Managing Patients Newly Diagnosed with Diabetes. Sud Dharmalingam MD, FRCPC Staff Endocrinologist William Osler Health System Brampton, ON

Transcription

1 Managing Patients Newly Diagnosed with Diabetes Sud Dharmalingam MD, FRCPC Staff Endocrinologist William Osler Health System Brampton, ON 1

2 Conflict Disclosure Information Conflict Disclosure Information Managing Patients Newly Diagnosed with Diabetes 2 FINANCIAL DISCLOSURE None that have a direct impact on today s presentation I have received honoraria in the past from the following companies for speaking engagements: Merck, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Novo Nordisk, Sanofi Aventis, Pfizer, Servier, GSK, Roche and others

3 Objectives Review screening and diagnostic criteria for type 2 diabetes Overview of the classes of agents in diabetes therapy and understand their advantages and disadvantages Learn to choose the appropriate agents in special situations such as renal failure and obesity 3

4 Prevalence rate per 100 Ontarians Age-adjusted prevalence rate of diabetes mellitus (DM) per 100 Ontarians aged 20 years and older, by sex, 1995/ /05 LHIN 5 (Central West) vs. Ontario LHIN 5 women LHIN 5 men Ontario women Ontario men /05 Men Women LHIN Ontario / / / / / / / / / /05 Fiscal year 4 Source: ICES

5 Family Physicians PROVIDE 92% OF DIABETES CARE 74% family physician care alone 92% 18% family physician and specialist care 7% no diabetes care (orphans) 1% specialist alone Jaakkimainen L. ICES

6 Pathophysiology of Type 2 Diabetes and Progression Over Time Prevention Treatment Macrovascular complications Microvascular complications b-cell function Insulin resistance Blood glucose IFG/IGT Type 2 diabetes 10 Years Pre-diagnosis Time of Diagnosis 10 Years Post-diagnosis IFG = impaired fasting glucose; IGT = impaired glucose tolerance. 6 Adapted from: DeFronzo RA. Med Clin N Am 2004; 88:

7 Percentage Decrease in Risk Corresponding to a 1% Decrease in A1C Adapted from Stratton IM, et al. BMJ 2000;321: Diabetes-related Complications and A1C Observational Analysis from UKPDS Any diabetes- Diabetes- Allrelated endpoint related death cause Myocardial mortality infarction Stroke Peripheral vascular disease Microvascular disease Cataract extraction 21% 14% 21% ** 14% ** 12% * 19% ** ** ** 43% 37% ** Lower extremity amputation or fatal peripheral vascular disease * p=0.035; **p< **

8 8 Holman R, et al. NEJM 2008; 359:1-13

9 UKPDS 10-year Follow-up: Relative Risk Reductions for Major Endpoints Intensive (sulfonylurea/insulin) vs. Conventional Therapy Aggregate Endpoint Any diabetes-related endpoint RRR p RRR p 12% % 0.04 Microvascular disease 25% % Myocardial infarction 16% % 0.01 All-cause mortality 6% % Adapted from Holman RR, et al: N Engl J Med 2008; 359(15):

10 UKPDS 10-year Follow-up of Intensive Glucose Control Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up 10 Holman RR, et al: N Engl J Med 2008; 359(15):

11 2008 CDA Guidelines: Recommended Glycemic Targets A1C (%)* FPG or preprandial PG (mmol/l) 2-hour postprandial PG (mmol/l) Type 1 and type 2 diabetes ( if A1C targets not being met) * Treatment goals and strategies must be tailored to the individual with diabetes, with consideration given to individual risk factors. Glycemic targets for children 12 years of age and pregnant women differ from these targets. Evidence shows that approximately half of Canadian patients do not achieve their A1C targets (DICE 2 and DRIVE 3 studies) 1. CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S Harris SB, et al. Diabetes Res Clin Pract 2005; 70(1): Braga M, et al. Presented at the American Diabetes Association 68th Scientific Sessions 2008, San Francisco.

12 The Ideal Anti Hyperglycemic Agent Efficacious Safe / No serious side effects No hypoglycemia Well tolerated No weight gain / potential weight loss Durable Cost-effective 12

13 2008 CDA Pharmacotherapy Algorithm L I F E S T Y L E Clinical assessment Lifestyle intervention (initiation of nutrition therapy and physical activity) A1C < 9.0% A1C 9.0% Initiate metformin Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or Initiate insulin If not at target Add an agent best suited to the individual: Alpha-glucosidase inhibitor Incretin agent: DPP-4 inhibitor Insulin Insulin secretagogue: meglitinide, sulfonylurea TZD Weight-loss agent If not at target Add another drug from a different class; or Add bedtime insulin to other agent(s); or Intensify insulin regimen Symptomatic hyperglycemia with metabolic decompensation Initiate insulin ± metformin See next slide for details Timely adjustments to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6-12 months CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.

14 2008 CDA Algorithm: Individualized Treatment Class Alpha-glucosidase inhibitor Incretin agent: DPP-4 inhibitor A1C Hypoglycemia Other advantages Other disadvantages Rare Improved postprandial control; weight neutral to Rare Improved postprandial control; weight neutral Insulin Yes No dose ceiling; many types, flexible regimens Insulin secretagogue: Meglitinide Sulfonylurea to Yes Yes Improved postprandial control Newer SUs (gliclazide, glimeripide) are associated with less hypoglycemia than glyburide GI side effects New agent (unknown long-term safety) Requires TID to QID dosing Weight gain TZD Rare Durable monotherapy Requires 6-12 weeks for maximal effect; weight gain; edema, rare CHF, rare fractures in females Weight-loss agent None Weight loss GI side effects (orlistat); increased heart rate/bp 14 (sibutramine) CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.

15 Action Profiles of Bolus & Basal Insulins lispro/aspart /glulisine4 6 hours regular 6-10 hours BOLUS INSULINS BASAL INSULINS NPH hours detemir ~ 6-23 hours (dose dependant) glargine ~ hours Hours Note: action curves are approximations for illustrative purposes. Actual patient response will vary. 15 Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491 Plank, J. et.al. Diabetes Care, May 2005; 28(5):

16 Types of Human Insulins and Analogues Currently Available in Canada INSULIN PREPARATIONS Addresses Fasting Glucose Addresses Post-meal Glucose Addresses Basal Insulin Needs Insulin lispro Insulin aspart Insulin glulisine X Insulin regular X Insulin NPH X X Insulin detemir X X Insulin glargine X X Insulin lispro 25% / insulin lispro protamine 75% Insulin aspart 30% / insulin aspart protamine 70% X X X Insulin lispro 50% / insulin lispro protamine 50% Insulin reular 30 % / insulin NPH 70% 16 CDA Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diab Sept. 2008;S46(suppl 1).

17 Major Pathophysiologic Defects in Type 2 Diabetes Islet-Cell Dysfunction Glucagon (α cell) Pancreas Hepatic glucose output Liver Insulin (β cell) Hyperglycemia Insulin resistance Glucose uptake Muscle Adipose tissue 17 Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus.

18 Hypoglycemia May Be a Barrier to Glycemic Control in Patients With Type 2 Diabetes Hypoglycemia is an important limiting factor in glycemic management and may be a significant barrier to treatment adherence. Fear of hypoglycemia is an additional barrier to control. A study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increased. 18 Amiel SA et al. Diabet Med. 2008;25(3):

19 A 1c (%) UKPDS: Long-Term Glucose Control 9 Conventional ULN* = 6.2% Years of Treatment Intensive ULN* = upper limit of A1C non-diabetic range UKPDS Study Group. Lancet 1998;352:

20 Earlier Use of Combination Therapy May Improve Treating to Target Compared With Conventional Therapy: Published Conceptual Approach A1C goal Diet and exercise OAD monotherapy OAD up-titration OAD combination OAD + basal insulin OAD + multiple daily insulin injections Mean A1C of patients 6 Duration of Diabetes Conventional stepwise treatment approach Earlier and more aggressive intervention approach OAD = oral antidiabetic agent. Adapted from: Campbell IW. Br J Cardiol 2000; 7(10): Del Prato S, et al. Int J Clin Pract 2005; 59:

21 Contribution (%) Pre and post prandial glucose levels and HbA1c 100 FPG PPG % 50% 55% 60% 70% % 50% 45% 40% 30% 0 < > 10.2 A1c range (%) FPG, fasting plasma glucose; PPG, post-prandial glucose. 21 Adapted from Monnier L, et al. Diabetes Care 2003;26:881

22 Patient Self-management Skills Knowledge of diet and risk of complications Motivation Conviction about the importance of glycemic control and risk reduction ( both microvascular and macrovascular) Chronic, progressive, generally asymptomatic disease with devastating consequences if ignored The importance of Diabetes Education 22

23 Official indication Slide Antihyperglycemic Agents and Renal Failure Metformin Terminal (<15) Not recommended Severe (15-29) 30 Caution / Reduced dose Moderate (30-59) Mild (60-89) 60 Safe Glyburide Gliclazide/Glimepirid e Repaglinide TZD Sitagliptin Saxagliptin Linagliptin 30 Liraglutide Exenatide Acarbose 25 Insulin Yale JF. December Glomerular Filtration Rate (ml/min)

24 Evidence- Based Slide Antihyperglycemic Agents and Renal Failure Terminal (<15) Not recommended Severe (15-29) Caution / Reduced dose Moderate (30-59) Mild (60-89) Safe Metformin Glyburide Gliclazide/Glimepirid e Repaglinide TZD Sitagliptin Saxagliptin Linagliptin 30 Liraglutide Exenatide Acarbose 25 Insulin Yale JF. December Glomerular Filtration Rate (ml/min)

25 Antihyperglycemic Agents and Weight Gain Agents associated with potential weight gain Thiozolidinediones-TZDs Sulphonylureas Glinides Insulin Agents that are weight neutral or potentially promote weight loss Metformin Alpha glucosidase inhibitors DPP4 inhibitors GLP-1 Analogs/Mimetics 25 Phuong OJ et al; JAMA 2010 Apr 14; 303(14)1410-8

26 Case 1 J.S 45 year old male FBS 8.2 on routine annual exam No previous diabetes No symptoms. Feels well No other significant past history No medications What next? HbA1c 8.5% 26

27 Case 1 Is there a role for lifestyle modifications? What lifestyle changes would you recommend? Is there a role for diabetes education? Is it useful? What about an antihyperglycemic agent? Which one? What about cardiovascular risk modification? 27

28 Case 2 D.M 46 year old female Well, except for asthma which is stable and controlled Has been losing wt, fatigued, otherwise well Random blood sugar 14 HbA1c 10.2% 28

29 Case 2 What therapy would you choose for glycemic control? Is there a role for combination therapy? Is there a role for lifestyle modification? Would anyone go for insulin? 29

30 2008 CDA Pharmacotherapy Algorithm L I F E S T Y L E Clinical assessment Lifestyle intervention (initiation of nutrition therapy and physical activity) A1C < 9.0% A1C 9.0% Initiate metformin Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class; or Initiate insulin If not at target Add an agent best suited to the individual: Alpha-glucosidase inhibitor Incretin agent: DPP-4 inhibitor Insulin Insulin secretagogue: meglitinide, sulfonylurea TZD Weight-loss agent If not at target Add another drug from a different class; or Add bedtime insulin to other agent(s); or Intensify insulin regimen Symptomatic hyperglycemia with metabolic decompensation Initiate insulin ± metformin See next slide for details Timely adjustments to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6-12 months CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.

31 Case 3 S.T 42 year old male Has not seen a doctor in 5 years. Fatigue and weight loss over last year Polyuria, polydipsia Random blood sugar 25 HbA1c 12.3% 31

32 Case 3 What now? What treatment here for glycemic control? Anyone for insulin? Is there a role for oral agents? If you are going to start insulin how are you going approach it? 32

33 Types of Human Insulins and Analogues Currently Available in Canada INSULIN PREPARATIONS Addresses Fasting Glucose Addresses Post-meal Glucose Addresses Basal Insulin Needs Insulin lispro Insulin aspart Insulin glulisine X Insulin regular X Insulin NPH X X Insulin detemir X X Insulin glargine X X Insulin lispro 25% / insulin lispro protamine 75% Insulin aspart 30% / insulin aspart protamine 70% X X X Insulin lispro 50% / insulin lispro protamine 50% Insulin reular 30 % / insulin NPH 70% 33 CDA Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diab Sept. 2008;S46(suppl 1).

34 Case 4 M.D 54 y.o male Hypertensive for many years Nephrolithiasis Chronic renal insufficiency On irbesartan 150 mg od, amlodipine 5 mg od, atorvastatin 10mg od Fasting blood glucose 9 on routine testing Creatinine 150 GFR 45 34

35 Case 4 What are your choices here for glycemic control? What oral agents are safe in renal insufficiency? Is insulin appropriate here? 35

36 Evidence- Based Slide Antihyperglycemic Agents and Renal Failure Terminal (<15) Not recommended Severe (15-29) Caution / Reduced dose Moderate (30-59) Mild (60-89) Safe Metformin Glyburide Gliclazide/Glimepirid e Repaglinide TZD Sitagliptin Saxagliptin Linagliptin 30 Liraglutide Exenatide Acarbose 25 Insulin Yale JF. December Glomerular Filtration Rate (ml/min)

37 Case 5 JF 48 y.o female Overweight BMI 27 Otherwise well; HTN on Adalat XL 60 mg od Routine testing shows FBS 8.5 HbA1c 8.7% Could not tolerate metformin due to severe diarrhea 37

38 Case 4 What are your therapeutic choices here? What antihyperglycemic agents would you choose and why? 38

39 Antihyperglycemic Agents and Weight Gain Agents associated with potential weight gain Insulin Thiozolidinediones-TZDs Sulphonylureas Glinides Agents that are weight neutral or potentially promote weight loss GLP-1 Analogs Metformin DPP4 inhibitors Alpha glucosidase inhibitors 39 Phuong OJ et al; JAMA 2010 Apr 14; 303(14)1410-8

40 Conclusions and Take Home Messages HbA1c is part of the new criteria for diagnosis of diabetes Metformin remains the first choice for most patients The choice of additional agents should be individualized to the patient When metformin is contraindicated or not tolerated alternate agents should be chosen according to the individual situation In severe hyperglycemia insulin should be used first-line Life style modification is central to management of diabetes at all stages With the proper regimen including insulin most patients will maintain glycemic control on a long-term basis 40

41 Questions? 41

42 42 Thank you.