IDF Regions and global projections of the number of people with diabetes (20-79 years), 2013 and Diabetes Atlas -sixth Edition: IDF 2013

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2 IDF Regions and global projections of the number of people with diabetes (20-79 years), 2013 and 2035 Diabetes Atlas -sixth Edition: IDF 2013

3 Diabetes Atlas -sixth Edition: IDF 2013

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5 Chronic complications 400 Diab. Patients (HMC) Retinopathy Nephropathy Neuropathy Cardiovascular Qatar Medical Journal, Vol. 12. No. 2, Dec. 2003

6 Diabetes Atlas -sixth Edition: IDF 2013

7 Insulin and Glucagon Regulate Normal Glucose Homeostasis Fasting state Glucagon (α cell) Fed state Pancreas Insulin (β cell) Glucose output Glucose uptake Liver Blood glucose Muscle Adipose tissue

8 Major Pathophysiologic Defects in Type 2 Diabetes Islet-cell Dysfunction Glucagon (α cell) Pancreas Hepatic glucose output Liver Insulin (β cell) Hyperglycemia Insulin resistance Glucose uptake Muscle Adipose tissue

9 Proportion Not Experiencing Secondary Failure SECONDARY FAILURE OF ETFORMIN MONOTHERAPY (N=1051) BY DURATION OF DIABETES AT METFORMIN INITIATION Months 21.4% year 0-3 Months 12.2% year 4-11 Months 17.7% year Months 18.4% year 0.2 > 36 Months 21.9% year Months on Metformin Brown et al, Diabetes Care 33: , 2010

10 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH Sulfonylurea Glyburide Glimepiride SU Glyburide GLY SU Gliclazide Glyburide Gliclazide Glyburide Alvarsson (n=39) Alvarsson (n=48) RECORD (n=272) Hanefeld (n=250) Charbonnel (n=313) UKPDS (n=1,573) Chicago (n=230) ADOPT (n=1,441) PERISCOPE (n=181) Tan (n=297) TIME (years)

11 SULFONYLUREAS and coronary disease outcomes sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: Retrospective cohort study CVD outcomes (acute myocardial infarction and stroke) or death. Among patients initiating treatment ( with sulfonylurea therapy and with metformin therapy composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin. More CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [ahr], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (ahr, 1.26 [CI, 1.16 to 1.37]) and glipizide (ahr, 1.15 [CI, 1.06 to 1.26]) Ann Intern Med. 2012

12 SULFONYLUREAS and coronary disease outcomes : Newer sulfonylureas All Danish residents>20 years, initiating single-agent sulfonylurea or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) A total of subjects were included, of whom 9607 had previous MI. CONCLUSION: Monotherapy with glimepiride, glibenclamide, glipizide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than others Eur Heart J. 2011

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14 TREATMENT OF TYPE 2 DIABETES Metformin TZDs Impaired Insulin Secretion Sulfonylureas TZDs Hyperglycemia Increased Lipolysis TZDs TZDs Metformin Increased HGP

15 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES 1 0 Hanefeld (n=250) Charbonnel (n=317) PERISCOPE (n=178) RECORD (n=301) PIO Chicago (n=232) ADOPT (n=1,456) Rosenstock (n=115) Tan (n=249) Rosiglitazone -1 PIO ROSI PIO PIO PIO TIME (years)

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18 Kaplan-Meier Event Rate PIOGLITAZONE & CARDIOVASCULAR EVENTS PROACTIVE (n=5238): TIME TO DEATH, MI, OR STROKE META-ANALYSIS OF CLINICAL TRIALS Plc PIO # Events Year Estimate 14.4% 12.3% Placebo P=0.027 HR = 0.84 Pioglitazone TIME (months) (n = 5,203) Comparator CI = Pioglitazone (n = 5,944) TIME (weeks) HR= 0.75 LANCET 366: ,2005 FDA and Center for Drug Evaluation & Research; July 30,2007

19 Pioglitazone and risk of bladder cancer among diabetic patients in France population-based cohort study. The French national health insurance information system Age: 40 to 79 years, follow for up to 42 months 1,491,060 diabetic patients, 155,535 of whom were exposed to pioglitazone. Incidence rates were 49.4 and 42.8 per 100,000 person-years, respectively. Pioglitazone exposure was significantly associated with bladder cancer incidence (adjusted HR 1.22 [95% CI 1.05, 1.43]). Dose-effect relationship, with a significantly increased risk for high cumulative doses and long duration of exposure ( 24 months) Diabetologia. 2012

20 Risk of bladder cancer among diabetic patients treated with pioglitazone: Interim report of a longitudinal cohort study. 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were 40 years of age between 1997 and pioglitazone treated comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI ]), with similar results in men and women. category of>24 months of therapy, there was an increased risk (1.4 [ ]). Diabetes Care. 2011

21 Major pathophysiologic defects in Type 2 DM: Impaired Insulin Secretion Insulin Resistance Lipotoxicity Hepatic overproduction of Glucose HYPERGLYCEMIA Reduced Incretin Effect

22 Insulin (pmol/l) Glucose (mmol/l) The Incretin Effect 10 iv oral 5 70 % of post-glucose insulin secretion is due to the incretin effects Incretin effect 0 Time

23 INCRETIN HORMONE PHYSIOLOGY Gastric emptying K-cells L-cells Satiety Fullnes s + GIP Glucagon GLP Insulin

24 Degradation of GLP-1 DPP-4 Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1 GLP Des-HA-GLP-1 (inactive) Two possible solutions to utilize GLP-1 action therapeutically: 1) Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics 2) DPP-4 inhibitors / incretin enhancers Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994

25 GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildagliptin Oral agents Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

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27 Adverse effects DPP4 inhibitors Hepatic function Although uncommon, cases of hepatic dysfunction (liver enzyme elevations, hepatitis) have been reported in patients taking vildagliptin and alogliptin., Liver function tests should be evaluated prior to initiation of vildagliptin and alogliptin, and at three-month intervals during the first year of therapy. Skin- In post-marketing reports, sitagliptin, saxagliptin, and alogliptin have been associated with hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome.

28 Cardiovascular effects DPP4 inhibitors In one trial, 16,492 patients with type 2 diabetes and either a history of cardiovascular disease or multiple risk factors for vascular disease were randomly assigned to saxagliptin or placebo, in addition to other diabetes medications. After a median follow-up of two years, the primary endpoint (a composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke) occurred in a similar proportion of patients (7.3 and 7.2 percent in the saxagliptin and placebo groups, respectively Significantly more patients in the saxagliptin group were hospitalized for heart failure, HR 1.27, 95% CI ). N Engl J Med. 2013

29 Pathogenesis of Type 2 Diabetes Multiple defects contribute to the progression of type 2 diabetes mellitus Decreased Incretin Effect Decreased Insulin Secretion Increased Lipolysis Increased Glucagon Secretion Islet-a cell Hyperglycaemia Increased Glucose Reabsorption PHEM/MET/1212/1245 Increased Hepatic Glucose Production Neurotransmitter Dysfunction Decreased Glucose Uptake Adapted from DeFronzo RA. Diabetes. 2009;58:

30 Renal Glucose Reabsorption in the Proximal Tubule Glomerulus Proximal tubule S1 S2 GLUCOSE FILTRATION S3 ~90% Collecting duct GLUCOSE REABSORPTION ~10% NO GLUCOSE Glucose is freely filtered at the glomerulus and is reabsorbed via active transport mechanisms in the proximal convoluted tubule 1 Up to 180 g glucose filtered/24 h 2 PHEM/MET/1212/1245 Adapted from: Bays H. Curr Med Res Opin. 2009;25: Wright EM, et al. J Int Med. 2007;261:32 43.

31 Sodium-Glucose Co-Transporters (SGLTs) SGLT1 SGLT2 Site Intestines and kidney Almost exclusively kidney Sugar specificity Glucose or galactose Glucose Affinity for glucose High K m = 0.4 mm Low K m = 2.0 mm Capacity for glucose transport Low High Role Dietary (intestinal) glucose absorption Renal glucose reabsorption Renal glucose reabsorption PHEM/MET/1212/1245 Lee YJ, et al. Kidney Int Suppl. 2007;72:S27 S35

32 Renal Glucose Transport S1 and S2 Segments of Proximal Renal Tubule SGLT2 accounts for ~ 90% renal glucose reabsorption Tubular lumen Blood Na + SGLT2 Na+ K + Na + K+ Na+ Na + /K + ATPase pump Glucose High capacity Low affinity Glucose Glucose Glucose GLUT2 PHEM/MET/1212/1245 Adapted from: Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34 42 Marsenic O. Am J Kidney Dis. 2009;53:875 83

33 Urinary Glucose Excretion (g/day) The Renal Glucose Threhold (RT G ) is Increased in Subjects with Type 2 Diabetes Below RT G minimal glucosuria occurs Above RT G glucosuria occurs Healthy RT G T2DM RT G 50 ~10 mmol/l ~13.8 mmol/l Plasma Glucose (mmol/l) Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels RTG, renal threshold for glucose excretion. PHEM/MET/1212/1245 Adapted from Polidori D, et al. Diabetologia 2010;53[Suppl1]:S350 [Poster 875]; Sha S, et al. Diabetes Obes Metab 2011;13: ; Devineni D, et al. Diabetes Obes Metab 2012;14:

34 Dapagliflozin Add-on to Insulin Results Summary PHEM/MET/1212/1245 Rohwedder K, et al. Diabetologia 2012:55[Suppl1]:S309 [Poster 753]

35 Dapagliflozin Add-on to Insulin Results Summary PHEM/MET/1212/1245 Rohwedder K, et al. Diabetologia 2012:55[Suppl1]:S309 [Poster 753]

36 SGLT2 Inhibitors Canagliflozin: is taken orally before the first meal of the day. The initial dose is 100 mg once daily, and it can be increased to 300 mg daily. In patients with moderate renal impairment (estimated glomerular filtration rate [egfr] 45 to 59 ml/min), the dose should not exceed 100 mg daily. should not be given to patients with egfr <45 ml/min or in patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment. Dapagliflozin:(10 mg once daily) can be taken any time of day, with or without food. It is not recommended for use in patients with egfr <60 ml/min. For patients with severely reduced liver function, a starting dose of 5 mg is recommended

37 SGLT2 Inhibitors: Overview of Adverse Events Increases in mycotic genital infections; these AEs were generally mild to moderate in severity and led to few study discontinuations Small increase in urinary tract infections, but most infections were mild to moderate, and rarely resulted in discontinuation from treatment Some reports of symptoms attributable to osmotic diuresis No evidence of renal impairment Stenlof K et al. Diabetologia (2012) 55:[Suppl1] S312. [Poster766]; Niskanen L et al. Diabetologia (2012) 55:[Suppl1]S314. [Poster763]; Shernthaner G et al. poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy); 2012; Nov 8-11: Barcelona; Spain. P70; Wilding J et al. Diabetologia (2012) 55:[Suppl1]S315. [Poster766]; Forst T et al. poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy); 2012; Nov 8-11: Barcelona; Spain. P64 ; Matthews D et al. Diabetologia (2012) 55:[Suppl1]S314. [Poster764]; Dapagliflozin; EU Summary of Product Characteristics, December 2012 PHEM/MET/1212/1245

38 SURGICAL TREATMENT OF OBESITY one-year trial, 120 obese patients (BMI 30 to 39.9) with type 2 diabetes (mean duration nine years) who were participating in an intensive lifestyle and medically-managed weight control program were randomly assigned to receive Roux-en-Y gastric bypass surgery while continuing the lifestyle program or to continue the lifestyle program alone After one year, a greater proportion of patients in the gastric bypass group achieved the composite outcome (A1C <7 percent, low-density lipoprotein [LDL] cholesterol <100 mg/dl, and systolic blood pressure less than 130 mmhg, 49 verus 19 percent, odds ratio [OR] 4.8, 95% CI ). The mean percentage weight loss was 26.1 and 7.9 percent, respectively Serious adverse events were more frequent in the gastric bypass group (22 versus 15 events). JAMA. Jun,2013

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46 Multifactorial Interventionon. N Engl J Med 2008;358:

47 HbA 1c, % Earlier Use of Combination Therapy May Improve Treating to Target Compared with Conventional Therapy Diet and OAD exercise monotherapy OAD OAD up-titration combination OAD plus basal insulin OAD plus multiple daily insulin injections 10 9 Mean HbA 1c of patients Time Duration of Diabetes 18

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