Glycemic control A combination of life style interaction and the use of drugs

Transcription

1 Multifactorial management to reduce cardiovascular risk in patients with diabetes mellitus Glycemic control A combination of life style interaction and the use of drugs Eberhard Standl Munich Diabetes Research Institute at the Munich Helmholtz Center Master class in preventive cardiology Focus on diabetes and cardiovascular disease April 14, 2011 Geneva

2 UKPDS Landmark study in type 2 diabetes Patients studied n=5102

3 UKPDS: Clinical Outcomes after 10 years Life style plus drugs Intensive policy Conventional policy 7.0% HbA versus 1c 7.9% HbA 1c 12% 16% 25% 21% Any diabetes related endpoint Myocardial infarction Microvascular complications Retinopathy at 12 years Cardiovascular and all cause mortality P=0.029 P=0.052 P= P=0.015 NS UKPDS Group. Lancet 1998;352:

4 G Lowering Intensity & Diabetes Complications Trials in People with Dysglycemia and Type 2 Diabetes Yrs from Dx UKPDS (DCCT) ACCORD VADT ADVANCE Eye, Kidney, Nerve Disease CVD High IFG &/or IGT Type 2 Diabetes (T2DM) Dysglycemia

5 Glycemic control Meta-analysis of 5 prospective randomised trials (intensive vs standard) n= Mean HbA1c difference 0.9% Non-fatal MI (17% reduction) All cause mortality 0.83 ( ) 1.02 ( ) (Ray K et al. Lancet 2009;373:1765)

6 Issues beyond watch out for potential severe downsides, e.g. severe hypoglycemia and weight gain, especially in patients with preexisting CVD!

7 Intensive Glucose Lowering in Type 2 Diabetes ACCORD and ADVANCE HbA1c(%) HbA1c (%) Glycemia trial (n=10 251) HbA1c <6.0% vs HbA1c % Standard Severe hypoglycemia: 1.0 vs 3.1 %/yr Intensive Time of follow up (years) Glycemia trial (n=11 140) HbA1c 6.5% vs local guidelines Severe hypoglycemia: 0.4 vs 0.7 %/yr Standard Intensive (Gerstein et al. NEJM 2008;358:2545) (Patel et al. NEJM 2008;358: 2560) Time of follow up (months)

8 Hypoglycaemia requiring third-party assistance Standard Intensive Stand Inten Stand Inten HbA1c % Hypo %/yr UKPDS Newly diagnosed SU Ins PROactive High SV risk <0.25 ADOPT Recently diagnosed <0.2 Steno microalbu ~1 ~1 4T No ins, >1yr diagnosed ACCORD Older high CV risk ADVANCE Older high CV risk VADT Older high CV risk ~1.6 ~ 4?

9 Differences between the ACCORD and ADVANCE studies Characteristic ACCORD ADVANCE Baseline N 10,251 11,140 Mean age (Y) Duration of diabetes (Y) 10 8 Median HbA1c at baseline History of macrovascular disease (%) Intervention Target HbA1c (%) < Median duration (Y) Medical treatment at study completion (intensive vs standard) (%) Insulin 77 vs vs 24 Metformin 95 vs vs 67 Secretagoue (sulphonylurea or glinide) 87 vs vs 62 Thiazolidinedione 92 vs vs 11 use of Acarbose in 19% Dluhy et al. N Engl J Med 2008;358:2630-3

10 ACCORD Adjusted cause of death in relation to treatment strategy and by occurrence of hypoglycemia Standard participants Intensive participants No hypo event n=4.832 At least one severe hypo n=175 No hypo event n=4.290 At least one severe hypo n=528 All cause mortality 4% 10% 5% 6% CVD death 2% 5% 2% 4% Cancer death 1% 2% 1% 1% Non CVD/ Non cancer death Unable to classify 1% <1% 1% 1% 1% 1% <1% <1% Bonds DE et al. BMJ 2010: 340:b4909 doi: /bmj.b4909

11 Risk of Death over a Range of Average HbA1c Adjusted log (Hazard Ratio) by Treatment Strategy Relative to Standard at HbA1c of 6% Steady increase of risk from 6 to 9% HbA1c with intensive strategy Intensive strategy Standard strategy Calles-Escandon et al NEJM 2010 HR for 1% higher average HbA1c Intensive Strategy: 1.66 Standard Strategy: 1.14 Raising A1c to 7.2 % in the intensive group did not reduce excess mortality NEJM 2011; 364: Average HbA1c % Excess risk with intensive strategy vs standard occurred above HbA1c 7% Riddle M et al. ADA Congress, New Orleans June 2009

12 Primary outcome subgroup analyses Subgroup Patient Events no no (Gerstein et al. NEJM 2008;358:2545)

13 UKPDS 30 y Follow-up: Reduction of diabetes-related endpoints and myocardial infarction Holman R et al. New Engl J Med 2008;359, epub 10 September 2008

14 Guidelines recommend target HbA 1c as near to normal as safely possible 1 ADA. Diabetes Care 2007; 30 (Suppl. 1):S4 S41. 2 ACE/AACE Diabetes Road Map Task Force, Available at: 3 IDF Clinical Guidelines Taskforce, Available at: 4 CDA. Can J Diabetes 2003; 27 (Suppl. 2):S1 S NICE, Available at: 6 ALAD. Rev Asoc Lat Diab 2000; 8 (Suppl. 1): Asian-Pacific Type 2 Diabetes Policy Group, Available at: 8 NSW Health Department, 1996.

15 The AACE recommendations on glycaemic control No problem even to normalize glycemia, provided it can be achieved without side effects Near-normal targets (without hypoglycaemia) are advocated: HbA1c 6.5% Fasting plasma glucose <110 mg/dl 2-h post-prandial glucose <140 mg/dl Post-prandial hyperglycaemia is linked to macrovascular disease Effective management of post-prandial glucose can reduce this burden AACE Diabetes Mellitus Clinical Proactice Guidelines Task Force. Endocrine Practice vol 13 (Suppl 1); May/June 2007.

16 A HbA1c of 7 % is a reasonable deal: It can be attained by the patient by the doctor Needs less intensive polypharmacy (less costs) Reduces microvascular complications Reduces macrovascular complications (legacy effect) Further aggressive HbA1c reduction may increase the risk of side effects, e.g. weight gain, hypoglycemia, even cardiovascular mortality Conversely, the further gain of further HbA1c lowering is rather little (NNT 30 to 50) and only proven for (functional) renal parameters (e.g. microalbuminuria), not for macrovascular outcomes

17 Blood glucose patterns with progressive Type 2 Diabetes Breakfast 15 Postabsorptive (Night phase) Postprandial (Day phase) HbA 1c -Value ,5 9 % ,0 8 8,9 % Morning phase L. Monnier et al. Diabetes Care ,4 4,4 0,7 7 7,9 % 6,5 6,9 % < 6,5 % Duration of Diabetes mellitus (in years) )

18 New ESC/EASD Guidelines Suggested policy for the selection of glucoselowering therapy according to the glucometabolic situation ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, GUIDELINES ON DIABETES, PRE-DIABETES AND CARDIOVASCULAR DISEASES,DPP4-I, GLP1-A.,DPP4-I, GLP1-A.

19 Mean efficacy of pharmacotherapeutic options in Type 2 diabetes* Drug Option Mean HbA 1c Lowering Capacity (%) Incretin enhancers (DPP-IV-inhibitors) GLP-1 analogues 1.0 -Glucosidase inhibitors Biguanides Glitazones (TZDs) Sulfonylureas (and analogues) Insulins CB-1 receptor antagonist 0.7 * Treatment effects vary with treatment dose and patient characteristics. CB-1=cannabinoid Type 1. DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. DeFronzo RA. Ann Intern Med. 1999;131: Nathan DM. N Engl J Med. 2002;347: Todd JF, Bloom SR. Diabet Med. 2007;24: Scheen AJ. Best Pract Res Clin Endocrinol Metab. 2007;21: Vinik A. Clin Ther. 2007;29 Spec No:

20 Early combination strategy in blood glucose lowering therapy additive efficacy through different mode of actions therapy of different abnormalities at medium dose 70-80% of maximum effect less side effects α-glucosidase inhibitors Incretin enhancers/glp1-ag. Sulfonylureas und Analogs Glitazones Metformin

21 Guideline Recommendations: Drug Combinations with Different Mechanisms 2007 AACE Guidelines Combination therapy with different mechanisms antihyperglycemic drugs is more beneficial 2009 ADA /EASD Consensus combination of anti-hyperglycemic drugs with different mechanisms can achieve the maximum synergy

22 Target-driven strategy for sustained glycaemic control HbA 1C (%) Monotherapy Insulin +/- oral agents Diet +Combinations of oral agents ULN Failure-based treatment of symptoms approach HbA 1C < 7% approach Diagnosis +5 yrs +10 yrs + 15 years Campbell IW. Br J Cardiol 2000;7:625-31

23 Options of insulin therapy in type 2 diabetes fasting hyperglycemia: long acting insulin (or analogue) at bedtime postprandial hyperglycemia: prandial insulin therapy with rapid acting insulin analogues or regular insulin constant hyperglycemia: pre-mixed insulin (50/50 to 25/75) before breakfast and supper, respectively NB! All options may by combined with oral agents: e.g. Metformin!

24 4TStudy: Results over 3 Years incl. Hypoglycaemia Mean±1SD N Engl J Med 2009;361:

25 Adverse Events Biphasic N=235 Prandial N=239 Basal N=234 p value Any serious event 105 (44.7%) 79 (33.1%) 78 (33.3%) Death from any cause 7 (3.0%) 9 (3.8%) 4 (1.7%) 0.23 Cardiovascular death 4 (1.7%) 9 (3.8%) 1 (0.4%) Any adverse event 228 (97.0%) 235 (98.3%) 227 (97.0%) 0.58 No significant differences were seen between groups in: Serious adverse events occurring in more than 1% in any group Non-serious adverse events occurring in more than 10% in any group N Engl J Med 2009;361:

26 New ESC/EASD Guidelines Potential downsides of pharmacological treatment modalities in patients with type 2 diabetes ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, GUIDELINES ON DIABETES, PRE-DIABETES AND CARDIOVASCULAR DISEASES, GLP1-A, DPP4-Inhibitors, DPP4-Inhibitors

27 Look AHEAD Trial: 1 year follow-up Look AHEAD research group. Diabetes Care 2007;30:

28 Look AHEAD trial: changes of glycaemic and blood pressure control after 1 year Measure Intensive lifestyle intervention N Use of diabetes medications (%) Baseline Year 1 Change 86.3± ± ±0.6 Diabetes support and education 86.5± ± ±0.5 P 0.93 <0.001 <0.001 Fasting glucose (mg/dl) Baseline Year 1 Change 151.9± ± ± ± ± ± <0.001 <0.001 HbA1c (%) Baseline Year 1 Change 7.25± ± ± ± ± ± <0.001 <0.001 Use of antihypertensives (%) Baseline Year 1 Change 75.3± ± ± ± ± ± SBP (mmhg) Baseline Year 1 Change 128.2± ± ± ± ± ± <0.001 <0.001 DBP (mmhg) Baseline Year 1 Change 69.9± ± ± ± ± ± <0.001 <0.001 Look AHEAD research group. Diabetes Care 2007;30:

29 New ESC/EASD Guidelines Recommended treatment targets for patients with diabetes and CAD (2) ESC Pocket Guidelines adapted from European Heart Journal (2007) 28, GUIDELINES ON DIABETES, PRE-DIABETES AND CARDIOVASCULAR DISEASES

30 T2D n = year follow up HbA1c baseline: 7.6% Diabetes duration: 7.6 years Advice for physical activity: moderate, aerobic endurance training (30-60% of max. HF), aim: > 10 MET/ h /wk) 7 visits, total of ca 2 h counselling, 1 visit every 3 Month Di Loreto et al, Diabetes Care, 2005

31 Effects of physical activity in T2D Walking / Hours / Week* 0 1,5 4 5,5* 7,5 12 Weight (kg) + 0,8 + 0,6 + 0,1-2,2-3,0-3,2 Waist (cm) + 1,0 + 1,0-0,9-3,8-5,5-7,1 HbA 1c (%) + 0,03-0,06-0,44-0,8-1,11-1,19 BD syst. (mmhg) - 1,8-1,5-6,4-5,5-6,6-9,2 BD diast. (mmhg) - 4,6-2,4-2,9-4,8-5,3-7,1 Chol. (mg/dl) - 3,8-5,6-10,2-10,7-7,4-10,9 LDL-Chol. (mg/dl) - 4,5-7,1-3,4-5,3-6,3-7,7 HDL-Chol. (mg/dl) + 0,1 + 1,1 + 2,9 + 5,6 + 10,4 + 6,3 Triglycer. (mg/dl) + 3,4 + 2,1-48,2-55,2-57,4-68,4 CAD Risk (%) + 0,1-0,3-2,6-3,7-4,8-4,3 * e.g MET: 45 min walking (4 mph) /day, ca. 5 km/day) p <0,05 Di Loreto C. et al. Diabetes Care (2005)28:

32 - 593 $ drug costs Effects of physical activity in T2D Walking / Hours / Week* 0 1,5 4 5,5* 7,5 12 Weight (kg) + 0,8 + 0,6 + 0,1-2,2-3,0-3,2 Waist (cm) + 1,0 + 1,0-0,9-3,8-5,5-7,1 HbA 1c (%) + 0,03-0,06-0,44-0,8-1,11-1,19 BD syst. (mmhg) - 1,8-1,5-6,4-5,5-6,6-9,2 BD diast. (mmhg) - 4,6-2,4-2,9-4,8-5,3-7,1 Chol. (mg/dl) - 3,8-5,6-10,2-10,7-7,4-10,9 LDL-Chol. (mg/dl) - 4,5-7,1-3,4-5,3-6,3-7,7 HDL-Chol. (mg/dl) + 0,1 + 1,1 + 2,9 + 5,6 + 10,4 + 6,3 Triglycer. (mg/dl) + 3,4 + 2,1-48,2-55,2-57,4-68,4 CAD Risk (%) + 0,1-0,3-2,6-3,7-4,8-4,3 * e.g MET: 45 min walking (4 mph) /day, ca. 5 km/day) p <0,05 Di Loreto C. et al. Diabetes Care (2005)28:

33 ADA and EASD consensus 1. Well-validated core therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive insulin STEP 3 STEP 1 STEP 2 2. Less wellvalidated therapies Lifestyle + Metformin + Pioglitazone Lifestyle + Metformin + GLP-1 agonist Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal insulin (Nathan et al. Diabetes Care 2009;32:193)

34 The New IDF Therapeutic Algorithm (still under review) Lifestyle measures = usual approach Then, at each step, if not to target (generally HbA 1c <7.0 %) Consider first line Metformin Sulfonylurea or α-glucosidase inhibitor = alternatives as per Guideline Consider second line Sulfonylurea Metformin (if not first line) or Thiazolidinedione, or DPP-4 inhibitor, or α-glucosidase inhibitor Consider third line Basal insulin, or Pre-mix insulin or Thiazolidinedione, or DPP-4 inhibitor, or α-glucosidase inhibitor GLP-1 mimetic Consider fourth line Basal + meal-time insulin Basal insulin, or Pre-mix insulin (later basal+meal-time)

35 Present approach to diabetes management in type 2 diabetic patients Consult endocrinologist / diabetologist for Structured education Blood glucose self-monitoring (also post-prandial glucose) Appropriate nutrition counselling Pharmacotherapy discussing pros and cons Benefits Caveats Insulin Yes Heart? Metformin Yes Impaired kidney function Sulfonylureas Yes Cardiac K-channels? α-glucosidase-inhibitors Yes Glitazones Yes(pio)/? CHF (CHD rosiglitazone?) Glinides No (NAVIGATOR) Incretin-based agents? CHF=congestive heart failure CHD=coronary heart disease

36 Beyond HbA1c targets after ADVANCE/VADT/ACCORD/UKPDS 2011 No change of targets (<7% or <6.5%), in particular in view of the prevention of microvascular (and most likely also cardiovascular) complications but Go slow, especially in patients with high baseline HbA1c values and pre-existing CV disease Avoid hypoglycaemia and weight gain Early treatment and perhaps prevention appears to give the best results Some pharmacotherapies (e.g. insulin, rosiglitazone, SUs) cannot be excluded as a culprit in patients with cardiovascular disease The beneficial effects of improved blood glucose therapy on cardiovascular disease do emerge longer term and there is a legacy effect (metabolic memory) Weight neutral, nonhypoglycemic options (e.g. metformin, acarbose, DPP4-inhibitors) appear to be preferable

37 1. Lifestyle intervention (healthy eating, weight control, physical activity) 2. Metformin (glycaemic control, reduced CV events) No hypoglycaemia, no weight gain 3. Second (oral) agent (glycaemic control) SU Glinide TZD -Gluc. Inh. DPP-4 Inh. Incretin Mimetic Insulin (basal) Cheap Hypo BW Rapid acting Costs Hypo BW ø Hypo Costs BW CV safety CV Ev.? ø Hypo Weak GI-AE ø Hypo ø BW No AE ß-cell health? ø Hypo BW ß-cell health? Nausea etc. Always works Hypo BW Nauck 2008

38 WHO

39 Hyperglycaemia is common and often undiagnosed in patients with CAD in Europe and Asia Euro Heart Survey 1 (n=4,961) China Heart Survey 2 (n=3,513) 31% 29% 33% 23% 12% 3% 21% 25% 2/3 of patients have hyperglycaemia 20% 24% ~3/4 of patients have hyperglycaemia Normal glucose tolerance Prediabetes (IFG) Prediabetes (IGT) CAD: coronary artery disease; OGTT: oral glucose tolerance test; FPG: fasting plasma glucose; IFG: impaired fasting glucose; IGT: impaired glucose tolerance 1. Bartnik M, et al. Eur Heart J 2004;25: Hu DY, et al. Eur Heart J 2006;27: Newly diagnosed diabetes Previously known diabetes

40 Euro Heart Survey: Improved cardiovascular outcomes in patients with newly detected diabetes and implementation of diabetes pharmacotherapy Anselmino, Malmberg, Standl, Rydén, EuroHeartJ, (2008) 29: Prof. Eberhard Standl 44

41 Mortality trends in subjects with and without diabetes during 33 years of follow-up CVD CVD CHD CHD Jansson SPO et al, Diabetes Care 2010; 33:

42 Guidelines of the European Society of Cardiology (Euro Heart J: 2007; 28: ) The first Joint ESC/EASD Guidelines in Cardio-Diabetology : A perspective in reducing CV risk L. Ryden & E.Standl Co-chairs

43 Multifactorial intervention in type 2 diabetes The Steno 2 study Composite endpoint CV-death, MI or stroke, CABG or PCI, limb amputation or vascular surgery (Gaede et al N Engl J Med 2008;358:580-91) European guidelines: diabetes and cardiovascular disease

44 Steno 2 Study 13 year follow up: negative trends in weight management may have challenged the benefits of blood glucose lowering therapy (Gaede et al N Engl J Med 2008;358:580-91)

45 Ten important recommendations (1) To reach (all) treatment targets including those for glycaemic control To screen for DM and IGT by means of an OGTT in all patients with coronary artery disease and in other high risk individuals To let life style counselling be the cornerstone in preventing DM and CVD To offer patients with DM and ACS standard guideline based treatment, early angiography and mechanical revascularisation To apply strict, when needed insulin based, glucose control in acutely ill DM patients Europ Heart J 2007; 28:

46 Ten important recommendations (2) To favour CABG over PCI when revascularising DM patients To use drug-eluting stents in PCI with stent implantation To include investigations for cardiac autonomic dysfunction, heart failure, arrhythmias, hypotension, PVD (Doppler-Index), GFR and (micro) - albuminuria To use a multifactorial (tight glucose, BP and lipid-control and antiplatelet therapy) approach To establish a collaboration between cardiologists and diabetologists Europ Heart J 2007; 28:

47 Variable Lifestyle modification Smoking cessation BP ESC/EASD Guidelines Treatment targets of multifactorial therapy Target Structured education Obligatory <130 / 80 mm Hg Renal dysf <125/75 HbA1c (DCCT standard) 6.5% mmol/l mg/dl Venous plasma glucose < Cholesterol < LDL < HDL male >1.0; female >1.2 40; 46 Triglycerides <