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The Influence of Type 2 Diabetes on Cardiovascular Disease and Glycemic Treatment Options Rocky Mountain/ACP Internal Medicine Conference Banff, AB November.

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Presentation on theme: "The Influence of Type 2 Diabetes on Cardiovascular Disease and Glycemic Treatment Options Rocky Mountain/ACP Internal Medicine Conference Banff, AB November."— Presentation transcript:

1 The Influence of Type 2 Diabetes on Cardiovascular Disease and Glycemic Treatment Options Rocky Mountain/ACP Internal Medicine Conference Banff, AB November 22, 2012 David C.W. Lau, MD, PhD, FRCPC Depts. of Medicine, Biochem. & Molec. Biol. Julia McFarlane Diabetes Research Centre University of Calgary

2 Program Faculty Dr. Ronald Goldenberg, MD, FRCPC, FACE Consultant Endocrinologist, North York General Hospital and LMC Endocrinology Centers, Thornhill, Ontario Dr. Mansoor Husain MD, FRCPC Director, Toronto General Hospital Research Institute and Heart and Stroke Richard Lewar Centre for Excellence Senior Scientist, Division of Experimental Therapeutics Professor of Medicine, University of Toronto Dr. David C. W. Lau MD, PhD, FRCPC Professor of Medicine, Biochemistry and Molecular Biology Julia McFarlane Diabetes Research Centre University of Calgary

3 Disclosures: David C. W. Lau Research funding: AHFMR, Alberta Cancer Board, CIHR, AstraZeneca, Boehringer- Ingelheim, BMS, Dainippon, Eli Lilly, Novo Nordisk, Pfizer and sanofi Consultant or advisory board member: Abbott, Allergan, Amgen, AstraZeneca, Bayer, Boehringer- Ingelheim, BMS, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi Speaker bureau: CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, BMS, Eli Lilly, Merck, Novo Nordisk, sanofi Some slides are selected from accredited CHE programs sponsored by Novo Nordisk and AstraZeneca/BMS

4 Objectives At the end of the presentation, the participant will be able to: Understand the cardiovascular burden in diabetes Review the mechanisms of actions of incretin-based therapies for diabetes Compare the cardiovascular effects of incretins and other glucose-lowering agents Review current and ongoing data on incretin-based therapies and cardiovascular disease outcomes

5 Frequency of Diagnosed &Undiagnosed DM and IGT by Age Rising Prevalence of Diabetes Mellitus Adapted from M Harris. Diabetes Care 1993;16:642-52

6 Diabetes is a global disease! Estimated global prevalence of diabetes International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition million 366 million552 million

7 Diabetes Prevalence Rates in Canada, 2008/09 Canada 6.8%, N=2,359,252 Age- and sex-adjusted diabetes prevalence increased by 40% in the next 10 years, from 6.8% in a population to 9.9% or 3.4 million in 2020! Public Health Agency of Canada, Diabetes in Canada. Ottawa, 2011

8 Relative Risks for Fatal CAD in Diabetes Huxley R et al., Br Med J 2006;332:73-78 Pooled RR = 1.7 from 37 studies; Meta-analysis of 22 studies

9 People with DM2 and CVD Derive Less Benefit from Preventive and Interventional Therapies Patients with diabetes treated with antiplatelet treatments continue to have a higher risk of adverse CV events compared with nondiabetic patients 1  Reduced antiplatelet drug responsiveness may play a role in these worse outcomes Diabetes may abolish the beneficial effect of primary percutaneous coronary intervention on long-term risk of reinfarction after acute ST-segment elevation MI 2 1.Angiolillo DJ. Diabetes Care 2009;32: ; 2.Madsen MM, et al. Am J Cardiol 2005;96: CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction

10 Stratton IM, et al. BMJ 2000;321: % A1C reduction 21%reduction21%reduction 14% reduction 14%reduction12%reduction37%reduction 19%reduction43%reduction16%reduction Diabetes-related endpoints Cataract extraction Diabetes-related mortality All-cause mortality Fatal/non-fatal MIFatal/non-fatal strokeMicrovascular endpoints Amputation/death from PVD Heart failure A1C Predicts Cardiovascular Disease: Reduction Has Important Benefits

11 11 Diabetes Increases Mortality Following ACS Donahoe SM, et al. JAMA 2007;298: Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS 7.2% 3.1% 13.2% 8.1% ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; UA/NSTEMI, unstable angina/non- STEMI; TIMI, Thrombolysis in Myocardial Infarction Pooled data from 11 independent clinical 11 TIMI Study group clinical trials (1997–2006) of ACS patients suggest that, despite modern therapies for ACS, diabetes confers a significant adverse prognosis during the first year after an event P<.001

12 Glycemic Control and CVD Events Mean A1C 0.9%  9%  major CV events 15%  fatal/ nonfatal MI No overall effect on stroke, CHF or all-cause mortality Turnbull FM et al. Diabetologia 2009;52:

13 DCCT/EDIC: Glycemic Control Reduces the Risk CV Death, MI, Stroke in Type 1 Diabetes Conventional treatment Intensive treatment *Intensive vs conventional treatment Cumulative incidence of non-fatal MI, stroke or death from CVD Conventional treatment Intensive treatment Years DCCT (intervention period) EDIC (observational follow-up) A1C (%) DCCT (intervention period)EDIC (observational follow-up) Years 1.DCCT. N Engl J Med 1993;329:977–986 2.DCCT/EDIC. JAMA 2002; 287:2563– DCCT/EDIC. N Engl J Med 2005;353:2643–2653 CVD death, MI & Stroke RR 57%  (p = 0.02, 95%CI 12-79%) Legacy effect: Benefit of early aggressive glycemic control on CVD outcomes

14 Treatment goals and targets must be individualized with considerations given to individual risk factors Target 2-3 months for lifestyle management before initiating pharmacotherapy Recommended Targets for Glycemic Control Can J Diabetes 2008;32(Suppl 1):S29-S31 FPG (Fasting Plasma Glucose) 4.0 – 7.0 mmol/L 2-hour PPG (Postprandial glucose) 5.0 – 10.0 mmol/L (5.0 – 8.0 if A1C targets are not being met) A1C ≤ 7.0% Type 1 and Type 2 Diabetes 2008 CDA Clinical Practice Guidelines

15 Initiate metformin Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin ± metformin If not at target Add an agent best suited to the individual: Alpha-glucosidase inhibitor Incretin agent: DPP-4 inhibitor Insulin Insulin secretagogue: Meglitinide, Sulfonylurea TZD Weight loss agent If not at target: Add another drug from a different class; or Add bedtime basal insulin to other agent(s); or Intensify insulin therapy 2008 CDA Clinical Practice Guidelines Clinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity) A1C < 9.0%A1C ≥ 9.0% Symptomatic hyperglycemia with metabolic decompensation 2008 CDA CPGs. Can J Diabetes 2008;32(Suppl 1):S53–S61

16 How do glucose-lowering drugs work?

17 Main Classes of Glucose-Lowering Medications TZD = thiazolidinedione; DPP = dipeptidyl peptidase; GLP = glucagon-like peptide Krentz AJ, Bailey CJ. Drugs 2005;65: SUs and rapid-acting secretagogues (stimulate insulin secretion) Biguanides (reduce hepatic glucose production and intestinal absorption of glucose; increase peripheral glucose uptake) α-glucosidase inhibitors (delay digestion and absorption of intestinal carbohydrate) TZDs (reduce insulin resistance in target tissues) DPP-4 inhibitors (prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release) GLP-1 analogues (increase GLP-1 action, stimulate insulin secretion, suppress glucagon release, decrease appetite, delay gastric emptying) Insulin (improves insulin secretion and peripheral insulin sensitivity)

18 Food intake Stomach GI tract Intestine Increases and prolongs GLP-1 effect on alpha-cells: Alpha-cells Pancreas Insulin release Net effect: Blood glucose Beta-cells Increases and prolongs GLP-1 and GIP effects on beta-cells: DPP-4 inhibitor Glucagon secretion Incretins DPP-4 DPP-4 Inhibitors Enhance Incretin and Insulin Secretion Adapted from: Barnett A. Int J Clin Pract 2006;60: Drucker DJ, Nauck MA. Nature 2006;368: Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

19 GLP-1 receptor agonists improve glucose control through multiple mechanisms Ussher J & Drucker DJ, Endocrine Rev 2012;33:

20 Saxagliptin Canadian Product Monograph, Bristol Myers Squibb/Astra Zeneca, 2009; Sitagliptin Canadian Product Monograph, Merck Frosst, 2010.; Linagliptin Canadian Product Monograph, Boehringher Ingelheim (Canada) Ltd. July 26, 2011.; Liraglutide Canadian Product Monograph, Novo Nordisk Canada, 2011; Exenatide Canadian Product Monograph, Eli Lilly Canada, Drucker DJ, et al. Lancet 2006;368: Slide Courtesy of Novo Nordisk sponsored accredited CHE program GLP-1 analogue: Liraglutide modified human GLP-1 GLP-1 analogue: Liraglutide modified human GLP-1 GLP-1 mimetic: Exenatide modified from Gila monster lizard saliva DPP-4 inhibitors: Linagliptin Saxagliptin Sitagliptin DPP-4 inhibitors: Linagliptin Saxagliptin Sitagliptin Incretin Therapies Currently Available InjectableOral

21 Questions to consider when choosing a glucose-lowering agent What is the efficacy in A1C reduction? What is the glycemic durability? Is the patient at risk for hypoglycemia? Is weight a concern? What are the long-term side-effects? Does the patient have a drug plan? What is your prescribing comfort level? What is your patient’s preference?

22 *p<0.05, **p<0.01, ***p<0.001, ****p< vs. liraglutide 1.8 mg ; Henry RR, et al. Endocr Pract 2011;17(6):907 Diabetes disease progression ≤7.5%>7.5% - 8.0%>8.0% to 8.5%>8.5% to 9.0%>9.0% * ** * * * *** **** Change in A1C from baseline to 26 weeks (%) Exenatide Liraglutide Sitagliptin Glimepiride Rosiglitazone Glargine Glucose Lowering Therapy in Diabetes: A1C Reduction by Baseline A1C

23 Kahn SE et al. N Engl J Med 2006;355: ADOPT: Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years

24 Adverse Outcomes Among Patients with Type 2 Diabetes Experiencing Severe Hypoglycemia 25 No. of adverse outcomes Months from severe hypoglycemia to event –12 13–24 25–36 37–48 Macrovascular event Microvascular event Death from any cause Cardiovascular death Noncardiovascular death Zoungas S, et al. N Engl J Med 2010;363(15):1410–18 The median time from hypoglycemic episode to related adverse event or death was ≤ 1.6 years! N=11,140

25 Estimated Rates of Emergency Hospitalisations for Adverse Drug Events in Older U.S. Adults, 2007–2009 Budnitz DS, et al. N Eng J Med 2011;365: % 11% Emergency Hospitalizations for Adverse Drug Events in Older Americans Oral agents and insulin account for > 25% of hospitalizations in adults > 65 years!

26 Antihyperglycemic Drugs & Risk of Hypoglycemia High Insulin Insulin secretagogues  Sulfonyureas  Meglitinides Low Metformin DPP-4 inhibitors GLP-1 receptor agonists TZDs Acarbose Orlistat

27 Garber A et al. Lancet 2009;374: (LEAD-3); Marre M et al. Diabet Med 2009;26:268–78 (LEAD-1); Nauck M et al. Diabetes Care 2009;32:84–90 (LEAD-2); Zinman B et al. Diabetes Care 2009; 32: (LEAD-4); Russell-Jones Det al. Diabetologia 2009;52: (LEAD-5); Buse J et al. Lancet 2009;374:39-47 (LEAD-6); Pratley R et al. Lancet 2010;375: (Lira vs. sitagliptin) LEAD 3 Liraglutide monotherapy vs SU Diet/exercise Met: metformin SU: sulfonylurea TZD: thiazolidinedione +1 OAD +2 OAD +3 OAD or +2 OAD, Insulin +3 OAD or +2 OAD, Insulin LEAD 2 Liraglutide+Met vs SU+Met LEAD 1 Liraglutide+SU vs TZD+SU LEAD 6 Liraglutide+met/SU/both vs exenatide+met/SU/both LEAD 4 Liraglutide+met&TZD vs placebo+met&TZD LEAD 5 Liraglutide+Met&SU vs glargine+Met&SU Type 2 diabetes treatment continuum Liraglutide Effect and Action in Diabetes (LEAD) Clinical Trials Liraglutide+Met vs sitagliptin+Met

28 Garber A et al, Lancet 2009;373:473–81 (LEAD-3); Nauck M et al, Diabetes Care 2009;32:84-90 (LEAD 2); Marre M et al. Diabetic Med 2009;26: (LEAD 1); Zinman B et al. Diabetes Care 2009;32: (LEAD 4); Russell-Jones D et al. Diabetes 2009;52: (LEAD 5); Buse J et al. Lancet 2009;374:39-47 (LEAD 6); Pratley R et al. Lancet 2010;375: *significant vs. comparator LEAD Program: A1C Lowering with Liraglutide

29 Weight Reduction with Liraglutide in People with Type 2 Diabetes Change in body weight (kg) % 43% Exenatide -2.9 Placebo Glimepiride Rosiglitazone Glargine Glimepiride Liraglutide 1.8 mg *Significant vs. comparator * * * * * * * * Liraglutide 1.2 mg * Sitagliptin * * LEAD 1 SU combination LEAD 2 Met combination LEAD 4 Met + TZD LEAD 5 Met + SU combination LEAD 3 Monotherapy LEAD 6 Met ± SU combination Met combination (Lira vs sita) Marre M et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck M et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber A et al. Lancet 2009;373:473–81 (LEAD-3); Zinman B et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones D et al. Diabetologia 2009;52: (LEAD-5); Buse J et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Pratley R et al. Lancet 2010;375: (Lira vs sitagliptin)

30 Exenatide: 3 AMIGOS Trials A1C changes After 30 weeks Change in A1C (%) Placebo BID -0.4 * -0.8 * Add-on to MET 1 (n=336) 1. DeFronzo et al. Diabetes Care 2005 ITT population; Mean (SE); *p < 0.05 vs. placebo Baseline 8.2% Exenatide 5 µg BID Add-on to SU 2 (n=377) * * -0.9 Baseline 8.6% 2. Buse et al. Diabetes Care 2004 Exenatide 10 µg BID Add-on to MET+SU 3 (n=733) * * -0.8 Baseline 8.5% 3. Kendall et al. Diabetes Care 2005

31 Add-on to MET (n=336) * * ** -3.5 * Change in weight (kg) Time (weeks) ITT population; Mean (SE); *p<0.05 vs. placebo; * *p<0.001 vs. placebo Exenatide: 3 AMIGOS Trials Weight changes After 30 weeks 1. DeFronzo et al. Diabetes Care 2005 Add-on to SU (n=377) * Time (weeks) 2. Buse et al. Diabetes Care 2004 Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID Add-on to MET+SU (n=733) * * * * * * Time (weeks) 3. Kendall et al. Diabetes Care 2005

32 Changes in A1C and Body Weight: Liraglutide, Exenatide and Sitagliptin = LEAD-6 = Lira-DPP-4 Adapted from Niswender K et al, Diab Obes Metab 2012 doi: /j x

33 Glucose-lowering Drugs and CVD Risk

34 SUs May Increase CV Risk in Patients with T2DM: 34 In a meta‐analysis of 20 observational studies representing 1,311,090 patients (median follow-up, 4.6 years), SUs were associated with a significantly increased risk of CV death and of a composite CV events compared with other oral diabetes drugs Phung OJ, et al. Diabetes 2012;61:Suppl 1A. Abstract 2-LB n = the total number of comparisons for that analysis; one study may contribute more than one comparison to the analysis CV composite = MI, stroke, CV-related hospitalization, or CV death

35 SUs May Increase Mortality and CV Risk versus Metformin 35 In a Danish study (n=107,806), monotherapy with glimepiride, glibenclamide, glipizide, and tolbutamide was associated with significantly increased all- cause mortality vs metformin in patients with and without previous MI Results were similar for CV mortality and the composite CV end point Schramm TK, et al. Eur Heart J. 2011;32: Hazard Ratio (95% confidence interval) No Previous MIPrevious MI Risk for All-Cause Mortality

36 Increased Mortality with Sulfonylureas in Patients with DM2 May Be Dose-related In a retrospective cohort Canadian study of patients with newly diagnosed DM2 (n=12,272), first- or second-generation sulfonylurea monotherapy was associated with increased mortality in a dose-related manner Simpson SH, et al. CMAJ 2006;174: All-cause Mortality a a Either chlorpropamide or tolbutamide

37 Holman RR, et al. N Engl J Med 2008;359: UKPDS 10-year Follow-up: Kaplan-Meier Curves for Outcomes Legacy effect; benefit of early aggressive glycemic control on CVD outcomes Holman RR, et al. N Engl J Med 2008;359: Ins-SU End-pt 9% MI 15% Micro 24% Death 13% Met End-pt 21% MI 33% Micro NS Death 27%

38 Cardioprotective Effects of GLP-1 GLP-1 improves cardiac function in heart failure 1,2 GLP-1 increases myocardial glucose uptake 3 GLP-1 improves functional recovery following myocardial ischemia 4-6 Incretins reduce infarct size 7-9 GLP-1 improves endothelium dysfunction 10,11 1 Nikolaidis et al. Circulation 2004;110:955–61 2 Poornima I et al. Circ Heart Fail. 2008;1: Zhao et al. J Pharmacol Exp Ther 2006;317:1106–13 4 Nikolaidis et al. J. Pharm Exp Ther 2005;312:303 5 Nikolaidis et al. Circulation 2004;109:962 6 Ban et al. Circulation 2008;117: Bose A et al. Diabetes 2005;54:146 8 Noyan-Ashraf et al. Diabetes 2009;58:975 9 Sauve et al. Diabetes 2010;59:1063–73 10 Basu et al. Am J Physiol Endocrinol Metab 2007;293:E1289–95 11 Nyström et al. Am J Physiol Endocrinol Metab 2004;287:E1209–15

39 Cardioprotective Effects of Incretins in People with Type 2 Diabetes Increased GLP-1 may improve endothelial function and peripheral vascular tone in DM2 GLP-1 improves myocardial performance in heart failure and myocardial survival in ischemic heart disease GLP-1 reduces infarct size and may have anti-atherogenic effects Increased SDF1-α leading to a greater number of circulating EPCs and cardiac repair Increased NO, which improves endothelial function Antithrombotic effects and reduced levels of markers of inflammation Increased BNP may exert beneficial CV effects in heart failure 39

40 GLP-1 Actions on the Heart: Direct or Indirect? Ussher J, Drucker DJ, Endocrine Rev Apr;33(2):

41 GLP-1 Receptor Agonists Reduce BP LEAD 6 Systolic blood pressure: Liraglutide vs. Exenatide Buse J et al. Lancet 2009;374:39–47

42 n=60 per group Liraglutide 200 µg/kgPlaceboSham operation Survival (%) Days Overall survivalDeath due to cardiac rupture Dead mice (n) Liraglutide 75 µg/kg Pre-treatment with Liraglutide Improves Survival Following MI Noyan-Ashraf et al. Diabetes 2009;58:975–83. MI, myocardial infarction

43 Liraglutide Placebo Arrows represent extent of infarct Pre-treatment with Liraglutide Reduces Infarct Size Noyan-Ashraf et al. Diabetes 2009;58:975–83 Infarct (%) P < 0.05

44 GLP-1 Reduced Infarct Size in Isolated Rat Hearts 44 a P < vs control PC, ischemic pre-conditioning; VP, valine pyrrolidide (inhibitor of GLP-1 breakdown) Infarct Within the Risk Zone, I/R% ControlPCVP Before Ischaemia GLP-1/VP as a PC Mimetic VP at Reperfusion a GLP-1/VP at Reperfusion a a Bose AK et al. Cardiovasc Drugs Ther 2005;19:9-11

45 3-month GLP-1 Treatment Prolongs 12-month Survival In SHHF Rats Poornima I et al. Circ Heart Fail. 2008;1: Weeks of Treatment 45

46 Mechanisms Underlying Potential CV Benefits of DPP-4 Inhibitors Fadini and Avogaro Vasc Pharmacol 2011

47 Mice Lacking DPP-4 Have Improved Outcomes After Experimental MI Sauve et al. Diabetes 2010;59:1063–73 * Days post-MI Survival (%) 50 Dpp4 +/+ and -/- sham (n=26) Dpp4 -/- LAD (n=31) Dpp4 +/+ LAD (n=26) DPP-4 +/+ and DPP-4 -/- mice Normal chow diet (7% fat) Age (weeks) LAD ligationEndpoint: infarct size Infarct (%) 0 (n=10) Dpp4 genotype +/+-/- *p < 0.05 MI, myocardial infarction; LAD, left anterior descending artery

48 Rieg T et al. Am J Physiol Renal Physiol 2012;303(7):F963-71*P<0.05 vs. vehicle. n=5–6 per group WT Mice Urinary flow rate (µl/min/g) * Urinary flow rate (nmol/min/g) 40 NaKCl * VehicleExendin GLP-1r -/- Mice Urinary flow rate (µ/min/g) Urinary flow rate (nmol/min/g) 40 NaKCl VehicleExendin Urinary flow rate (µl/min/g) * Urinary flow rate (nmol/min/g) NaKCl * * VehicleAlogliptin Urinary flow rate (µl/min/g) * Urinary flow rate (nmol/min/g) NaKCl * VehicleAlogliptin Effects of GLP-1 RA and DPP-4i on Mouse Renal Function

49 Diabetic Mice with Pharmacological Inhibition of DPP-4 Have Increased Expression of Cardioprotective Proteins Sauve et al. Diabetes 2010;59:1063–73 0 Relative units HFD/STZSitagliptin MetforminLiraglutide HFD/STZSitagliptinMetforminLiraglutide p-AKT HSP90 p-AKT *** * 20 *P < 0.05 ***P < HFD, high-fat diet; STZ, streptozotocin; p-AKT, phosphorylated cell survival kinase

50 Downregulation of BNP Gene Expression Following DPP-4 Inhibition in Rats 50 Chaykovska L, et al. PLoS One 2011;6(11):e27861 Results suggest that DPP-4 inhibition leads to:  cardiac myocyte stress Improved cardiac function TGF , TIMP, Col1α1 and Col3α1 are markers of fibrosis *P<0.05; **P<0.001

51 Effects of DM2 on Endothelial Progenitor Cells (EPCs) The quantity and function of EPCs are diminished in patients with type 2 diabetes 1,2  EPCs play an important role in cardiac tissue repair following ischemic events 3 Preclinical data in animals show the homing of EPCs to sites of vascular injury is impaired in diabetes 4 In patients with ischemic heart disease, there are a decreased number of bone marrow-derived circulating progenitor cells with further reductions in those with diabetes Hill JM, et al. N Engl J Med 2003;348: Tepper OM, et al. Circulation 2002;106(22): Zaruba M-M, et al. Cell Stem Cell 2009;4: Li M, et al. Circ Res Mar 17;98: Bozdag-Turan I, et al. Cardiovasc Diabetol 2011;10(1):107

52 Mobilisation with G-CSF Treatment Ischemic myocardiumBone Marrow Release of SDF-1 CXCR + Stem cells SDF-1 CXCR4 DPP-4 (CD26) N-terminal Cleavage: Diminished Homing DPP-4 (CD26) Inhibition SDF-1 CXCR4 Prevention of Cleavage- Enhanced Homing Enhanced Homing by CD26 Inhibition CXCR, chemokine receptor G-CSF, granulocyte colony-stimulating factor SDF-1, stromal cell-derived factor 52 Mechanism for DPP-4 Inhibition and SDF-1- mediated Improvements in Cardiac Function Zaruba M-M, et al. Cell Stem Cell 2009;4:

53 Risk ratio for major CV events Ratner R, et al. Cardiovascular Diabetology. 2011;10:22; 2. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; 3. Accessed Sept. 23, 2011; 4. Frederich R, et al. Postgrad Med. 2010;122(3):16–27; 16–27; 5. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7 Total patients in analysis CV composite endpoint Comments Incretin agent betterComparator better MedDRA terms for MACE Post-hoc/ No formal adjudication Sitagliptin MI, stroke, CV death Post-hoc/ Independent adjudication Saxagliptin No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors or GLP-1R agonists Exenatide MedDRA terms for Stroke, MI, cardiac mortality, ACS, revascularization Post-hoc/ No formal adjudication 1.8 Liraglutide Post-hoc/ No formal adjudication MedDRA terms for MACE CV death, MI, stroke, hospitalisation due to angina pectoris Pre-specified/ independent adjudication Linagliptin ,945 5,239 6,638 4,607 10,246 FDA Upper Bound 95% Criterion for Approvability CV Meta-analyses of Individual Incretin Agents

54 1. Golden SH. Am J Cardiol 2011;108 (Suppl):59B-67B 2. Fonseca V. Am J Cardiol 2011;108 (supp):52B–58Bl 3. Clinicaltrials.gov TherapiesNPopulationEndpointsResults TECOSSitagliptin/ Placebo 14,000Established CVDCV death, NF MI or CVA, unstable angina hospital. Dec 2014 SAVOR-TIMI 53Saxagliptin/ Placebo 16,500 3 CVD or ≥ 2 RFCV death, NF MI or ischemic stroke June 2014 CAROLINALinagliptin/ Glimepiride 6000CVD or ≥ 2 RFCV death, NF MI or CVA, unstable angina hospital. Sept 2018 LEADERLiraglutide/ Placebo 8754 CVD, PAD, CKD, CHF or RF if > 60yrs CV death, NF MI or stroke, revasc Jan 2016 EXSCELExenatide LAR/Placebo 9500Not specified CV death, NF MI or stroke Mar 2017 Ongoing Cardiovascular Outcome Trials: DPP-4 Inhibitors and GLP-1 Agonists

55 Diabetes Cardiovascular Outcomes Trials recruitment 11/09 canagliflozin (CANVAS) 3/13 completion recruitment 9/09 alogliptin (EXAMINE) 5/14 completion recruitment 5/10 Aleglitazar (ALECARDIO) 11/14 completion 9/03 Glargine (Lantus) (ORIGIN) 12/12 completion 7/14 completion Acarbose (GlucoBay) (ACE) recruitment 2/09 recruitment 5/10 Saxagliptin (Onglyza) (SAVOR-TIMI 53) 4/14 completion insulin SGLT2 GLP1 DPP4 AGI PPAR recruitment 3/10 Exenatide (Byetta) (EXSCEL) 3/17 completion recruitment 12/08 Sitagliptin (Januvia) (TECOS) 12/14 completion Empagliflozin recruitment 12/10 7/18 completion 1/16 completionrecruitment 8/10 Liraglutide (Victoza) (LEADER) 10/13 completionrecruitment 6/10 lixisenatide (ELIXA) recruitment 10/10 linagliptin (Trajenta) (CAROLINA) 9/18 completion N=12,500 N=4,500* N=6,000 N=7,000 N=5,400 N=7,500 N=6,000 N=14,000 N=16,500 N=8,754 N=12,000 N=6,000 Assessed likely to deliver benefit

56 Diabetes and Atherosclerosis

57 CVD Management in Diabetes Benefits of multiple CVD risk factor management on CVD outcomes

58 Steno 2: Effects on Combined CV Outcomes Gaede P, et al, NEJM 2003;348(5): P = Conventional therapy Intensive therapy Months of Follow-up No. at Risk Conventional Intensive Rx 20% absolute RR RRR 53%

59 CV Outcomes: Number Needed to Treat (NNT) NNT = 1/absolute risk reduction (AAR) AAR = Event rate (control) – event rate (treatment) Microvascular complications  UKPDS (  blood glucose)39.2  UKPDS (  blood pressure)12.2  Steno (  BG, BP, lipid and UAE) 5 Major CHD  HOT study16  4S study 5  CARE study12 Screening for breast cancer1000 Gaede P et al. N Engl J Med 2003;348:

60 Intensive Therapy Conventional Therapy Number of Cardiovascular Events Amputation Revascularization Percutaneus Coronary Intervention Myocardial Infarction Stroke Death from Cardiovascular Causes Coronary Artery Bypass Graft Gaede P, et al. N Engl J Med 2003;358:580−591 STENO-2: Dramatic  in Cardiovascular Events

61 Intensive Therapy Conventional Therapy BP Value at 7.8 Years FPG (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Systolic BP (mm Hg) Diastolic BP (mm Hg) A1C 7.9% A1C 9.0% P <.01 Gaede P, et al. N Engl J Med 2008;358:580−591 BP = blood pressure; FPG = fasting plasma glucose; A1C = Hemoglobin A1C; HDL-C = high-density lipoprotein; LDL-C = low-density lipoprotein STENO-2: Fasting Glucose, LDL-C, and BP at 7.8 Years With Intensive Treatment

62 Gaede P, et al. N Engl J Med 2008;358: STENO-2 13-year Follow-up: Kaplan-Meier Curves of the Risk of Death and CV Events Absolute RR 20% All cause mortality 46%  CVD mortality 57% 

63 Global CVD Risk Reduction in Diabetes CVD risk estimates in diabetes should be patient-centred and not disease-based: 1.Identify individual CVD risk factors 2.Consider all risk factors in estimating particular patient’s CVD risk 3.Appropriate therapies should be evidence-based 4.Integrate all therapies to optimize best management for global CVD risk reduction Gerstein HC Diabetologia 2011;54:230–232

64 Guidelines on Vascular Protection: Summary of Diabetes Management Achieve healthy weight and exercise regularly Treat to glycemic target  BG 4-10 mmol/L  A1C ≤ 7%, ≤ 6.5% to reduce nephropathy in DM2  Regular surveillance for complications Treat lipid and BP to goal targets:  LDL-C ≤ 2.0 mmol/L or 50% reduction, or ApoB < 0.8g/L  TC/HDL-C ratio < 4  BP < 130/80 mmHg ACE inhibition (ACEi or ARB) for vascular protection ECASA in patients with stable CAD Smoking cessation and moderate alcohol intake Can J Diabetes 2008;32(Suppl 1):S102-S118

65 Initiate metformin Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or insulin Initiate insulin ± metformin If not at target Add an agent best suited to the individual: Alpha-glucosidase inhibitor Incretin agent: DPP-4 inhibitor/GLP-1 receptor agonist Insulin Insulin secretagogue: Meglitinide, Sulfonylurea TZD Weight loss agent If not at target: Add another drug from a different class; or Add bedtime basal insulin to other agent(s); or Intensify insulin therapy 2013 CDA Clinical Practice Guidelines Clinical Assessment - Lifestyle intervention (Nutrition therapy and physical activity) A1C < 8.5%A1C ≥ 8.5% Symptomatic hyperglycemia with metabolic decompensation 2013 CDA draft CPGs. Can J Diabetes 2013

66 Summary Glycemic control reduces macro- and microvascular complications of both type 1 and type 2 diabetes In choosing antihyperglycemic agents, select drugs that do not cause hypoglycemia, as severe hypoglycemia is associated with adverse CV outcomes Metformin and incretins (DPP-4 inhibitors and GLP-1 receptor agonists) are associated with lower CV risk Sulfonylureas and TZDs are associated with increased CV risk Definitive CV effects of antihyperglycemic agents in DM2 will await the results of ongoing CV trials

67 “Superior Doctors Prevent the Disease. Mediocre Doctors Treat the Disease Before Evident. Inferior Doctors Treat the Full Blown Disease.” Huang Dee, 2600 B.C. In Nai Ching, 1 st Chinese Medical Text

68 Thank you Questions?


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