add basal insulin (most effective) Add sulfonylurea (least expensive) Add TZD If HbA1c ≥7% Intensify insulin*** Add basal insulin*** Add sulfonylurea Add TZD Key Point The ADA/EASD recommends lifestyle modifications and metformin as the first step in treatment for patients with newly diagnosed diabetes. References: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8):1963-72. Nathan DM et al. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy : Update regarding the thiazolidinediones. Diabetologia 2008;51(1):8-11. If HbA1c ≥7% Add basal or intensify insulin Intensive insulin + metformin +/− TZD** Nathan DM et al. Diabetes Care 2006;29(8):1963-72. Nathan DM et al. Diabetologia 2008;51(1):8-11. 16

ADA/EASD Consensus Algorithm for Management of Diabetes Diabetes Care Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin Lifestyle+Metformin + Basal Insulin Lifestyle+Metformin + Intensive insulin Lifestyle+Metformin + Sulfonylurea Step 1 Step 2 Step 3 Tier 2: less well-validated therapies Lifestyle+Metformin + Pioglitazone Sulfonylurea Lifestyle+Metformin + Pioglitazone (No hypoglycemia, edema, CHF, bone loss) *Useful when hypoglycemia is to be avoided Lifestyle+Metformin + GLP1 (No hypoglycemia, wt loss, Nausea/vomiting) Lifestyle+Metformin + Basal Insulin Amylin agonists, Glinides DPP-4 inhibitors may be appropriate in selected patients

AACE consensus Algorithm (2009) Life style modification AACE consensus Algorithm (2009) 18 18

Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007 Big SU Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094. 19

Leading Diabetes Medications by Treatment Class SU SU+Met Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094. 20

Egyptians one hand

Sulfonylureas - Drug Profile Advantages Potent glucose lowering effect Favorable adverse effect profile Disadvantages *Hypoglycemia, less with Glimipride *Weight gain, less with Glimipride Concomitant use with other drugs Can be used as monotherapy and with all classes including insulin

Sulfonylureas Divided into First, Second, and Third Generation First Generation: rarely used today Second Generation: glipizide, Gliclazide Third Generation: glimepiride The duration of action depends on the affinity to SUR and which part of it , the rate of metabolism, activity of metabolites and rate of excretion Action: Directly stimulate Beta cells (secretagogue) Increase tissue sensitivity to insulin Divided into First, Second, and Third Generation First Generation: (Orinase, Diabinase): rarely used today Second Generation: glyburide (Diabeta), glipizide (Glucatrol) Third Generation: glimepiride (Amaryl) More potent, smaller doses needed 12- 24 hour action- take once or twice per day Shorter half life, shorter duration than first generation Less risk of hypoglycemia than first generation Side effects: (all) GI upset, skin rashes,photosensitivity Alcohol sensitivity (especially Diabenase) Prolonged hypoglycemia (drug action 12-24 hours)

Modes of action: Glimepiride Most Sulphonylureas Glimepiride K+ 140 kDa 65  - cell membrane KATP channel Most Sulphonylureas Glimepiride Sulphonylurea Receptor The duration of action depends on the affinity to SUR, rate of metabolism, activity of metabolites and rate of excretion So What ??

Pharmakokinetics of sulphonylurea: *Glimepiride has a lower affinity to the -cell membrane than others *The metabolites of glibenclamide are active while those of glimipride and gliclazide are inactive.

Glimepiride Controls Glycemia with Less Insulin Secretion Mean ratio between increased level of insulin and reduced glycemia Sulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/ blood glucose decrease 3 Ratio 2 1 0.20 n=16 0.15 n=13 0.10 5 n=14 10 0.05 n=16 15 0.00 20 Glibenclamide Glipizide Gliclazide Glimepiride Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37

Hypoglycemia vs Glibenclamide Significantly lower incidence of severe hypoglycemic events with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years) 6 Prospective, population-based, 4-year study to compare frequency of severe hypoglycemia in patients with T2DM treated with Amaryl® (estimated n=1768) versus glibenclamide (estimated n=1721) 6.5x less risk of hypo 4 5.6 # Episodes/1000 person-years The reasons for the differences noted in hypoglycemia rate in this study are probably multifactorial. One factor is thought to be related to the differences in receptor binding between the two medications. Glimepiride has a considerably lower binding affinity to the -cell receptor and a higher exchange rate, associating with its receptor (65 kDa protein on the pancreatic sulfonylurea receptor in the cell membrane) 2 to 3 times faster than glyburide (which binds to 140 kDa protein) and dissociating about 8 to 9 times faster than glibenclamide. Additionally, glibenclamide accumulates after long-term use. Taken together, these factors can lead to a high risk of severe hypoglycemia. Furthermore, for the same blood-glucose lowering effect, glimepiride stimulates the secretion of smaller amounts of insulin than glibenclamide, both when fasting and postprandially. This ability to suppress endogenous insulin production between meals (and during exercise) is clearly different from glibenclamide and presumably lessens the risk of hypoglycemia. Holstein et al. Diabetologia 2000;43:A40. 2 0.86 Glibenclamide Glimepiride *Defined as requiring IV glucose or glucagon Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

Less weight gain: Weight gain is seen with all agents, glimepride has been reported to be the most weight-neutral sulphonylurea

Müller G, Wied S. Diabetes. 1993;42: 1852-1867 Insulin Resistance The extrapancreatic effect of Glimipride ↑ Translocation of GLUT4 transporters from low-density microsomes to plasma membrane of insulin-resistant fat and muscle cells In extrapancreatic tissues, sulfonylureas promote the synthesis of glucose transporters (Jacobs, Hayes, & Lockwood, 1989), improving insulin sensitivity by potentiating glucose transport in adipose tissue and glycogen synthesis in skeletal muscle (Groop, 1992). Müller G, Wied S. Diabetes. 1993;42: 1852-1867 1

Glimepiride Increases Plasma Adiponectin Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12 weeks treatment + 54% Rimonabant (Acomplia) 20 mg from Sanofi also has amazing results in 1,041 obese American patients in adiponectin increase of 1 year (+41%) Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly Type 2 Diabetic Subjects Diabetes Care 26:285–289, 2003 

Glimepiride Dual Mechanism for Dual Problem INSULIN RESISTANCE FPG / PPG HbA1C INSULIN SECRETION Normal IGT Type 2 Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000 Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3): 799-816

Expected HbA1c reduction according to intervention Expected ↓ in HbA1c (%) Lifestyle interventions 1 to 2% Metformin Sulfonylureas Insulin 1.5 3.5% Glinides 1.5%1 Thiazolidinediones 0.5 1.4% -Glucosidase inhibitors 0.8% GLP-1 agonist 1.0% Pramlintide DPP-IV inhibitors 1. Repaglinide is more effective than nateglinide Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203. 34

UKPDS: legacy effect of earlier SU/insulin therapy –30 –25 –20 –15 –10 –5 Relative risk reduction (%) All-cause mortality Any diabetes-related end point Myocardial infarction Microvascular disease 9% 24% 15% 13% P = 0.040 P = 0.001 P = 0.014 P = 0.007 10 9 8 7 6 0 5 10 15 5 10 1977 1997 2007 Years from randomization UKPDS Active Conventional Intensive Intervention ends Follow-up Median HbA1c (%) Biochemical data no longer collected Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247. Holman RR, et al. N Engl J Med 2008; 359:1577–1589. Copyright © 2008. Reprinted by permission of SAGE.

Glycemic Control In Monotherapy

Glimepiride Efficacy Proven in Monotherapy Glimepiride decreased FPG by 46 mg/dL more and 2-hour PPG by 86 mg/dL more than placebo (p<0.001) HbA1c<7.2% was achieved in 69% of Glimepiride patients and 32% of placebo patients Baseline HbA1c FPG PPG 9.1% 8.9% n=117 n=118 n=108 n=101 -1% -1 -20 -13 -2.4%# -40 -31 Δ in median HbA1c (%) -2 7.9% Δ in glucose concentration (mg/dL) -60 -59* -3 -80 -4 6.7% -100 HbA1c at Endpoint -120 -117* *p<0.001 vs placebo -140 Glimepiride Placebo Schade DS et al. J Clin Pharmacol 1998;38:636-51

Suitable for Combination Therapy Efficacy of Glimepiride + Metformin Efficacy of Glimepiride + Gliptins Efficacy of Glimepiride + Insulins

Baseline HOMAIR values Glimepiride + Metformin Combination Reduces Insulin Resistance More than Metformin Monotherapy Percent change in homeostasis model assessment for insulin resistance (HOMAIR) at week 10 7.8 11.7 6.4 Baseline HOMAIR values -10 Metformin + diet & exercise (n=29) -20 Δ in HOMAIR (%) -30 Metformin + Glimepiride + diet & exercise (n=21) -40 -46.9 Diet & exercise (n=9) -52.4 -50 -60 -65.3* -70 *p<0.01 vs metformin and vs diet and exercise alone Bermúdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202

Efficacy: Glimepiride + Gliptin Combination Baseline HbA1c 8.4% 8.3% -0.1 -0.2 Glimepiride + sitagliptin -0.3 -0.4 Glimepiride + metformin + sitagliptin ∆ in HbA1c (%) -0.57* -0.5 -0.6 -0.7 -0.89* -0.8 -0.9 -1 1Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745 *p<0.001 vs placebo The EU’s Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin be approved for use in combination with a sulfonylurea and for triple therapy in combination with metformin + sulfonylurea2 2European Medicines Agency, 15 Nov 2007: Available at http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf

Efficacy: Glimepiride + Insulin Combination Reduced insulin requirement and faster glycemic control Mean insulin dosage required to restore glycemic control Evolution of mean FPG over time 100 100 150 200 250 300 4 8 12 16 20 24 * 78 U/day * * 75 * * * * -38% 50 Units/day Mean FPG (mg/dL) † 49 U/day 25 4 8 12 16 20 24 Weeks Weeks Placebo + Insulin (n=62) Glimepiride + Insulin (n=70) * p<0.001; † p<0.05 vs Glimepiride Riddle et al. Diabetes Care 1998;21:1052-1057

Additionnal Benefits for the Patient Beyond Blood Glucose Control

Mode of action: Different SURs in different tissues Pancreatic beta-cell SUR1/Kir6.2 Cardiac and skeletal muscle SUR2A/Kir6.2 Vascular smooth muscle SUR2B/Kir6.1 Non-vascular smooth muscle SUR2B/Kir6.2 Brain SUR1-2B/Kir6.2 KATP channels have been identified in many tissue types, including myocardial cells. In most tissues, Kir6.2 serves as the pore-forming subunit, but it associates with different SUR subunits; for example, it associates with SUR1 in the pancreas and brain; SUR2A in heart and skeletal muscle; and SUR2B in brain and smooth muscle. In vascular smooth muscle, the KATP channel is composed of Kir6.1 in association with SUR2B. Amaryl® is highly selective for pancreatic channels over cardiac potassium channels, and therefore has a neutral CV profile Proks P et al., Diabetes 2002; 51: S368-S376.

Glimepiride accompanied by a better CV risk marker Glimepride Efficient in reducing CV risk markers Lp(a), PAI-I and Hcy 12 months Lp (a) PAI - I Hcy Lp(a) is in mg/dL, PAI-I in ng/mL and Hcy in µmol/L : when present in high plasma concentration, these extraglycemic measures of risk factors. Lp(a) potentiates thrombosis. PAI-I has been suggested to be a major determinant in the plasmin formation in the circulatory system. The amino acid Hcy is an atherothrombotic. Signification des differences en termes de statistiques : P<0,05 vs baseline for all except p<0,01 vs baseline for glim for Lp(a) and Hcy and p<0,05 vs repaglinide for Hcy Glimepiride accompanied by a better CV risk marker Lp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor – I ; Hcy = homocysteine 45

Glimepiride Beneficial Effects on HDL-C and Adiponectin Baseline 3 months 5 10 15 Time Plasma adiponectin (g/dL) 7.5 8.3* Baseline 3 months 10 20 30 40 50 60 70 Time HDLcholesterol (mg/dL) 53* Uncontrolled study in Japan enrolling 40 patients with T2D. Plasma adiponectin and HDL cholesterol levels were measured at baseline and after 3 months of treatment with Glimepiride 1mg/day. Plasma adiponectin and HDL cholesterol levels at baseline and after 3 months of treatment Glimepiride significantly increases plasma adiponectin and HDL cholesterol levels *P < 0.05 vs baseline Motoyama K, et al. Diabetes 2006; 55 (Suppl. 1): 468 [conference abstract]

NO ISCHEMIC PRECONDITIONING ISCHEMIC PRECONDITIONING Ischemic preconditioning is a powerful, endogenous mechanism by which the heart protects itself from lethal ischemic insult IP occurs when cardiac KATP channels open automatically during brief episodes of mild myocardial ischemia Drugs that inhibit cardiac KATP channel opening (e.g. glibenclamide) may be harmful to the ischemic myocardium by blunting the KATP channel-dependent component of the ischemic preconditioning response NO ISCHEMIC PRECONDITIONING Prolonged occlusion of a major coronary artery leads to myocardial infarction ISCHEMIC PRECONDITIONING Repeated and brief occlusion of the same vessel preconditions the myocardium such that subsequent prolonged occlusion leads to a smaller infarct SULFONYLUREAS Sulfonylureas other than Glimepiride abolish ischemic preconditoning, resulting in large infarction size Brady et al. J Am Coll Cardiol 1998;31(5):950.

% change in mean ST shift Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioning p = 0.049 p = 0.01 p = NS 100 % change in mean ST shift 50 Glimepiride May Offer Cardiovascular Advantages Compared With Other Sulfonylurea Drugs The onset of ischemia causes the opening of the cardiovascular ATP-sensitive potassium (KATP) channels, a mechanism that plays a role in protecting the myocardium; this process is called ischemic preconditioning. It has been suggested that classical sulfonylureas such as glibenclamide have adverse effects on the cardiovascular system , mainly because they abolish the cardioprotective responses of the KATP channel opening, presumably by inhibiting mitochondrial KATP channel opening in cardiac myocytes. Unlike glibenclamide, data from animal and human studies show glimepiride does not block the beneficial effects of mitochondrial KATP channel opening in cardiac tissue. This may have implications for the treatment of T2DM patients who are typically at increased cardiovascular complications vs. non-diabetic subjects. Placebo (n=15) Glimepiride (n=15) Glibenclamide (n=15) Baseline After drug administration Mean ST segment depression during balloon occlusion according to treatment Klepzig et al. Eur Heart J 1999;20:439-446

Sulfonylureas More efficacy ( more reduction in HbA1c) Have an established long-term benefit with regard to decreased risk of micro and macro cardiovascular diabetes-related complications (UKPDS), You can lower risk of hypoglycemia in the case of second-generation sulfonylureas, such as glimepiride. Necessitate almost no precautions for use in patients with impaired renal function Have no detrimental effect on ischemic preconditioning, Have a favorable cost/efficacy/safety ratio. In contrast to DDP IV inhibitors, sulfonylureas 1Nathan et al. Diabetes Care 2009;32:193-203. 2Briscoe et al. Expert Opin Drug Metab 2010;6:225-235. 50

Advantages of Glimepiride Single daily dosing Comparable hypoglycaemic side effect profile to other SU Safer in the presence of cardiac disease Peripheral action conserves endogenous insulin Safer to use in the physically active

Review Annals of Internal Medicine Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHS Conclusions: Compared with newer, more expensive agents older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points. Ann Intern Med. 2007;147:386-399