Glycemic control what can be achieved with life-style and when and how to use pharmacological agents?

Transcription

1 Glycemic control what can be achieved with life-style and when and how to use pharmacological agents? Eberhard Standl Munich Diabetes Research Institute At the Munich Helmholtz Center

2 Pathogenetic key organs and hormones in Type 2 diabetes Adipose tissue Leptin & Adiponectin Insulin Pancreas Glucagon Food Muscle Liver Artery Fuel Glucose Seeley et al, Nature Medicine (2004) 10 :454

3 Hormonal regulators of appetite control and energy expenditure in the hypothalamus - + Prof. Eberhard Standl Hall J Obes Facts 2009; 2:

4 Biological actions of incretins GLP-1 (7-36) amide Insulin Secretion Glucagon Secretion Gastric Emptying Food intake Satiety B-cell survival GIP-1 (1-42) Insulin Secretion B-cell survival Lipolysis Lipogenesis DPP-4 GLP-1 (9-36) amide Insulin-independent glucose cleareance Cardioprotective Vasoactive GIP-1 (3-42) No known biological activity (Adapted from Drucker Diabetes Care 2007;30:1335) Prof. Eberhard Standl 4

5 ADA / EASD consensus: Management of hyperglycemia in type 2 diabetes Diabetes Care 29; 2006:

6 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

7 Look AHEAD Trial (Intensive Life-Style Intervention): 1 year follow-up Look AHEAD research group. Diabetes Care 2007;30:

8 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:

9 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)

10 Multifactorial Risk Management: Percentage of patients achieving set intensive targets in the Steno 2 Study HbA1c<6,5% Cholesterol<175mg/dl Triglycerides<150mg/dl Syst BP<130mm Hg Diast BP<80mm Hg % of Patients Gaede et al. NEJM(2003) 348:

11 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

12 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:

13 - 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:

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

15 Median HbA 1c (%) UKPDS: glycaemic control worsens over time, accompanied by weight gain Initial mean weight loss of 4kg was followed by a decrease in HbA1c from 9.1 to 6.9% 9 8 Conventional (n=200) Insulin (n=199) Chlorpropamide (n=129) Glibenclamide (n=148) Metformin (n=181) 7 ADA goal 6 0 Upper limit of normal range (6.2%) Time from randomization (years) Adapted from UKPDS Group. Lancet 1998;352:854-65

16 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.

17 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.

18 % of Patienten HbA1c of 7 % is a realistic goal! IRIS-Study (representative cohort of 4575 type 2 diabetic patients in Germany): Proportion of patients achieving specific HbA1c targets <6.5% <7.0% <7.5% <8.0% HbA1c target Rihl, Biermann, Standl: Diabetes & Stoffw. (2002)11:

19 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

20 Mean efficacy of pharmacotherapeutic options in Type 2 diabetes* Drug Option Mean HbA 1c Lowering Capacity (%) Incretin enhancer GLP-1 analogue 1.0 -Glucosidase inhibitor Biguanides Glitazones (TZDs) Sulfonylurea (and analogues) Insulin 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:

21 Arguments in favor of early combination 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

22 Target-driven approach for sustained glycaemic control HbA 1C (%) Diet ULN +Monotherapy +Combinations of oral agents Insulin +/- oral agents 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 15 14 Blood glucose patterns with progressive Type 2 Diabetes Breakfast 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) )

24 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.

25 (Postprandial) Mechanism of Action of GLP-1-Agonists and Incretin Enhancers (e.g. DPP-4- Inhibitors) GLP-1 stimulates glucose dependent insulin secretion inhibits glucagon secretion delays gastric emptying has a potential of ß-cell regeneration and inhibits apoptosis of pancreatic ß-cell (in animals) has to be injected Incretin enhancers Inhibit GLP 1 / GIP inactivation (via DPP-4-inhibition) are effective as oral drugs

26 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

27 4-T-Study Treating to Target in Type 2 Diabetes Changes after one year of different strategies HbA1c FPG Postprandial Weight Hypoglycamia (baseline: (baseline: plasma glucose (baseline: Grade 2 or 3 8.5%) 9.6 mmol/l) (baseline: 85.8 kg) (events/pat/y) 12.6 mmol/l) Holman RR et al.: Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes. N Engl J Med 2007, 357 (online first )

28 Time-Action Profile of various Insulins

29 Nathan et al. Diabetes Care 2008;31:December 1-11 ADA / EASD consensus (update December 2008): Management of hyperglycaemia in type 2 diabetes Tier 1: Well validated core therapies At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Sulfonylurea* Lifestyle + Metformin + Intensive Insulin STEP 1 STEP 2 STEP 3 Tier 2: Less well validated therapies Lifestyle + Metformin + Pioglitazone No Hypoglycema Oedema / CHF Bone loss Lifestyle + Metformin + GLP1-agonist No Hypoglycema Weight loss Nausea /Vomiting Lifestyle + Metformin + Pioglitazone + Sulfonylurea* Lifestyle + Metformin + Basal Insulin

30 Intensive vs Standard Blood Glucose lowering and Non-Fatal Myocardial Infarction (n = ) Ray et al, Lancet 2009, 373

31 Can we change...? Yes, we can...! By 10 to 15 % per 1% decrease of HbA1c (new metaanalysis in Lancet 2009) BUT... Can we change (reduce) CVD by blood glucose lowering?

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

33 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

34 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/? CHF (CHD rosiglitazone?) Glinides No/? Incretin-based agents? CHF=congestive heart failure CHD=coronary heart disease

35 His doc has no idea how to use individualized therapy!