Evidence Based Medicine for Diabetes Past, Present, and Future: Individualizing Diabetes Treatments. Ken Kortas, PharmD

Transcription

1 Evidence Based Medicine for Diabetes Past, Present, and Future: Individualizing Diabetes Treatments Ken Kortas, PharmD

2 Evidence Based Medicine for Diabetes: Past, Present and Future Individualizing Diabetes Treatments Ken Kortas BS Pharm, PharmD Senior Regional Medical Liaison Diabetes Field Medical Team US Medical Affairs Sanofi U.S. ADA Northern Illinois Chapter

3 Disclaimer Senior Regional Medical Liaison Diabetes Field Medical Team US Medical Affairs Sanofi U.S.

4 Objectives Discuss the epidemic of diabetes and the clinical impact Discuss the association between diabetes, hyperglycemia and complications Discuss the Evidence Based Medicine for reducing the risk of diabetes complications Discuss various management strategies for diabetes

5 The Diabetes Epidemic and the Clinical Impact

6 Natl Hx DM2 & Incretin Effect

7 Natural History of Type 2 Diabetes A Progressive Disease Obesity IFG * Diabetes Uncontrolled Hyperglycemia Glucose (mg/dl) Relative Function (%) *IFG=Impaired Fasting Glucose Post-meal Glucose β-cell Failure Years Of Diabetes Fasting Glucose Insulin Resistance Insulin Level Adapted with permission from Bergenstal R et al. Endocrinology. W.B. Saunders Company; 2001:

8 Diagnosis of Diabetes and Categories of Increased Risk for Diabetes Test Categories of Increased Risk Pre-Diabetes Diabetes FPG IFG: FPG mg/dl FPG 126 mg/dl 2-h PG on the 75-g OGTT IGT: 2-h PG mg/dl 2-h PG 200 mg A1C 5.7%-6.4% 6.5% In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random PG 200 mg/dl is also a criterion for the diagnosis of diabetes. FPG = fasting plasma glucose; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test; PG = plasma glucose. ADA. Diabetes Care. 2010;33(suppl 1):S11-S61.

9 Overview of the Diabetes Epidemic in the United States 25.8 million people or 8.2% of the population have diabetes 7.0 million are undiagnosed CDC projection that one-third of all U.S. adults will have diabetes by : For people aged 20 years, 1.9 million were newly diagnosed with diabetes & 26.9% of adults 65 years (10.9 million) had diabetes Increasing incidence of T2DM in children and adolescents Increasing incidence related to obesity, age, physical activity, and growth of ethnic populations 79 million Americans (46 million in 2007) with prediabetes: 33% US adults >20 yoa Gestational and Drug-Induced diabetes The total estimated cost of diabetes in 2007 was $174 billion, including $116 billion in excess medical expenditures CDC. National Diabetes Fact Sheet, 2007, US Dept of Health and Human Services. Accessed February, 20, ADA June 2008, Diabetes Forecast Oct-Nov

10 The Diabetes Epidemic CDC

11 The Cost of Diabetes (105 Million Americans with Diabetes or Pre-Diabetes) The estimated annual cost of diabetes in the US in 2012 is 245 Billion dollars Every 24 hours in the US 132 people start dialysis 2º to DM (2008) 166 people have lower-limb(s) amputated (2006) 66 people lose their eyesight (2007) % of all DM patients die from CV events Average medical expenses are more than twice as high for a person with diabetes s they are for a person without diabetes The risk of death with diabetes is TWICE that of similar age people without diabetes Death rates for women aged years with diabetes are more than 3 times the rate for women without diabetes ADA. Diabetes Care April 2013;36(4):

12 Clinical Impact of Diabetes Seventh leading cause of death (likely to be underreported)-overall, the risk of death among people with diabetes is twice that of non-diabetics Major cause of premature death and disability in the United States 67% of adults with diabetes have blood pressure greater than 130/80 or use hypertensive medications Leading cause of new cases of blindness in working-aged adults (24,000 new cases each year: 66 cases per day) National Diabetes Fact Sheet, Dept. of Health and Human Services, CDC,

13 Clinical Impact of Diabetes (cont.) More than 60% of nontraumatic lower extremity amputations (82,000 amputations in 2002: 225 per day, 166 per day 2006) About 60-70% of patients with diabetes have some form of mild to severe nervous system damage 44% of new cases of end-stage renal disease (in ,215 patients with diabetes began ESRD treatment: 132 per day) 2 to 4 fold increase in cardiovascular risk and stroke: over 2/3 of people with diabetes die from heart disease National Diabetes Fact Sheet, Dept. of Health and Human Services, CDC, 2005,

14 IDF. Diabetes Atlas, 5th Ed The Diabetes Epidemic: Global Projections,

15 Diabetes, Hyperglycemia and Complications

16 Main Pathophysiological Defects in T2DM incretin effect gut carbohydrate delivery & absorption pancreatic glucagon secretion pancreatic insulin secretion HYPERGLYCEMIA? + hepatic glucose production peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

17 Complications of Type 2 Diabetes Heart Coronary heart disease Cardiovascular disease Blood Vessels Peripheral artery disease Intermittent claudication Kidneys Microalbinuria Nephropathy Hyperglycemia Eyes Retinopathy Glaucoma Nerves Neuropathy Gastroparesis Source: American Diabetes Association. Diabetes Care 2006;29(Suppl 1):S4-S42.

18 Diabetes: Magnitude of Complications Leading cause of blindness in working age adults Diabetic Retinopathy Stroke 2- to 4-fold increase in cardiovascular mortality and stroke CVD Diabetic Nephropathy Leading cause of end-stage renal disease Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations CVD = cardiovascular disease. National Diabetes Information Clearinghouse. At: Responsible for 66% of diabetesrelated mortality

19 Various Mechanisms Link Hyperglycemia and Atherothrombosis Hyperglycemia Inflammation Oxidative Stress Endothelial Dysfunction Thrombosis MMP-9 MMP-2 NF-κB ROS Generation O 2 (superoxide) enos Egr-1 Inflammatory activity TNF-α, IL-6 MCP-1 sicam-1 Lipid peroxidation Protein carbonylation DNA damage NO +O 2 ONO O 2 NO Vasoconstriction Cytotoxicity PAI-1 TF Thrombosis Fibrinolysis Atherothrombosis Beckman JA et al. JAMA. 2002;287: ; Garg R et al. Stroke. 2006;37:

20 Estimated Average Glucose (eag) and A1c (Normal 4-5.6%) A1c (%) eag mg/dl (95% CI)* 5 97 (76-120) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Data in parentheses are 95% CIs. *Linear regression eag (mg/dl) = 28.7 x A1c Nathan, et.al. DIABETES CARE, AUGUST 2008

21 Guidelines for Glycemic, BP, & Lipid Control HbA1C Preprandial glucose Postprandial glucose American Diabetes Assoc. Goals < 7.0% (individualization) mg/dl ( mmol/l) < 180 mg/dl Blood pressure < 130/80 mmhg Lipids HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides. LDL: < 100 mg/dl(2.59 mmol/l) < 70 mg/dl(1.81 mmol/l)(with overt CVD) HDL: > 40 mg/dl(1.04 mmol/l) > 50 mg/dl(1.30 mmol/l) TG: < 150 mg/dl(1.69 mmol/l) ADA. Diabetes Care. 2012;35:S11-63

22 Evidence Based Medicine Trials for Diabetes

23 Good Glycemic Control May Help Reduce Incidence of Complications DCCT Kumamoto UKPDS Complication A1C: 9%-7% A1C: 9%-7% A1C: 8%-7% % reduction Retinopathy Nephropathy Neuropathy 60 Macrovascular disease 41* 16 ** * Not statistically significant. **Myocardial infarction (P=0.052)-not statistically significant DCCT = Diabetes Control and Complications Trial; UKPDS = United Kingdom Prospective Diabetes Study. DCCT Research Group. N Engl J Med. 1993;329: Ohkubo et al. Diabetes Res Clin Pract. 1995;28: UKPDS 33. Lancet. 1998;352:

24 UK Progressive Diabetes Study (UKPDS) Newly diagnosed T2DM patients in 2 study arms UKPDS 33 Conventional treatment (diet) vs. Sulfonylurea or Insulin (n=3867, median age 54 years) 10 years of follow-up median (p<0.0001) C: A1c 7.9% I: A1c 7.0% incidence of weight gain and hypoglycemia in the intensive treatment group (P<0.001) 12% any diabetes-related endpoint (P=0.029) 25% microvascular endpoint (P=0.0099) UKPDS 33. Lancet 1998;352:

25 UK Progressive Diabetes Study (UKPDS) Newly diagnosed T2DM patients in 2 study arms UKPDS 34 Conventional treatment (diet) vs. Metformin (n=753, mean age 53 years) All patients overweight (>120% IBW) 10 year follow-up median C: A1c 8.0% vs. I: A1c 7.4% 32% any diabetes-related endpoint (P=0.0023) 42% any diabetes-related death (P=0.017) 36% all-cause mortality (P=0.011) UKPDS 33. Lancet 1998;352: UKPDS 34. Lancet 1998;352:

26 Results from the UKPDS: Correlation Between a 1.0% A1C Decrease and Reduced Risk of Complications P< for microvascular complications, diabetes-related death, myocardial infarction, and all-cause mortality. UKPDS = UK Prospective Diabetes Study. Stratton IM et al. BMJ. 2000;321(7258):

27 Glycemic Control Reduces Risk of Type 2 Diabetes Complications Risk reduction with 1% decline in updated A1c P< P=0.035 P=0.021 P< MI Stroke Heart failure Cataract extraction Microvascular disease PVD Source: Stratton IM, et.al (UKPDS). BMJ2000;321:

28 UK Progressive Diabetes Study (UKPDS) Newly diagnosed T2DM patients in 2 study arms UKPDS 34 Conventional treatment (diet) vs. Metformin (n=753, mean age 53 years) All patients overweight (>120% IBW) 10 year follow-up median C: A1c 8.0% vs. I: A1c 7.4% 32% any diabetes-related endpoint (P=0.0023) 42% any diabetes-related death (P=0.017) 36% all-cause mortality (P=0.011) Greater any diabetes-related endpoint, all-cause mortality or stroke with metformin vs. sulfonylurea/insulin group (P<0.03) UKPDS 33. Lancet 1998;352: UKPDS 34. Lancet 1998;352:

29 UKPDS 10 year follow-up Post UKPDS trial monitoring Does improved glucose control persist? What are the long-term effects on macrovascular outcomes? Results 3277 of the original 9311 patients Between group differences in A1c lost 1 year post UKPDS conclusion Holman RR, et al. N Engl J Med 2008;359:

30 UKPDS 10 year follow-up Sulfonylurea/Insulin vs. Conventional: 9% any diabetes-related endpoint (P=0.04) 24% microvascular disease (P=0.001) 17% diabetes-related death (P=0.01) 15% myocardial infarction (P=0.01) 13% death from any cause (P=0.007) Metformin vs. Conventional: 21% any diabetes-related endpoint (P=0.01) 33% myocardial infarction (P=0.005) 30% diabetes-related death (P=0.01) 27% death from any cause (P=0.002) Legacy Effect Holman RR, et al. N Engl J Med 2008;359:

31 UKPDS: Benefit of Intensified Treatment in Newly Diagnosed Type 2 Diabetes (Legacy Effect of Earlier Glucose Control) Median of 8.5 years post-trial follow-up of UKPDS sulfonylurea-insulin group Aggregate endpoint 1997* 2007 Any diabetes related endpoint RRR p 12% % 0.04 Microvascular disease RRR p 25% % Myocardial infarction RRR p 16% % 0.01 All-cause mortality RRR p 6% % Holman RR, et al. N Engl J Med 2008;359: UKPDS Group. Lancet 1998;352: *End of randomized intervention. p=log rank. RRR, relative risk reduction.

32 UKPDS: Post-Trial Monitoring Any Diabetes-related Endpoint To determine the longer-term impact of earlier improved glucose control on microvascular and on macrovascular outcomes Intervention Trial Median follow-up 10.0 years Intervention Trial + Post-trial monitoring Median follow-up 16.8 years RR=0.88 ( ) P=0.029 Conventional Conventional Sulfonylurea/ Insulin Sulfonylurea/ Insulin Holman et al. N Eng J Med 2008;

33 Diabetes Control and Complications Trial (DCCT) 1441 patient with T1DM average follow-up 6.5 years Intensive vs. conventional treatment Conventional arm: 1-2 daily insulin injections Intensive arm: 3 daily insulin injections or use of an insulin pump Goal to minimize symptomatic hyper or hypoglycemia Goal preprandial glucose mg/dl, postprandial <180 mg/dl, weekly 3 am >65 mg/dl and A1c <6.05% At study conclusion the A1c in the intensive treatment group was 7.4% versus 9.1% in the conventional treatment group DCCT. N Engl J Med 1993;329:

34 Good Glycemic Control May Help Reduce Incidence of Complications DCCT Kumamoto UKPDS Complication A1C: 9%-7% A1C: 9%-7% A1C: 8%-7% % reduction Retinopathy Nephropathy Neuropathy 60 Macrovascular disease 41* 16 ** * Not statistically significant. **Myocardial infarction (P=0.052)-not statistically significant DCCT = Diabetes Control and Complications Trial; UKPDS = United Kingdom Prospective Diabetes Study. DCCT Research Group. N Engl J Med. 1993;329: Ohkubo et al. Diabetes Res Clin Pract. 1995;28: UKPDS 33. Lancet. 1998;352:

35 Epidemiology of Diabetes Interventions and Complications (EDIC) Primary goal to determine the long-lasting effects of intensive vs. conventional glycemic control on cardiovascular disease incidence Approximately 17 years of follow-up of 93% of DCCT participants All patients offered intensive treatment Diabetes management returned to PCP A1C differences diminished quickly Average in each group was approximately 8% NEJM 2005:353(25):

36 DCCT EDIC: Intensive Diabetes Therapy Reduced Risk of CVD Events in Type 1 Diabetes Cumulative Incidence Any Predefined CVD Outcome 42% Risk Reduction (95% CI, 9%-63%; P = 0.02) Conventional Treatment Intensive Treatment Nonfatal MI, Stroke, or Death From CVD 57% Risk Reduction (95% CI, 12%-79%; P = 0.02) Years Since Entry Predefined CVD outcome = nonfatal MI or stroke; death judged to be due to CVD; subclinical MI; angina, confirmed by ischemic changes on exercise tolerance testing or by clinically significant obstruction on coronary angiography; or the need for revascularization with angioplasty or coronary artery bypass. Nathan DM et al for the DCCT/EDIC Study Research Group. N Engl J Med. 2005;353: Years Since Entry 36

37 ADA Scientific Conference: 30th Anniversary Symposium for DCCT/EDIC One of the most exciting presentations was the 30th Anniversary Symposium for DCCT/EDIC, the largest long-term study of people with diabetes. The program has continued to find that early efforts at intensive blood sugar management continue to lower the long-term risk of complications decades later. They reported that those interventions have reduced the risk of eye disease by 50%, heart disease and stroke by 60% and kidney disease by 61%. Even a five-year period of better A1cs means lower complications decades later. 37

38 DCCT/EDIC 30 Years Later: Positive Effects of Intensive Therapy Confirmed in Type 1 Diabetes We are very excited by the long-term results of these studies, David M. Nathan, MD, director of the Massachusetts General Hospital Diabetes Center and co-chair of the studies, What we knew about intensive insulin therapy before 1993 was that it caused hypoglycemia that we were concerned about. What surprised us most by the DCCT results in 1993 was that the magnitude of the effects was far greater than anyone ever anticipated. However, the demonstrated effects were on the early stages of complications (microvascular: retinopathy, neuropathay and nephropathy). 38

39 DCCT/EDIC 30 Years Later: Positive Effects of Intensive Therapy Confirmed in Type 1 Diabetes-Dr. Lachin We now have compelling data that intensive therapy prevents or delays the advanced stages of diabetes complications In particular, Dr. Lachin focused on results published in the New England Journal of Medicine in These data linked intensive therapy with about a 57% reduction in the risk for major CVD events during the first 11 years of EDIC combined with the 10 years of DCCT. It turns out that those treatment effects were almost all explained by differences in level of HbA1c in the former intensive treatment group during the DCCT. Metabolic or glucose memory John Lachin, ScD, the principal investigator of the DCCT/EDIC Coordinating Center at The George Washington University in Washington, D.C., ADA 73 rd Scientific Session, Chicago June 22,

40 DCCT/EDIC 30 Years Later: Positive Effects of Intensive Therapy Confirmed in Type 1 Diabetes-Dr. Lachin Another important outcome is mortality: In terms of diabetic eye disease, there was a 50% reduction in the severe stages of diabetic eye disease as well as the need for ocular surgery and procedures in the original intensive therapy group. Although we have means of treating severe eye disease to prevent vision loss, it is always better to reduce its development in the first place to avoid the need for expensive and only partly effective late-stage therapies, Intensive diabetes therapy effectively accomplishes this goal. 40

41 DCCT/EDIC 30 Years Later: Positive Effects of Intensive Therapy Confirmed in Type 1 Diabetes-Dr. Lachin Almost as impressive as the actual data is the length of follow-up. Ninety-five percent of the surviving patients who continue to participate after 30 years, which is unprecedented. The reason for this is that patients have benefited, This also demonstrates the importance of continued follow-up and long-term results from interventions in diabetes. Diabetes is a lifelong disease. By following these participants for 3 decades, instead of showing what a drug or therapy does over 6 months or 1 year, what matters to people is what s going to happen over the course of a life, both in terms of the effect of the therapy and also the course of type 1 diabetes in today s world with contemporary therapy. 41

42 DCCT/EDIC 30 Years: The Lesson Learned is to Start Intensive Diabetes Management as Soon and as Safely as Possible ADA 2013 June 22, 2013 In the Intensive-treatment group at year 14 of EDIC: Neuropathy findings: 30% reduction in development of confirmed neuropathy 31% reduction in confirmed autonomic neuropathy Microalbuminuria: at 18 years a 39% RR for development among patients who did not have at the start of DCCT., at 8 yrs-57% RR Retinopathy difference Intensive vs Conventional treatment 70% RR at 4 years, 53% at 10 years and 46% at 18 years At 9 years into EDIC, 42% decrease in any CVE and a 57% RR for nonfatal heart attack, stroke, or death from CVD (NEJM 2005)-extended thru 2012 RR of 33% and 35% Mortality in the EDIC-soon to be published, but stated no increased mortality among the intensive treated group (Dr Lachin ADA 2013) 42

43 Action to Control Cardiovascular Risk in Diabetes Trial (ACCORD) Whether tight glycemic control improves cardiovascular event rates in T2DM patients patients with an average age of 62 years and duration of diabetes of 10 years A1c target <6% vs % 35% positive history of CVD Glycemic control arm was terminated early Intensive arm: A1c 6.4% vs. Conventional arm: A1c 7.5% 3.5 year follow-up 22% death from any cause (P=0.04) Subgroup: Patients with shorter duration of diabetes, without positive CVD history and/or a baseline A1c <8% saw significant in nonfatal MI, nonfatal stroke, and death from cardiovascular causes Skyler JS, et al. Circulation. 2009;119:1-7 43

44 Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Effect of intensive glucose control on macrovascular and microvascular outcomes in T2DM patients patients with an average age of 66 years and duration of diabetes of 8 years 32% positive history of CVD A1c target 6.5% vs. local guidelines Achieved A1c 6.3% vs. 7.0% at 5 years of follow-up -10% in 1 outcome Combination of microvascular and major macrovascular events) Due to significant (14%) microvascular events No difference between groups for macrovascular event rate Skyler JS, et al. Circulation. 2009;119:

45 Veterans Affairs Diabetes Trial (VADT) Whether tight glycemic control improves cardiovascular event rates in T2DM patients 1791 patients with an average age of 60 years and duration of diabetes of 11.5 years 40% positive history of CVD A1c target 6% vs. planned separation of 1.5% Achieved A1c 6.9% vs. 8.5% at 5.6 years of follow-up No significant reduction in 1 end point MI, stroke, cardiovascular death, revascularization, heart failure hospitalizations, amputation Post hoc subgroup: Duration of DM < 12 years, lack of hypoglycemia in the previous 90 days and low baseline coronary artery calcium scores Intensive glycemic control significantly 1 end point Skyler JS, et al. Circulation. 2009;119:

46 Management Strategies 46

47 Normoglycemia and Recommended Glycemic Targets in T2DM Glucose Control Healthy 1 ADA 1 AACE 2 A1C, % <5.6 < Preprandial plasma glucose, mg/dl < <110 Peak postprandial glucose, mg/dl <140 <180 a <140 b a Peak postprandial capillary plasma glucose; b 2-hour postprandial glucose concentration; c Self-monitored blood glucose. ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists; 1. ADA. Diabetes Care. 2009;32(suppl 1):S13-S61; 2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):3-68;

48 What is the appropriate A1C target? What is the appropriate A1C target? Must individualize for each patient Challenges with Achieving A1c Goal: Late diagnosis and initiation of therapy Therapeutic inertia Lack of effective lifestyle intervention Secondary failure Adverse events associated with antihyperglycemic therapies Complexity of care Role of PPG in failure PPG = postprandial plasma glucose. Zambanini A et al. Diabetes Res Clin Pract. 1999;46: Clark M et al. Diabetic Med. 2003;20: Shah BR et al. Diabetes Care. 2005;28:

49 Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

50 Goals of Diabetes Management Individualize treatment regimens Physiological treatment goals As near to normoglycemia (A1C < 7.0%) as possible while reducing the risk of significant hypoglycemia for non-pregnant adults Reduce the risk of short-term crises Hypoglycemia Hyperglycemia DKA Treat the whole patient Reduce the risk of long-term complications Benefits of BG, blood pressure, and lipid management are proven Treat diabetes comorbidity (hypertension, CVD, lipids, weight) BG = blood glucose; CVD = cardiovascular disease; DKA = diabetic ketoacidosis. ADA. Diabetes Care. 2010;33(suppl 1): 50

51 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% (mean PG mg/dl [ mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( %+ ) -older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

52 Insulin Pathophysiologic Considerations BG Lowering Agents Insulin Insulin Insulin Kalusa, KM and Henry, RR, Expert Opin Pharmacother (2009) 10(5): (modified)

53 Lifestyle Intervention Medical nutrition therapy Weight loss for overweight or obese individuals Low-calorie diets Low-carbohydrate diets (monitor lipid profiles, renal function, and protein intake) Diets low in saturated fat Disease self-management education Should address psychological issues Skill-based approach: assist patients in making informed choices Individual- and group-based approaches Increase physical activity In appropriate individuals, at least 150 min/wk of moderate-intensity aerobic physical activity Higher levels of exercise intensity maybe associated with greater improvements in A1C ADA Clinical Practice Recommendations;

54 Numerous Pharmacologic Treatment Options Sulfonylureas: glipizide*, chlorpropamide, glyburide,* glimepiride, gliclazide Biguanides: metformin Thiazolidinediones (TZDs): rosiglitazone,* pioglitazone* α-glucosidase inhibitors: miglitol, acarbose Meglitinides: repaglinide, nateglinide Human insulin: regular human insulin (RHI), neutral protamine Hagedorn (NPH) Basal insulin analogs: insulins glargine and detemir Rapid-acting insulin analogs: insulins aspart, glulisine, and lispro Premix insulin: 70/30 NPH insulin/rhi; 50/50 NPH insulin/rhi; 70/30 NPA insulin/insulin aspart; 75/25 NPL insulin/insulin lispro Incretin mimetics (GLP-1): exenatide (Byetta and Bydueron ), liraglutide (Victoza ) Synthetic amylin: pramlintide DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin, dutogliptin Januvia (sitagliptin), Onglyza (saxagliptin) and Tradjenta (Linaglipitin) Bromocriptine-dopamine agonist: Cycloset Colesevelam-bile acid binder: Welchol *Also produced in combination with metformin; Not FDA approved. DPP-4 = dipeptidylpeptidase-4 enzyme; NPA = neutral protamine aspart; NPL = neutral protamine lispro. 54

55 Numerous Pharmacologic Treatment Options - Combination Pills Type 2 diabetes medications may be taken individually or in combination pills, such as those that combine glipizide with metformin (Metaglip), glyburide with metformin (Glucovance), sitagliptin with metformin (Janumet), linagliptin with metformin (Jentadueto), repaglinide with metformin (Prandimet), saxagliptin with extended-release metformin (Kombiglyze XR), and rosiglitazone with metformin (Avandamet) Combination pills offer convenience but can have the drawback of making it more difficult to determine which medication is causing a negative side effect. Diabetes Forecast, ADA,

56 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Implementation strategies: - Initial therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to & titrations of insulin Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

57 Diabetes Care, Diabetologia. 19 April 2012]

58 Approximating Nature With Insulin Therapy: The Basal/Prandial Concept Physiologic Insulin Secretion 24-Hour Profile Insulin (µu/ml) Glucose (mg/dl) Prandial Insulin 0 Basal Insulin Breakfast Lunch Supper Prandial Glucose AM PM Time of Day Basal Insulin Nearly constant levels Suppresses glucose production between meals and overnight 50% of daily needs Prandial Insulin Limits hyperglycemia after meals 10%-20% of total daily insulin per meal Basal Glucose Adapted with permission from Bergenstal RM et al. In: DeGroot LJ et al, eds. Endocrinology. 4th ed. WB Saunders Co.; 2001:821.

59 Cardiovascular Disease Coronary artery disease Avoid hypoglycemia Preferred drugs include: Metformin Pioglitazone, unless co-morbid heart failure Incretin-based therapies need long-term data Heart failure Avoid thiazolidinediones Metformin can be used if non-severe ventricular failure, stable cardiovascular status, and normal renal function Incretin-based therapies need long-term data Inzucchi SE, et al. Diabetes Care 2012;35:

60 Chronic Kidney Disease Increased risk for hypoglycemia Metformin should be avoided with more severe kidney disease US: if serum creatinine 1.5 mg/dl men and 1.4 mg/dl women UK: with GFR 30 ml/min and reduced dose at GFR of 45 ml/min Drugs not eliminated by kidneys (no restrictions) Pioglitazone Linagliptin Inzucchi SE, et al. Diabetes Care 2012;35:

61 Chronic Kidney Disease Caution with secretagogues (hypoglycemia risk) Glyburide should be specifically avoided Avoid exenatide if GFR < 30 ml/min All insulins are eliminated more slowly in patients with severe renal impairment Inzucchi SE, et al. Diabetes Care 2012;35:

62 Liver Disease Insulin is preferred in advanced disease Pioglitazone may benefit fatty liver disease Avoid if active liver disease or alanine transaminase > 2.5 times upper limit of normal Meglitinides can be used Avoid secretagogues in severe disease Avoid incretin-based drugs in comorbid pancreatitis Inzucchi SE, et al. Diabetes Care 2012;35:

63 Summary of ADA/EASD Position Statement Glycemic targets and glucose-lowering therapies must be individualized Diet, exercise, and education remain the foundation of any T2DM treatment program Unless there are prevalent contraindications, metformin is the optimal first-line drug After metformin, there are limited data to guide therapy Combination therapy with an additional 1 2 oral or injectable agents is reasonable, aiming to minimize side effects where possible Inzucchi SE, et al. Diabetes Care 2012;35:

64 Summary of 2012 ADA/EASD Position Statement Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain glucose control All treatment decisions, where possible, should be made in conjunction with the patient, focusing on his/her preferences, needs, and values Comprehensive cardiovascular risk reduction must be a major focus of therapy Inzucchi SE, et al. Diabetes Care 2012;35:

65 Diabetes Patients and Preventive Care : CDC 2012 We have work to do. Wisconsin Foot exams % eye exams % A1c 2x/yr-73.5% Daily SMBG- 60.1% Attended DM class -59.4% Annual Flu Vaccine- 62.4%

66 Impact of Diabetes-Take Home Message In the 60 minutes we ve spent here today talking about diabetes, the following has occurred: Leading cause of new cases of blindness in working-aged adults (24,000 new cases each year: 66 cases per day) 3 patients lost their eye site to diabetes More than 60% of non-traumatic lower extremity amputations (66,000 amputations in 2006: 180 per day) 8 patients had an amputation due to diabetes 44% of new cases of end-stage renal disease (in ,400 patients with diabetes began ESRD treatment: 122 per day) 5 patients started ESRD treatment due to diabetes National Diabetes Fact Sheet, Dept. of Health and Human Services, CDC,

67 Questions? Comments?