DIABETES IN 2007 What snew

DIABETES IN 2007 What snew 1 Objectives 1. Review recently published clinical trials in diabetes What does this mean to us? 1. Discuss novel concepts in the treatment of diabetes What should we expect? 2. Introduce future directions in diabetes prevention and management What does the crystal ball hold? 2 1

News in 2007 Diabetes in Canada Prevention Treatment Guideline update Novel Concept Future Directions 3 4 2

Glycemic Control in Canada One in two type 2 diabetes patients did not reach target A1C ( 7%) Uncontrolled A1C 49% Controlled A1C 51% Harris SB, et al. Diabetes Res Clin Prac 2005;70:90-97. Most recent A1C test results (n=2337) 5 Proportion of patients with A1C > 7.0 increases with duration of type 2 diabetes 53% 42% 31% 67% 62% Years T2DM Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease 6 on Morbid Load. >2 3-5 6-9 10-14 15+ 3

Glycemic Management: Drug Class Metformin 61% Sulfonylureas net 48% TZDs net 15% Other oral agents net 4% Insulin Lifestyle only 12% 15% 0 20 40 60 80 100 Patients currently taking medication (%) Despite suboptimal control, only 12% of patients were receiving insulin Harris SB, et al. Diabetes Res Clin Prac 2005;70:90-97. 7 So what does this trial tell us? 1) Current treatment practices are not aggressive enough to manage a substantial proportion of patients. 2) Physicians appear to know the diabetes guidelines, but are not putting them into practice = clinical inertia. 3) They need help with implementing the guidelines, ie, patient/physician-based programs. 8 4

We need to provide sufficient support for physicians so that they can offer patients the intensive care that they require. Dr. Stewart Harris, University of Western Ontario. 9 DREAM Diabetes REduction Assessment with ramipril and rosiglitazone Medication 10 5

The DREAM Trial Aims: Design: Sample: Pts: Outcome: Does ramipril 15 mg/d prevent diabetes? Does rosiglitazone 8 mg/d prevent diabetes? 2 X 2 factorial, double-blind RCT Age 30+; IGT (FPG <7 & 2 hr 7.8-11) &/or IFG (FPG 6.1-6.9) 5269 in 191 sites, 21 countries, & F/U 3 yrs Incident DM (confirmed FPG > 7 or 2 hr > 11.1; or MD diagnosis) or death* *because undiagnosed diabetes may be more frequent in those who die 11 than in those who do not Screening & Randomization Screened 24592 Excluded: 539 Run-in 5808 Randomized 5269 Excluded: 18784 Glucose or Primary Outcome Status in 94% at study end Vital Status in 98% 12 6

Summary & Conclusions: Ramipril Modestly improves glycemic status in IFG/IGT A nonsignificant 9% DM reduction Significant 16% increase in regression to normal glucose levels by at least 2 yrs Reduced 2 hr glucose by 0.3 mm by study end Significantly reduces BP in IGT / IFG Small, favourable effect on liver function 13 Summary & Conclusions: Ramipril Meta Analysis showed approximately 14% reduction with ACE inhibitor The DREAM results provide the best estimate of the effect of ACE-Is on diabetes prevention in people with IFG / IGT & no previous CV disease Ramipril cannot currently be recommended for DM prevention However, in people in whom there is an indication for ACE inhibitors (high BP, CHF, vascular disease, high risk DM) the favourable effects on glucose may be of added benefit 14 7

Summary & Conclusions: Rosiglitazone A dose of 8 mg/day reduces new DM by > 60% in people with IGT or IFG Promotes regression to normal FPG & 2 hr PG by >70% Effective in all regions of the world Eliminates the gradient of DM risk with increasing weight ~ 3% increase in body weight, but a favourable effect on waist/hip ratio Reduces ALT 15 Summary & Conclusions: Rosiglitazone Modestly lowers systolic BP & diastolic BP Increases the risk of CHF Too few events to draw any conclusions re the effect on other CV events or death For every 1000 people treated with rosiglitazone for ~ 3 years, 144 cases of DM will be prevented with an excess of ~ 4 cases of CHF 16 8

Conclusions of the DREAM Trial Rosiglitazone has a substantial benefit on prevention of diabetes & regression to normoglycaemia Ramipril has a modest benefit on regression to normoglycaemia The durability of the glycaemic effect of these drugs was assess in a washout phase. But will this dramatically change how we prevent diabetes??? 17 Intervention studies for diabetes prevention Study Da Qing IGT and Diabetes Study (N = 577) Finnish Diabetes Prevention Study (N = 522) Diabetes Prevention Program Study (N = 3234) TRIPOD (N = 266) STOP-NIDDM (N = 1418) XENDOS (N = 3305) Indian Diabetes Prevention Program (N = 531) Intervention Diet Physical exercise Diet and physical exercise Diet and physical exercise Lifestyle intervention Metformin Troglitazone* Troglitazone* Acarbose Orlistat Lifestyle intervention Metformin Metformin and lifestyle RR (%) 31 46 42 58 58 31 75 55 25 37 28.5 26.4 28.2 * Troglitazone is no longer available Pan XR, et al. Diabetes Care 1997; Tuomilehto J, et al. N Engl J Med 2001; Knowler WC, et al. N Engl J Med18 2002, 2004; Buchanan TA, et al. Diabetes 2002;51:2796 2803; Ramachandran A. 4th World Congress on Prevention of Diabetes and its Complications, Chennai Feb 2005; Chiasson JL, et al. Lancet 2002; Torgerson JS, et al. Diabetes Care 2004. 9

A Diabetes Outcomes Progression Trial An international, long-term, double-masked, randomised clinical trial to evaluate whether the thiazolidinedione rosiglitazone provides more durable and safe glycaemic control than the biguanide metformin or the sulphonylurea glyburide (glibenclamide) 19 2000 2001 ADOPT Timeline START: 28 February 10 April: 1st patient randomised 2002 2003 28 June: Recruitment completed 27 February: All baseline data in house 2004 2005 2006 FINISH: 13 June 20 10

Run-In 4 weeks ADOPT Design Treatment Period 4 to 6 years Rosiglitazone (N =1456) Diet/exercise reinforcement Metformin (N = 1454) Glyburide (N = 1441) Clinic visits every 2 months for 1 yr, then every 3 months Randomisation Study end 21 Primary Outcome: Monotherapy Failure FPG >10 mmol/l OR.Administrative withdrawal Secondary Outcomes Confirmed FPG >7.8 mmol/l Remaining on monotherapy with HbA1c <7% Longitudinal collection of glycaemic measures, anthropometrics, insulin sensitivity and beta-cell function 22 11

Cumulative Incidence of Monotherapy Failure (FPG >10 mmol/l) 40 30 Rosiglitazone vs Metformin 32% risk reduction, P<0.001 Rosiglitazone vs Glyburide 63% risk reduction, P<0.001 Glyburide Percent 20 10 Metformin Rosiglitazone Patients at Risk Rosiglitazone Metformin Glyburide 0 0 1 2 3 4 5 Time (years) 1393 1397 1337 1207 1205 1114 1078 1076 958 957 950 781 844 818 617 324 311 218 23 Cumulative Incidence of FPG >7.8 mmol/l Among Patients with Baseline FPG 7.8 mol/l 40 30 Rosiglitazone vs Metformin 36% risk reduction, P=0.002 Rosiglitazone vs Glyburide 62% risk reduction, P<0.001 Glyburide Percent 20 10 Metformin Rosiglitazone Patients at Risk Rosiglitazone Metformin Glyburide 0 0 1 2 3 4 5 Time (years) 511 520 480 445 456 412 393 403 343 351 348 264 295 296 200 107 112 63 24 12

8.0 7.5 HbA1c Over Time Rosiglitazone vs Metformin 0.13 ( 0.22 to 0.05), P=0.002 Rosiglitazone vs Glyburide 0.42 ( 0.50 to 0.33), P<0.001 Glyburide Metformin % 7.0 Rosiglitazone 6.5 6.0 0 0 1 2 3 4 5 Time (years) 25 Durability of Glycaemic Control: Time to Mean HbA 1c >7% Glyburide 33 Metformin 45 Rosiglitazone 60 0 20 40 60 Months 26 13

Adverse Events Rosiglitazone was associated with weight gain and oedema, and in women, fractures Metformin was associated with adverse gastrointestinal events Glyburide was associated with hypoglycaemia and weight gain Rosiglitazone and metformin had a similar risk of cardiovascular events. Glyburide had a lower risk of cardiovascular events than rosiglitazone 27 Limitation The proportion of patients who withdrew from the study was high Rosiglitazone 37% Metformin 38% Glyburide 44% But The characteristics of patients who withdrew were similar among groups Sensitivity analyses showed that withdrawals did not appear to bias efficacy results 28 14

Clinical Implications The progressive hyperglycaemia of type 2 diabetes can be slowed Rosiglitazone was most effective, probably due to its positive effects on both insulin sensitivity and beta-cell function Use of rosiglitazone early in the course of the disease is preferable to the use of glyburide Use of rosiglitazone as initial monotherapy in type 2 diabetes requires a full appreciation of its efficacy, adverse event profile and cost 29 DYSLIPIDEMIA GUIDELINES 2006 Achieving an LDL-C of <=2.0 mmol/l is the primary goal of therapy. Once the LDL-C goal has been attained, consideration to achieving the secondary target of an TC/HDL-C ratio of <4.0. The vast majority of patients with be able to attain the LDL-C goal on statin therapy. Although not formal goals of therapy, optimal TG is <1.5 mmol/l and apo B is 0.9 g/l Lifestyle modification should be seen as an important adjunct to, not substitution for, pharmacologic therapy. CDA CPG Expert Committee. Can J Diabetes. 2006;30:230-240 30 15

DYSLIPIDEMIA Effective risk reduction requires a multifaceted approach targeting all risk factors: -Obesity - Hypertension - Hyperglycemia - Dsylipidemia - Microalbuminuria -Smoking - Sedentary lifestyle -Diet CDA CPG Expert Committee. Can J Diabetes. 2006;30:230-240 31 Action to Control the Cardiovascular Risk Of Diabetes-ACCORD TRIAL Designed to test the effects on major CVD events of: intensive glycemia control treatment to increase HDLcholesterol and lower triglycerides (in the context of good LDL-C and glycemia control) of intensive blood pressure control (in the context of good glycemia control). 32 16

ACCORD Treatment goals: Glycemia intensive HbA1c <6%; - conventional target 7.5% Blood pressure intensive systolic < 120 - conventional systolic < 140 Lipids LDL C blinded but < 3.10 On either Zocor and Fibrate/Placebo in a double blind fashion Substudies MIND EYE GENETICS BONE 33 EDIC EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS Long term follow-up of DCCT 10 years and going A1C similar in both groups Microvascular disease still decreased in intensive group Cardiovascular disease 37% reduction in intensive versus conventional Glucose markers and mechanism more to come 34 17

DYSLIPIDEMIA RECOMMENDATIONS Most adults with type 1 or type 2 diabetes should be considered at high risk for vascular disease [Grade A, Level 1, Level 2]. The exceptions are younger adults with shorter duration of disease and without complications of diabetes (including established CVD) and without other CVD risk factors [Grade A, Level 1]. A computerized risk engine (e.g. UKPDS risk engine, Cardiovascular Life Expectancy Model) can be used to estimate vascular risk [Grade D, Consensus]. CDA CPG Expert Committee. Can J Diabetes. 2006;30:230-240 35 DYSLIPIDEMIA RECOMMENDATIONS In adults with serum TG >10.0 mmol/l despite best efforts at optimal glycemic control and other lifestyle interventions (e.g. weight loss, restriction of refined carbohydrates and alcohol), a fibrate should be prescribed to reduce the risk of pancreatitis [Grade D, Consensus]. For those with moderate hyper-tg (4.5 to 10.0 mmol/l), either a statin or fibrate can be attempted as first-line therapy, with the addition of a second lipid-lowering agent of a different class if target lipid levels are not achieved after 4 to 6 months on monotherapy [Grade D, Consensus]. CDA CPG Expert Committee. Can J Diabetes. 2006;30:230-240 36 18

New Guidelines: March - 08 37 WHAT SHOULD WE EXPECT IN 2007? 38 19

INCRETINS Gut peptides GLP-1(glucagon-like peptide-1) GIP (glucose dependent insulinotropic peptide or gastric inhibitory polypeptide) Incretins secreted from the gut during CHO absorption and increase insulin secretion Both are rapidly inactivated in the circulation by DPPIV (dipeptidyl peptidase IV) Incretin stimulation is thought to account for 30-60% of post prandial insulin release Insulintropic effects of both are dependent on blood glucose level being elevated above basal level So working on GLP1 and DPPIV 39 Synthesis and Secretion of GLP-1 and GIP L-Cell (ileum+ colon) Proglucagon K-Cell (jejunum) ProGIP GLP-1 [7-37] GIP [1-42] GLP-1 [7-36NH 2 ] 40 20

Overlapping and Contrasting Actions of GLP-1 and GIP GLP-1 Released from L cells in ileum and colon Stimulates insulin release from β-cell Potent inhibition of gastric emptying Potent inhibition of glucagon secretion Reduction of food intake and body weight Significant effects on β-cell growth and survival Insulinotropic actions preserved in type 2 diabetes Drucker DJ. Diabetes Care. 2003;26:2929 2940. GIP Released from K cells in duodenum Stimulates insulin release from β-cell Modest effects on gastric emptying No significant inhibition of glucagon secretion No significant effects on satiety or body weight Potential effects on β-cell growth and survival Defective insulinotropic action in type 2 diabetes 41 Summary of Incretin Actions on Different Target Tissues Brain Neuroprotection Appetite Stomach Heart Gastric emptying Liver Cardioprotection Cardiac output Glucose production Drucker D. J. Cell Metabolism 2006 Insulin sensitivity Muscle GLP-1 GI tract Insulin secretion Glucagon secretion Insulin biosynthesis β cell proliferation β cell apoptosis 42 21

Incretin Secretion and DPP-4 Mediated Inactivation Mixed Meal Intestinal GIP Release Intestinal GLP-1 Release GIP (1-42) Active Decreased gastric emptying, food intake and glucagon secretion GLP-1 (7-36) Active DPP-4 t 1/2 = 1 to 2 min Increased insulin secretion Enhanced β-cell proliferation Reduced β-cell apoptosis Reduced glucagon secretion (GLP-1) Drucker DJ. Diabetes Care 2003;26:2929-2940. DPP-4i GLP-1 (9-36) Inactive (> 80% of pool) 43 Differentiation vs. other therapies Inhibition of DPP-IV: different to: Novel mode of action (Combined Insulin Secretion and Sensitization) Effects on GLP-1 and GIP GLP-1 analogues Potential for Beta Cell Protection Very low risk of hypoglycemia SU, insulin 2 safeguards:- meal dependant insulin secretion -plasma glucose dependent insulin secretion No safety restrictions (contraindications e.g. renal, CHF) BW: at least no BW gain PPAR, metformin PPAR, insulin, SU 44 22

Non-Insulin Injectables What is up with that. 45 GLP-1 Exenatide (Byetta) approved in the US SC injection once daily Others in development NN and sa Naturally occuring GLP-1 feeds back from gut to pancreas to increase insulin production in response to food Nausea weight loss decreased GI motility decreased glucose excursions Type 2 diabetes 46 23

AMYLIN Amylin is a hormone?? secreted by the pancreas Secreted with insulin and glucagon Deficient in diabetes (likely both) Reduces gastric motility and thereby reducing glucose excursion Available in US as Symlin NAUSEA +++ Weight loss Can mix with insulin Dose with each meal Place in the tool box yet to be determined 47 Alternative Delivery Inhaled insulin Pfizer FDA Approved Being worked on by Eli Lilly Novo Nordisk MANKIND 48 24

Glucose Infusion Rate (mg/kg/min) 12 10 8 6 4 Time-Action Profile Glucose Infusion Rate Inhaled Insulin* Insulin Lispro Regular Insulin 2 0 0 60 120 180 240 300 360 420 480 540 600 Time (min) Heise T. et al. Diabetes 2000;49(Suppl 1):A10 49 Inhaled Insulin What do we tell our patients? replaces short-acting insulin injections at meals in Type I diabetes: still requires longer-acting insulin injections by needle to supply basal insulin needs at present has been approved and marketed in US Canadian approval pending early results indicate similar sugar control to conventional short-acting insulin by injection Studies comparing to Rapid insulin ongoing cannot be used by smokers Will required frequent PFT testing 50 25

ORAL AGENTS What s coming?? DPPIV Sitagliptin Merck - JANUVIA Vildagliptin Novartis - GALVUS Saxagliptin BMS Many others in development Working On Designer sensitizers Renal glucose absorption inhibitors 51 Dec, 2003 issue 52 26

The Population is Getting Heavier 53 WEIGHT LOSS AGENTS Endocannaboid system novel target Blockade of cannabinoid CB 1 receptor Stimulation of these receptors results in lipogenesis and decreased adiponectin Activation of the endocannabiniod system through CB 1 plays an important role in both the central and peripheral regulation of energy, balance, body weight and food intake. Rimonabant (Acomplia) is a selective CB 1 receptor blocker clinical trials decreased food intake, weight, waist (visceral obesity), lipids, glucose and A1c improve insulin sensitivity and adiponectin -??independent of weight loss Many other similar compounds in development 54 27

Islet Cell Transplants No real new updates Disappointing news at best Wait for the official word 55 COMPLICATIONS NOT MUCH IS NEW Protein Kinase C Microvascular disease Retinopathy Nephropathy Obesity - New agents Neuropathy Pregabalin/and more Many outcome trials are ongoing AND WHAT EVER ELSE 56 28

Diabetes In 2007 -Summary What do newly published clinical trial mean to us? What novel concept should we expect? What does the crystal ball hold? 57 We are trying but Author unknown HOLD ON TO YOUR HATS _ THE BEST IS YET TO COME 58 29