Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) 1994 2000 2009 No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Diabetes 1994 2000 2009 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
NGT Insulin IGT/ IFG Type 2 Diabetes Resistance Glucose Postprandial glucose Fasting glucose -10-5 0 5 10 15 20 25 30 Relative Activity Insulin level Insulin resistance hepatic and peripheral Beta-cell function 10 5 0 5 10 15 20 25 30 Years from Diabetes Diagnosis *Conceptual representation. NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.; and Ramlo-Halsted et al. Prim Care. 1999;26:771 789. Progressive decrease in β-cell insulin secretion in response to nutrients First manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion) Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretion Decreases in insulin processing with increased proinsulin:insulin ratio
Type 2 diabetes has been considered a PROGRESSIVE disease β-cell dysfunction first leads to impaired glucose tolerance, which in some individuals progresses to type 2 diabetes β-cell dysfunction starts long before blood glucose rises and worsens after diabetes develops Hyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity) Median A1C (%) 9 8 7 6 0 0 A1C Conventional Intensive 3 6 9 12 15 Time from randomization (y) β-cell function (%) 100 80 60 40 20 0-12 -10-8 -6-4 -2 0 2 4 6 Years from diagnosis UKPDS Group. Lancet. 1998;352:837-853. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. Normal β-cell adaptation to insulin resistance Increased secretion from each cell Increased β-cell mass Impaired β-cell adaptation in type 2 diabetes result of Decreased secretion from each cell Reduced β-cell mass
Glucotoxicity Lipotoxicity β-cell Insulin Secretion Apoptosis Elevated glucagon levels Loss of insulin-induced suppression Loss of glucose-induced suppression Increased stimulatory effect of arginine Islets can adapt to insulin resistance Failure of adaptation results in impaired glucose tolerance and eventually, type 2 diabetes Failure appears to be due to reduced insulin secretion per islet and a reduction in the number of islets Increased glucagon contributes to hyperglycemia in type 2 diabetes
Glucose Fasting Random (with symptoms) GTT (2 hr.) HbA1c Fasting glucose Glucose tolerance test HbA1c Glycemia: HbA 1c <7.0%, FPG 90-130 mg/dl, PP <180 mg/dl Blood Pressure: <130/80 mm Hg Lipids: LDL <100 mg/dl; TG <150 mg/ dl Yearly Dilated eye exam; urinary protein; foot exam; flu shot Other Aspirin usage; pneumococcal vaccine AACE goals HbA 1c 6.5% FPG 110 mg/dl PP 140 mg/dl" NCEP LDL 70 mg/dl! FPG fasting plasma glucose PP - Postprandial
63% of Pa)ents with Diabetes are not at ADA Goal A1c < 7% Adults aged 20-74 years with previously diagnosed diabetes who participated in the interview and examination components of the National Health Examination Survey (NHANES), 1999-2000 % of Subjects n = 404 100 80 60 40 20 63% 7% 12.4% 7.8% 17.0% 25.8% 37.0% 37.2% >8% A1C >10% >9% >8% 7-8% <7% 0 Only 7% of adults with diabetes in NHANES 1999-2000 attained: A1C level <7% Blood pressure <130/80 mm Hg Total cholesterol <200 mg/dl Saydah SH et al. JAMA. 2004;291:335-342. Length of time that the patient s A1c remained above 8.0% before a switch/addition in therapy* 25 20 20 months Months 15 14 months 10 5 0 Metformin Only Sulfonylurea Only (n=354) (n=2517) * Brown et al. Diabetes. 2003;52(suppl 1):A61-A62. Abstract 264-OR.
Metformin (glucophage) Sulfonylureas (glyburide, glipizide, glimepiride) Thiazolidinediones (actos, avandia) DPP-IV inhibitors (januvia, onglyza) Glucosidase inhibitors (acarbose, miglitol) Others: colesevelam ; bromocriptine Pramlintide (Symlin) Exenatide (Byetta) / liraglutide (Victoza) Insulins Native Analogues - Regular (short-acting) - Isophane (NPH : intermediate) - Mixtures - Glargine / Detemir (long-acting) - Humalog, Novolog, Apidra (rapid) - Mixtures STEP 1: LIFESTYLE to WT and Activity Treatment Me*ormin Insulin Sufonylurea TZD α Glucos- idase Inhibitor Exana>de Pramlin>de Primary Mode of Ac)on A1c Reduc)on Lifestyle: (1-2%) Advantages Lifestyle: Low $; Many benefits Disadvantages Lifestyle: Fails for most in 1 st yr
Treatment Me*ormin Insulin Sufonylureas / Glinides STEP 1: LIFESTYLE to WT and Activity TZD α Glucos- idase Inhibitor Exana>de/ DPP- 4 Inhibitor Pramlin>de Primary Mode of Ac)on Hepa)c Glucose Output; Fas)ng Glycemia Increases basal insulin supply Enhances Insulin secre)on Increases the sensi)vity of muscle, fat and liver to insulin Decreases rate of diges)on of Polysacchar ides Insulin secre)on; Glucagon secre)on; & slows gastric mo)lity Glucagon secre)on; & slows gastric mo)lity A1c Reduc)on 1.5% 1.5-2.5% 1.5% 0.5-1.4% 0.5-0.8% 0.5-1% 0.5-1% >2.5% Lifestyle: (1-2%) Advantages Lifestyle: Low $; Many benefits Weight control,; inexpensive No dose limit; inexpensive; Improved lipid profile Inexpensive Improved Lipid profile Wt Neutral; No BG Wt Loss (DPP- 4 I wt neutral) Wt Loss Disadvantages Lifestyle: Fails for most in 1 st yr GI side effects; rare lac)c acidosis Injec)ons, monitoring; hypoglyc - emia; wt gain Hypoglycemia (less with Glinides); wt gain Fluid reten)on, wt gain, expensive; increased incidence of fractures GI SE; TID dosing Injec)ons; GI SE; Expensive; Lible experience (DPP- 4 I: Expensive, lible experience) Injec)ons; GI SE; Expensive; Lible experience Insulin Sulfonylureas Glinides Metformin α-glucosidase inhibitors TZDs GLP analogue DPP-IV Inhibitors Amylin analogue Colesevelam Bromocriptine mesylate Higher baseline A1C levels predict greater drop in A1C Shorter duration of diabetes predicts greater drop in A1C with any oral agent All oral agents require presence of some endogenous β cell function, as they work by either increasing insulin sensitivity or augmenting β cell insulin release
Advantages Disadvantages Concomitant use with other drugs Advantages Disadvantages Concomitant use with other drugs Tier 1: Well-validated core therapies At diagnosis: Lifestyle Metformin LifestyleMetformin Basal Insulin LifestyleMetformin Sulfonylurea LifestyleMetformin Intensive insulin Tier 2: less well-validated therapies *Useful when hypoglycemia is to be avoided Amylin agonists, Glinides DPP-4 inhibitors may be appropriate in selected patients LifestyleMetformin Pioglitazone (No hypoglycemia, edema, CHF, bone loss) LifestyleMetformin GLP1 (No hypoglycemia, wt loss, Nausea/vomiting) LifestyleMetformin Pioglitazone Sulfonylurea LifestyleMetformin Basal Insulin
AGI: alpha glucosidase inhibitor SFU: sulfonylurea 300 200 100 50 300 SFU, glitinides, exenatide Post-meal glucose Fasting glucose Insulin resistance 200 100 0 At risk for diabetes Beta-cell failure Insulin output 10 5 0 5 10 15 20 25 30 Current A1C Duration of diabetes Body weight (BMI, abdominal obesity) Age of patient Co-morbidities Cost of medication Convenience 40 year old female patient with type 2 diabetes on glypizide 5 mg/d and metformin 1000 bid presents for follow up. She has a random blood sugar of 240 mg/dl and HbA1c 8.0% Weight 240 lb Ht 5 4 BMI 41.2 (6 months prior weight was 229, BMI 39.3)
1. Add pioglitazone 30 mg/d 2. Add insulin glargine 10 units qhs 3. Increase Glipizide to 10 mg daily 4. Start sitagliptin 100 mg/d 5. Start exenatide 5 mcg bid Overweight patients with type 2 diabetes requiring initial treatment Overweight patients with type 2 diabetes on metformin, sulfonylurea, or combination Addition to thiazolidinediones to avoid weight gain
Preliminary Analysis for Subjects Treated for 2 Years
Rationale The choice of antihyperglycemic agents should be based on: Effectiveness in lowering glucose Safety profiles Expense Extraglycemic effects that may reduce long-term complications Tolerability The overall emphasis in selecting an intervention should be its ability to achieve and maintain glycemic goals. Addition of medications is the rule, not the exception, if treatment goals are to be met over time. Although Meta-analysis regarding rosiglitizone are not conclusive regarding potential CV risks, given many other options for treatment, group unanimously advised against rosiglitizone Glucose Regulation Normal Goal Fasting plasma glucose < 100 < 110 (ADA: 90-130) 2-hour postprandial plasma glucose < 140 < 140 (ADA: <180) HbA1c < 6 < 6.5 (ADA: <7% or < 6%) Blood Pressure Regulation Systolic BP (mm Hg) < 120 < 130 Diastolic BP (mm Hg) < 80 < 80 Lipid Regulation Targets / Goals Plasma LDL cholesterol < 140 < 100 Plasma HDL cholesterol > 40 >45 men, >55 women Fasting plasma triglyceride < 150 < 150
Longer acting GLP-1 analogues More DPP-IV inhibitors More TZD s Newer drug classes : e.g., SGLT2- inhibitors NOTE : FDA requires longer duration studies in DM2 to better understand risk / benefit before approval
8 Lifestyle MET-hours/week 6 4 2 0 0 1 2 3 4 Years from Randomization Metformin Placebo The DPP Research Group, NEJM 346:393-403, 2002 Weight Change (kg) 0-2 -4-6 Placebo Metformin Lifestyle -8 0 1 2 3 4 Years from Randomization The DPP Research Group, NEJM 346:393-403, 2002
Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo) Placebo Metformin Lifestyle The DPP Research Group, NEJM 346:393-403, 2002 Placebo Metformin Lifestyle Incidence of diabetes 11.0% 7.8% 4.8% (percent per year) Reduction in incidence ---- 31% 58% compared with placebo Number needed to treat ---- 13.9 6.9 to prevent 1 case in 3 years The DPP Research Group, NEJM 346:393-403, 2002 115 Placebo FPG (mg/dl) 110 105 Lifestyle Metformin 100 0 1 2 3 4 Years from Randomization The DPP Research Group, NEJM 346:393-403, 2002