Update in Type 2 Diabetes

Transcription

1 Update in Type Diabetes Martin J Stevens MD, FRCP, Endocrinologist and Professor of Medicine, University of Birmingham Every Day in the United States Approximately people people lose lose their eyesight eyesight their because of of diabetes diabetes because 18 people people begin begin 18 treatment for for end-stage end-stage treatment renal disease disease (ESRD) (ESRD) renal More than than 4 4 new new More cases ofof diabetes diabetes will will be be cases diagnosedtoday today diagnosed 19 lower-limb lower-limb 19 amputations are are performed performed amputations because of of diabetes diabetes because 4 people people die die from from 4 diabetes and and its its diabetes complications complications Patients ages years. Centers for Disease Control. National Diabetes Fact Sheet. Accessed August 8, Million (1.7%) Americans Years or Older Have Diabetes (Diagnosed or Undiagnosed) 3.8 Percentage Age group Data is from 3, projected to year 7. NIDDK. National Diabetes Statistics. 7. Available at: Accessed February 11, 9.

2 Initial Defect is Post-prandial Hyperglycemia Hyperglycemia due to an increase in post prandial glucose 4 Plasma glucose (mg/dl) 1 1 DM 1 Meal Meal Meal Normal Plasma glucose (mmol/l) 3 Time of day (hours) Comparison of 4-hour glucose levels in control subjects vs patients with diabetes (p<.1). Adapted from Polonsky K, et al. N Engl J Med 1988;318: Rising Prevalence We are getting older, less active, heavier, and eating foods much higher in fat. fat. Epidemic of Diabetes and Obesity I have more flesh than another man, and therefore more frailty Shakespeare, Henry IV, Part One, III:3

3 Prevalence of Diabetes Macrovascular and Microvascular Complications Percentage with complications Diagnosed diabetes Normal blood sugar levels Heart attack Chest pain Coronary heart disease Congestive heart failure Stroke Chronic kidney disease Macrovascular Foot Eye damage problems Microvascular In NHANES, chronic kidney disease" refers to people with microalbuminuria (albumin:creatinine ratio >3 µg/mg). the NHANES analysis, "foot problems" includes foot/toe amputations, foot lesions, and numbness in the feet. "Eye damage" includes a positive response by NHANES participants to the question, "Have you been told diabetes has affected your eyes/had retinopathy?" Retinopathy is damage to the eye's retina. In NHANES, people without diagnosed diabetes were not asked this question, therefore, prevalence information for nondiabetics is not available. In American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at: Accessed April 18, 7 14 NA. Mortality (%) Mortality and Glycemic Control: A Continuum, Not a Threshold EPIC-Norfolk Study A1C (%) < Diabetes All cause Ischaemic heart disease Khaw et al. BMJ. 1;:1.4 Why Do Patients with Type Diabetes Develop Cardiovascular Disease? Type diabetes Risk Hypertension Raised LDL cholesterol Obesity CVD Low HDL cholesterol Hypertriglyceridaemia CVD, cardiovascular disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein

4 UK Prospective Diabetes Study -year Interventional Trial from 1977 to 1997,1 patients with newly-diagnosed type diabetes recruited between 1977 and 1991 Median follow-up 1. years, range to years 1-year Post-Trial Monitoring from 1997 to 7 Annual follow-up of the survivor cohort Clinic-based for first five years Questionnaire-based for last five years Median overall follow-up 17. years, range 1 to 3 years UKPDS 8 NEJM 8 39 Microvascular Disease Hazard Ratio (photocoagulation, vitreous haemorrhage, renal failure) Intensive (SU/Ins) vs. Conventional glucose control HR (9%CI) UKPDS 8 NEJM 8 39 All-cause Mortality Hazard Ratio Intensive (SU/Ins) vs. Conventional glucose control HR (9%CI) UKPDS 8 NEJM 8 39

5 Intensive Treatment Reduced Incidence of Cardiovascular Events DCCT/EDIC Cumulative Incidence.1.1 Conventional.8 Risk Reduction 4% 9% CI: 19, 3 Log-rank P=.1..4 Intensive Years from Study Entry Number at Risk Intensive: 7 Conventional: Epidemiology of Diabetes Interventions and Complications (EDIC): Observational follow-up of DCCT patient cohort DCCT/EDIC. N Engl J Med. ;33: New Controversy: More Questions and Some Answers.. ACCORD ADVANCE VADT Action to Control CardiOvascular Risk in Diabetes ACCORD Study Background Study enrollment: February 3 October 1 N = 1,1, projected median follow-up of. years1 73 patients were taking rosiglitazone Median duration of diabetes ~1 years >% patients had either established CVD or additional CV risk factors Study evaluated effects of intensive vs standard control of glycemia, lipids, and blood pressure Primary Endpoint: MACE (non-fatal MI/stroke, CV death) 1. Byington RP et al. Am J Cardiol. 7;99(suppl):1i 3i.. Buse JB et al. Am J Cardiol. 7;99(suppl):1i 33i.

6 Action to Control CardiOvascular Risk in Diabetes Cessation of Intensive Glycemia Arm of ACCORD On February, 8, NHLBI announced they decided to stop the intensive glycemic treatment arm of the trial1 3 7 Number of deaths Per DSMB scheduled review After 3. years of follow-up Higher incidence of deaths in the Intensive Group (HbA1c <.%) vs the Standard Group (HbA1c 7.% 7.9%) Death from any cause was 7 in the Intensive Group vs 3 in the Standard Group (HR 1.; CI 1.1,1.4; P =.4) Intensive Group Standard Group NHLBI = National Heart, Lung, and Blood Institute; DSMB = Data and Safety Monitoring Board; HR = hazard ratio; CI = confidence interval. 1. NHLBI. Accessed August 8, 8.. ACCORD Study Group. N Engl J Med. 8;38: Insulin Glargine vs NPH Insulin Added to Oral Therapy Patients (%) With 1 Hypoglycemia Episode Symptomatic Hypoglycemia by Time of Day Basal insulin 3 3 Insulin glargine NPH insulin 1 1 B L 1 1 D Time of Day (hr) P<. vs insulin glargine B, breakfast; L, lunch; D, dinner; hypoglycemia defined as PG 7 mg/dl Riddle et al. Diabetes Care.3;:38 Please see accompanying prescribing information

7 Patient Profile: The High-Risk Cardiovascular Patient -year old male BMI = 3 kg/m Recent discharge from hospital with myocardial infarction has LVH A1C = 8.% Current treatment: maximal doses of MET Microalbuminuria Currently treated for hypertension with losartan mg/day BP 14/8 Currently treated for dyslipidemia Atorvastatin 8 mg/day LDL cholesterol 7 mg/dl ADVANCE 11,14 patients with type diabetes year follow up HbA1c 7.3% vs.% 1% reduction of combined macro and microvascular events Primarily due to 1% reduction of nephropathy No reduction in cardiovascular risk, but no increased risk with any treatment modality New Engl. J. Med. 8; 38: -7 Veterans Affairs Diabetes Trial VADT Study Population Previously uncontrolled on insulin or maximum doses of one or more OADs 97% were male with a mean age of years Mean duration of TDM was 1 years and baseline A1C was 9.4% Mean BMI was 31 kg/m More than 4% of participants had prior CV events, 8% had hypertension, % had lipid abnormalities, and majority were obese Duckworth WC et al. Diabetes Care. 1;4:94 94.

8 Veterans Affairs Diabetes Trial VADT Results The primary result did not show that intensive blood sugar control (HbA1c levels below 7%) had a statistically significant effect on reducing major CV events associated with diabetes There was a favorable trend in reducing all CV events, except CV death, among the patients in the intensive arm American Diabetes Association. Accessed June 1, 8. Stepwise Management of Type Diabetes: Treat-to-Failure Approach Diet, Exercise, Lifestyle Wait for Failure Monotherapy Wait for Failure Dual Combination Wait for DualOral Oral Agent Combination Wait forfailure Failure Based on Failure, Consider: Triple oral agent therapy Adding/switching to insulin There is Nothing New Under the Sun Better use medicines at the outset than at the last moment Publilius Syrus, First Century BC

9 Traditional Therapeutic Approaches Often Fail United Kingdom Prospective Diabetes Study (UKPDS) 1 Median A1C (%) 9 8 ADA/EASD Goal 7 IDFGoal Conventional Insulin Glibenclamide (glyburide) Metformin 1 Time From Randomization (Years) Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical practice. If FPG exceeded 7 mg/dl, then patients were re-randomized to receive non-intensive metformin, chlorpropamide, glibenclamide, or insulin. If FPG exceeded 7 mg/dl again, then those on SU would have metformin added. If FPG exceeded 7 mg/dl after this, then insulin was substituted. Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;3:84-8, 1998, with permission from Excerpta Medica, Inc. The Problem The Rationale for Combination Therapy: Multiple Mechanisms of Action Targeting Multiple Sites Glucose Primarily Decreases Hepatic Glucose Production1 Liver Increase Insulin Secretion in Functioning Pancreatic β-cells Sulphonylureas/Secretagogues Metformin Insulin Pancreas DPP-4 Inhibitors Slow the inactivation of incretin hormones resulting in: Skeletal Muscle Decrease Insulin Resistance and Increase Peripheral Glucose Uptake3 Increased synthesis and release of insulin from functioning pancreatic ß-cells Lower glucogon secretion from pancreatic α-cells4 Adipose Tissue Thiazolidinediones Also decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization. 1.Glucophage [prescribing information]. Bristol-Myers Squibb..Amaryl (glimepiride) [prescribing information]. Aventis Pharmaceuticals. 3. AVANDIA (rosiglitazone maleate) [prescribing information]. GlaxoSmithKline. 4.JanuviaTM (sitagliptin phosphate) [prescribing information]. Merck & Co., Inc.

10 The Incretin Effect is Reduced in Patients with Type Diabetes Intravenous Glucose Oral Glucose Patients with type diabetes 8 8 Insulin (mu/l) Insulin (mu/l) Control subjects Time (min) Time (min) P. compared with respective value after oral load. Nauck MA, et al. Diabetologia 198;9:4. GLP-1 Effects in Humans Understanding the Natural Role of Incretins GLP-1 secreted upon the ingestion of food.brain: Promotes satiety and reduces appetite4,.α.α-cell: Suppresses postprandial postprandial glucagon secretion1 3.Liver: reduces hepatic glucose output 1. -cell: cell: Enhances glucoseglucose-dependent insulin secretion in the pancreas1 4.Stomach: slows the rate of gastric emptying3 Adapted from 1Nauck MA, et al. Diabetologia 1993;3: ; Larsson H, et al. Acta Physiol Scand 1997;1:413 4; 3Nauck MA, et al. Diabetologia 199;39:14 13; 4Flint A, et al. J Clin Invest 1998;11:1 ; Zander et al. Lancet ;39: GLP-1 Effects are Glucose-Dependent in Type Diabetes Placebo (PBO) GLP-1-3 Insulin (pmol/l) Glucose (mmol/l) 1 PBO GLP-1 3 PBO GLP Time (min) Mean (SE); N = 1; P <.. Nauck MA, et al. Diabetologia 1993;3: Time (min) Glucagon (pmol/l) PBO GLP Time (min)

11 Development of Exenatide: an Incretin Mimetic Synthetic version of salivary protein found in the Gila Gila monster1 More than % overlap with human GLP-11 Binds GLP-1 receptors on β-cells (in vitro) Resistant to DPP-IV inactivation3 Exenatide GLP-1 HA A E G T F TSD V S SY K E F I AW A LVKGR VK R -NH SYLLE GQAA GQ AKE Human Site of DPP-IV Inactivation,3 Following injection, exenatide is measurable in plasma for up to 1 hours4 1Eng J, et al. J Biol Chem 199;7:74 74; Adapted from Nielsen LL, et al. Regul Pept 4;117:77 88; DJ. Diabetes Care 3;:99 94; 4Calara F, et al. Clin Ther ;7:1 1. 3Drucker Pivotal Phase III Clinical Studies Combined (ITT) Exenatide Lowered HbA1c Placebo BD Exenatide µg BD Exenatide 1 µg BD SU MET 1 MET + SU3. P <. vs placebo P <.1 vs placebo.1.1 HbA1c (%). P <.1 vs placebo N Baseline wk data; Mean (SE) 1DeFronzo RA, et al. Diabetes Care ;8:19 11; Buse JB, et al. Diabetes Care 4;7:8 3; DM, et al. Diabetes Care ;8: Kendall Change in Body Weight Over Time, ITT Population Exenatide with Metformin Placebo Exenatide µg Exenatide 1 µg Mean (±SE) change in body weight from baseline (kg) ±.3 kg ±.4 kg ±. kg Time (week) ITT population, N = 33 (Placebo, N = 113; exenatide µg, N = 11; exenatide 1 µg, N = 113) P. P.1 compared to placebo DeFronzo RA, et al. Diabetes Care ;8:

12 DPP-4 Inhibition Leads to Improved Glycaemic Control Through Improved Islet Function Insulin β cell TDM Incretin response diminished Further impaired islet function Hyperglycaemia Glucagon α cell DPP-4 inhibitor Insulin β-cell Incretin activity prolonged Improved islet function Improved glycaemic control Glucagon α cell DPP-4=dipeptidyl peptidase-4; TDM=type diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 3: Ahrén B. Curr Enzyme Inhib. ; 1: 73. Sitagliptin: Active Comparator (Glipizide) Controlled Add-On to Metformin Study: Results Hypoglycemia Change in Body Weight Δ between groups =.kg (p<.1) Body weight (kg) 4% % p<.1 % 4.9% % Weeks glipizide glipizide sitagliptin sitagliptin Individual data points were not reported Stein P. Late Breaking Clinical Trials ADA Scientific Session ADOPT: A Diabetes Outcome Progression Trial Rosiglitazone Sustained A1C Over Time 8. Treatment Difference at 4 Years RSG vs MET.13 (. to.), P=. RSG vs SU.4 (. to.33), P<.1 SU HbA1C (%) 7. MET RSG Time (years) Number of patients: Mean A1C values per visit are based on a repeated measures mixed model. Kahn SE et al. N Engl J Med. ;3:

13 Bakris study (RSG/MT versus GLIB/MET matched for glucose control) Urinary Albumin:Creatinine Ratio ITT With LOCF GLY+MET N = 18 Baseline Geo Mean 3. mcg/mg RSG+MET N = 19 Baseline Geo Mean.7 mcg/mg Treatment Effect =-7.1 P=.317 % Change From Baseline =-1. P=.71 =-.8 P=. November 7, Five Long-term Studies Showed No Increased Risk of Total Mortality Duration of relevant studies A comparison of relevant studies ADOPT 1, 4 years DREAM,3 N = 43 patients N = 9 patients RECORD (Interim Studies),4 N = 4447 patients ACCORD (Interim Studies), N = 1,1 patients 7 years VADT 7, N = 1791 patients Duration, years Mean duration: 41 months. Not prospectively designed to assess the safety of AVANDIA. Independent non-gsk-sponsored studies. 1. Kahn SE et al. N Engl J Med. ;3:47 443;. Prescribing Information for AVANDIA; 3. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC et al. Lancet. ;38:19 11; 4. Home PD et al. N Engl J Med. 7;37:8 38;. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 8;38:4 9;. NHLBI. nhlbi-.htm. Accessed August, 8; 7. American Diabetes Association Web site Accessed August 8, Abraira C et al. Diabetes Obes Metab. 8; [Epub ahead of print]. PROactive: Pioglitazone vs Placebo and Time to Primary Composite Endpoint Kaplan-Meier event rate. 3-year estimate:. placebo 3.% pioglitazone 1.%.1 N events: What if this was a month trial? 7 / 33 W.1 14 /. Pioglitazone vs. placebo. 38 N at Risk: Time from randomization (months) Dormandy JA Lancet ; 3: HR 9% CI P value (8)

14 PERISCOPE: Primary Endpoint-Change in % Atheroma Volume Median Change in atheroma volume % P= Glimipiride Pioglitazone APPROACH: Primary Endpoint-Change in % Atheroma Volume Median Change in atheroma volume % P= Glipizide Rosglitazone The Extent of Glycemic Burden with Traditional Treatment Years with HbA1c >7% 4 Years with HbA1c >7% All treatments combined Including those treated with diet and exercise, sulphonylurea monotherapy, metformin monotherapy, and sulphonylurea and metformin in combination Diet and exercise Sulfonylurea Metformin Sulfonylurea monotherapy monotherapy and metformin combination therapy Brown JB et al. Diabetes Care 4; 7:

15 Ideal Basal/Bolus Insulin Absorption Pattern (US) 7 Breakfast Lunch Dinner Plasma Insulin (µu/ml) 4: 8: 1: 1: : 4: 4: 8: Time 1. Skyler JS. In: Therapy of Diabetes Mellitus and Related Disorders. Lebovitz HE, ed. Alexandria, Va: ADA; 4.. McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; :193-. Ideal Basal/Bolus Insulin Absorption Pattern (UK) 7 Breakfast Lunch Tea Dinner Plasma Insulin (µu/ml) 4: 8: 1: 1: : 4: 4: 8: Time 1. Skyler JS. In: Therapy of Diabetes Mellitus and Related Disorders. Lebovitz HE, ed. Alexandria, Va: ADA; 4.. McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; :193-. Addition of Biphasic, Prandial or Basal Insulin to Oral Therapy in Type Diabetes: Which is Best? Holman R et al; NEJM 7; 37:171

16 The Early Portable Insulin Infusion Device Targeting Therapy to Patient Profiles: Initial Factors to Consider Glycemic control Magnitude Complications of hyperglycemia Current medications Onset of action Symptoms Durable response Renal Cardiac Hepatic Weight Age Hypoglycemia ADA/EASD Guidelines 8: Validated Therapies Lifestyle + metformin If HbA1c 7% (Insulin if HbA1c >8. % or catabolic) Add basal insulin Add sulfonylurea If HbA1c 7% Lifestyle + metformin + Intensive insulin Nathan et al Diab Care 8; 31: 1-11.

17 ADA/EASD Guidelines 8: Less Validated Therapies Lifestyle + metformin If HbA1c 7%: If hypoglycaemia a risk of major weight concerns Add exenatide Add pioglitazone If HbA1c 7% Lifestyle + metformin + pioglitazone + sulphonylrea Lifestyle + metformin + basal insulin Nathan et al Diab Care 8; 31: Glycemic Control: Summary Unlike BP and lipid lowering, intensification of glucose control can transiently accelerate diabetes complications: early events therefore do not predict long-term outcomes Intensified glycemic control early in the course of TDM ultimately results in sustained microvascular protection and emergence of macrovascular benefits Aggressive, rapid (<3 month) lowering of HbA1c with insulin can increase cardiovascular events in higher risk subjects Long-term interventional trials have not confirmed an increase in cardiovascular risk with rosiglitazone Glycemic Control: Summary Glitazones/DPP-IV inhibitors/glp-1 analogs would need to be used early in the course of TDM to invoke metabolic memory or glucose legacy The importance of hypoglycemia in mediating adverse cardiovascular events needs to be considered. Glycemic targets and their speed of attainment should be individualised and based upon factors such as age, diabetes duration and complication status The relative costs, profiles of adverse events and potential risks and benefits need to be considered and discussed with your patients when choosing pharmacotherapy