ADA/EASD Algorithm. Landmark studies in diabetes. Presentation outline. Glycaemic targets in guidelines

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1 Presentation outline 1 Landmark studies in diabetes Bruce H.R. Wolffenbuttel, MD PhD University Medical Center Groningen The Netherlands url: 2 glycaemic targets in guidelines postprandial blood glucose treatment algorithm what is successful diabetes treatment, and for whom? results of recent trials hypoglycaemia predicts CV events hypoglycaemia limits optimized control tailored therapy is necessary 3 Glycaemic targets in guidelines ADA / EASD For microvascular disease prevention, HbA1c goal for adults in general is < 7% For selected patients, providers may suggest even lower HbA1c goals, if this can be achieved without significant hypoglycaemia Less stringent control may be appropriate for patients with a history of severe hypoglycaemia, limited life expectancy, advanced complications IDF Advise people with diabetes that maintaining a DCCTaligned HbA1c below. % should minimize their risk of developing complications 4 Imagine your outpatient-clinic next week: the first patient in front of you is... A -year old male Type 2 diabetes since 1, borderline hypertension, statin user, mildly obese Failing oral therapy (SU + metformin), HbA1c.% FBG of -1 mmol/l, p.p. p BG up to 1 mmol/l Teacher at a junior high school Sedentary work during the week, but likes to bicycle in the weekends Diabetes Care 2; 32 (suppl.1): S-12; IDF Global Guideline for Type 2 Diabetes Imagine your outpatient-clinic next week: the second patient in front of you is... ADA/EASD Algorithm Type 2 Diabetes Lifestyle Intervention & Metformin A 72-year old female Type 2 diabetes since 1, hypertension, triple antihypertensives, myocardial infarction in 24, statin and aspirin user, mildly obese Failing oral therapy (SU + metformin), HbA1c.% FBG of -1 mmol/l, p.p. BG up to 1 mmol/l Sedentary lifestyle Likes to go to the zoo with her grandchildren No A1C 7% Yes Add Basal Insulin Add Sulfonylurea Add Glitazone Most Effective Least Expensive No Hypoglycemia No A1C 7% Yes No A1C 7% Yes No A1C 7% Yes Intensify Insulin Add Glitazone Add Basal Insulin Add Sulfonylurea No A1C 7% Yes No A1C 7% Yes Add Basal or Intensify Insulin Intensive Insulin + Metformin +/- Glitazone Adapted from Nathan DM, et al. Diabetes Care 2;2:

2 Stapsgewijze behandeling type 2 diabetes 1. Lifestyle interventie (gezonde voeding, afvallen, lich. inspanning) Additional goals of therapy? Still many questions left! Evidence suggest to normalize glucose, blood pressure, lipids, body weight 2. Metformine (metabole regulatie, minder CV events) geen hypoglycemie, geen toename gewicht Should we strive for HbA1c below 7%? If yes, what evidence that lower HbA1c will prevent CVD? Special focus on postprandial blood glucose control? SU Glin TZD α-gi 3. Tweede (oraal) middel DPP-4-Inh. Ins. Incretine mimetica weinig gebruikt weinig gebruikt nieuw nieuw Timeline of development of diabetes therapies and landmark trials 12 Banting/Best Insulin isolated from dogs 14 SU many statin and BP lowering studies 1 Biguanide UGDP 17 1 Rec Human insulin UKPDS DCC T 1 Insulin Analogs ACCORD ADVANCE BARI 2D HEART 2D VADT PROactive RECORD ORIGIN NAVIGATO R ACE STOP- NIDDM DREAM 2 present GLP analogues Amylin analogues DPPIV-inhibitors 1 2 Metformin Alpha-glucosidase inhibitors Thiazolidinediones Glinides 1 Glucose lowering to prevent CVD: Trials in people with dysglycaemia ACCORD VADT NAVIGATOR ACE ORIGIN ADVANCE UKPDS PROACTIVE RECORD BARI 2D HEART 2D High IFG &/or IGT Type 2 Diabetes (T2DM) Dysglycaemia UKPDS glucose control study Diabetes is a progressive disease Conventional Policy 3% (n=113) Main Randomisation n=42 (2%) 37 Sulphonylurea n=173 Intensive Policy 7% (n=272) 342 allocated to metformin Insulin n=11 Intensive, HbA 1c 7.% Conventional, HbA 1c 7.% c (%) Median HbA 1c tion Beta-cell func Years after randomisation Insulin Oral medic. Diet, exercise Adapted from: UKPDS Study Group 1 2

3 UKPDS: with advancement of time more insulin Strict glycaemic control with sulphonylurea* or insulin saves lives or limbs! * chlorpropamide, glibenclamide!! ing insulin (%) Patients needi 4 2 Chlorpropamide Glipizide <-- P=.2 all diabetes events myoc infarction retinopathy albuminuria microvasc. endpoints Years after randomisation intensive (HbA1c 7.%) vs % reduction conventional (HbA1c 7.%) Adapted from: Diabetes Care 22;2:33 Metformin reduces complications, but please be patient (and obese) Non UKPDS Trials: Metformin vs. other interventions 1 ts with events Proportion of patien..4.2 Conventional (411) Intensive (1) Metformin (342) M v C p= Years from randomisation M v I p=.34 recent onset diabetes & obesity 1 RR (Fixed) % CI MET Favours Favours Weight RR (fixed) Study n/n Comparison Metformin Comparison (%) % CI All-cause mortality DeFronzo 1 1/21 / [.12, 72.] Horton 2 1/17 / [.12, 7.] Subtotal (% CI) [.31, 2.1] Ischemic heart disease DeFronzo 1 1/21 / [.12, 72.] Hallsten 22 1/13 / [.14, 72.] Horton 2 1/17 / [.12, 7.] Teupe 11 1/ / [.13, 71.2] Subtotal (% CI) [.2, 14.7] Saenz A, et al. Cochrane Database Syst Rev. 2;(3):CD 17 Pioglitazone reduces c.v. events in type 2 diabetics with existing CVD 1 IVUS at Screening Visit IVUS = intravascular ultrasound PERISCOPE: Study Design Randomization Pioglitazone 1 Months Glimepiride IVUS at Final Visit Adapted from Nissen SE, et al. JAMA. 2;2:

4 PERISCOPE primary efficacy parameter: change in percent atheroma volume 2: the results of three long-awaited studies are presented 1 p <.1 2 rcent me (%) Change in per atheroma volum,,,4,2 -,2.73 P =.2.1 p =.44 VADT Which lessons can be learned from these clinical trials? -,4 Glimepiride (n=11) Pioglitazone (n=17) Adapted from Nissen SE, et al. JAMA. 2;2:11-73 AAV: heterogenic inclusion criteria Macrovascular Outcomes 21 ADVANCE: age > 4 yrs, and earlier macrovascular or microvascular complication, or at least one other risk factor for c.v. disease 22 ACCORD: HbA1c 7.%, and a. 4-7 yrs and c.v. disease, or b. -7 yrs and 1. significant atherosclerosis, albuminuria, LVH, or 2. at least 2 additional risk factors for c.v. disease VADT: veterans, age > 41 yrs, HbA1c > 7.%, no major c.v. events in the previous months AAV overall results AAV: differences in baseline characteristics 23 ADVANCE: no cardiovascular benefit, but reduction proteinuria 24 ACCORD ADVANCE VADT Diabetes duration (yr) Median 1.±.4 11.±7.7 ACCORD: no benefit primary endpoint in pat s without baseline c.v. events reduction non-fatal MI 3-fold increase severe hypoglycemia intensive arm stopped prematurely because of side-effects Age (yr) 2±7 ± ±1 BMI (kg/m 2 ) 32.2±. 2± 31.3±4. Baseline HbA1c (%) 3±1.3± ±1.4±1. On trial HbA1c.4 vs 7.. vs 7.3. vs.4 VADT: no benefit primary endpoint 3-fold increase severe hypoglycaemia Blood pressure 13 / 7 14 / / 7 Hypertension (%)? > 7 72 Prior macrovasc events (%) adapted from: ADA presentations ADVANCE, ACCORD, VADT, June 2 4

5 ACCORD vs. ADVANCE vs. PROactive in perspective Speculations on possible causes of increased mortality in ACCORD 2 ACCORD ADVANCE VADT Std Int Std Int Std Int On trial HbA1c (%) Insulin use (%) * Metformin use (%) All-cause mortality (/1/yr) Nonfatal MI (/1/yr) Nonfatal stroke (/1/yr) * at study end HR HR Specific population characteristics avg age 2 yrs, diabetes duration 1 yrs. Rapid reduction of HbA1c Hypoglycaemia and consequent c.v. event Drug interactions Statistical error Other Does VADT give an answer?? Coronary Artery Calcium Score (CAC) Primary endpoint in VADT substudy 27 2 std int CAC= (low risk) VADT substudy RACED: Risk Factors, Atherosclerosis and Clinical Events in Diabetes CAC=31 (moderate-high risk) CAC score in 31 VADT participants 4% had CAC score > CAC predicted new events 2 1 Intensive therapy is especially effective in low CAC score 1 p<.1 <1 >1 CAC score CAC=, (very high risk) RACED: Risk Factors, Atherosclerosis and Clinical Events in Diabetes adapted from: Reaven. ADA presentation VADT, June 2 Diabetes duration and risk of c.v. events during intensive (insulin) therapy (VADT) Hypoglycaemia predicts c.v. events 2 Risk 2 1 Benefit Damage 3 Hypoglycaemia provokes physiological changes that affects cardiovascular system Can have adverse effect on vasculature already damaged in diabetes Increased risk of localized tissue ischaemia and major vascular events Myocardial infarction Cerebral ischaemia Diabetes duration (yrs) adapted from: Duckworth. ADA presentation VADT, June 2 Wright RJ and Frier BM. Diab Metab Res Rev. 2;24:33 3

6 Diabetes metabolic syndrome Genes? Hypoglycaemia limits optimized control results from the DURABLE trial 31 treatment hypoglycaemia low grade inflammation upregulation HPA -axis/ GH 32 Human premixed 7/2 insulin bid + SU + metformin SU + Metformin wks Insulin glargine od + SU + metformin HbA1c at Week 24 dietary factors? metabolic imbalances acceleration of atherosclerosis ischaemia <7.% 7. to <.%.% Glargine n Mean * LM 7/2 n cardiac arrhythmia Mean * C.V. event * Hypoglycemia Rate (episodes/pt/year) at Week 12 Buse J, et al. in press Multifactorial treatment in the STENO-2 study type 2 diabetes + microalbuminuria STENO-2 effects of multifactorial therapy Intensive treatment by combining medication and behavioral changes Targets of therapy: HbA1c <.% serum cholesterol < 4. mmol/l serum triglycerides < 1.7 mmol/l systolic bloodpressure < 13 mm Hg diastolic bloodpressure < mm Hg All received inhibitor of renin-angiotensin system (microalbuminuria!) Low dose aspirin STENO-2 effects on individual endpoints Recent Landmark Studies have been showing 3 Treatment of traditional risk factors, such as blood pressure and lipids, reduces cardiovascular disease events in patients with diabetes Assessing c.v. benefits of glycaemic interventions needs long-term follow-up of patients Intensified BG-lowering treatment appears to have benefit if initiated early, but can be dangereous in longterm diabetics and those with the most severe complications

7 Recent Landmark Studies have been showing 37 Hypoglycaemia predicts c.v. events For some patients and/or physicians, hypoglycaemia limits their willingness to increase insulin doses. 3 Postprandial BG as a target? a little dessert HEART2D: prandial vs. basal strategy in type 2 diabetic patients post-mi HEART2D: no effect of prandial strategy in type 2 diabetic patients post-mi 3 4 Age 1±1 yrs BMI 2.1±4. Diabetes duration.2± 7 yrs Raz I, et al. Diabetes Care 2; 32: 3 Raz I, et al. Diabetes Care 2; 32: 3 NICE: better postprandial BG control with ultrafast-acting insulin analog reduces cumulative c.v. events (MI, angina, PCI/CABG, TIA/CVA) HbA1c (%) FBG (mmol/l) Time (yrs) HbA1c 7. HbA1c Time (yrs) PPBG (mmol/l) 1 1 * * * * * Time (yrs) * p< Japanese pat s w. T2DM 3 injections fast-acting insulin, NPH if needed Regular (Actrapid) vs Insulin aspart (NovoRapid) Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) adapted from: Nishimura et al. Diabetologia 2 (A134) 42 vents (%) C.V. e Nippon ultrapid Insulin & diabetic Complications Evaluation (NICE) ClinicalTrials.gov NCT % Time (years) HR.7 CI:.34-. (p<.2) adapted from: Nishimura et al. Diabetologia 2 (A134) 7

8 Distribution of CAC scores (Agatston units) by cohort and treatment group years after DCCT 43 These data on postprandial BG control support the concept of intensified BG-lowering treatment early in the course of diabetes 44 This concept is comparable with data in type 1 diabetes (DCCT) Cleary et al. Diabetes 2; : 3- Incidence of CVD in type 1 diabetes during follow-up after DCCT Howlin' Wolf, 2 DCCT/EDIC Study Research group. NEJM 2; 33:243-