CURRENT STATEGIES IN DIABETES MELLITUS Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Diabetes Mellitus: U.S. Impact ~1 Million Type 1 DIABETES 16.7 Million IFG (8.3%) 12.3 Million (6.3%) ~16 Million Type 2 TOTAL: 29 Million (14.4%) Declaration of full disclosure: No conflict of interest 2/3 Diagnosed 1/3 Undiagnosed (4.9 Million) Summary: Screening and prevention Recommendations for Adults FPG or 75 g OGTT can be used to diagnose diabetes Both IGT and IFG are associated with increased risk of diabetes but IGT is more strongly associated with cardiovascular outcomes Targeted screening Prevention with lifestyle;? meds (ADA says no) Glycemic Control A1C: <7. Preprandial: 9-13 mg/dl Postprandial: <18 mg/dl Blood Pressure: <13/8 mmhg Lipids LDL: <1 mg/dl TG: <15 mg/dl HDL: >4 mg/dl ADA Diabetes Care 26
Action to Control Cardiovascular Risk in Diabetes (ACCORD) NIH RCT in DM 2, 1, patients, complete 29 Intensive vs. standard BP (12 v. 14) Lipid control (fibrates v. statins + fibrates Normalization v. standard BS control (A1c 6 v. 7-7.9) Action to Control Cardiovascular Risk in Diabetes (ACCORD) Standard Intensive A1c 7.5% 6.4% Deaths 23 257 11/1/y 14/1/y Number Needed to Harm: 333 ACCORD, NEJM, 28 February 28: NIH stops this arm of study ADVANCE TRIAL RCT in DM 2; 1114 patients; 2 countries Intensive vs. standard BS control Intensive HbA1C goal 6.5% or less ADVANCE TRIAL Standard Intensive p Combined Events 2.% 18.1%.1 Microvasc events 1.9% 9.4%.1 Nephropathy 5.2% 4.1%.6 Intensive: 6.5% Standard: 7.3% ADVANCE, NEJM 28 Do differences in: Macrovascular events CV death Death from all causes ADVANCE, NEJM, 28
CLASSES OF DRUGS FOR DIABETES Secretagogues Metformin Acarbose Thiazolidinediones Exenatide DPP-IV inhibitors Pramlintide Insulin In my practice, I have prescribed 1. Exenatide (Byetta) 2. Sitagliptin (Januvia) 3. Both exenatide and sitagliptin 4. Inhaled insulin 5. Pramlintide (Symlin) 6. Three or all four of the above 7. None of the above 48 yo woman with DM, BMI 33, on diet and exercise. HbA1C is 9.2. Your next best step is: 1. Begin metformin 2. Begin a sulfonylurea 3. Begin a thiazolidinedione 4. Begin insulin 5. Begin exenatide 48 yo woman with DM, BMI 33, on diet and exercise and metformin. HbA1C is now 8.. Your next best step is: 1. Continue current therapy 2. Begin a sulfonylurea 3. Begin a thiazolidinedione 4. Begin insulin 5. Begin exenatide
Metformin Decrease Hepatic Glucose Output Treatment of Type 2 Diabetes Acarbose/ Miglitol Delay digestion of carbohydrates Improved Glycemic Control SFUs/Insulin Increase Insulin Secretion Generic Oral Hypoglycemic Slide Change from Drug A to B, C, or D Add Drug A to B, or B to A HgA 1c Add Drug C Decrease insulin resistance Thiazolidinediones Add Drug D Time Change in Mean HbA 1c (%) 1 1 2 3 Adding Instead of Switching DeFronzo, et al. N Engl J Med. 1995;333:541-549, * * * 9 13 17 21 25 29 Treatment (wk).4% * Continue glyburide Switch to metformin Glyburide+ metformin +.2% 1.7% Attaining Glycemic Goals Using Monotherapy in Obese Patients With Type 2 Diabetes Proportion of Patients With HbA 1c <7% (%) 6 5 4 3 2 1 Turner RC et al. JAMA. 1999;281:25-212. Diet Alone Sulfonylurea Metformin Insulin 3 Years 6 Years 9 Years 5-2
Weight Changes Associated with Anti- Hyperglycemic Therapies for Type 2 Diabetes ARE THIAZOLIDINEDIONES SUPERIOR? 12 1 8 6 4 2-2 -4-6 1.84 7.32 3.94-5.29 Change in Weight Sulfonylurea Metformin Insulin TZD Thiazolidinedione use slows progression to combination therapy Thiazolidinediones reduce microalbuminuria and hyperfiltration Reduced intimal proliferation ARE THIAZOLIDINEDIONES INFERIOR? Meta-analysis of 42 trials of rosiglitazone: Odds CI MI 1.43 (1.3-1.98) Death 1.64 (.98-2.74) ARE THIAZOLIDINEDIONES INFERIOR? Critique of Nissen Meta-analyses: Studies not designed to evaluate CV outcomes. Low frequency of events Variable duration Heterogenous populations No access to original data Nissen, NEJM 27
ARE THIAZOLIDINEDIONES INFERIOR? YES Meta-analyses: Nissen, NEJM, 27 Singh, JAMA, 27 GSK FDA Submission 27 Retrospective Cohort Study Lipscombe, JAMA, 27 ARE THIAZOLIDINEDIONES INFERIOR? NO Home, RECORD, NEJM, 27 Kahn, ADOPT, NEJM, 27 Gerstein DREAM, Lancet, 26.25 PROactive Primary Endpoint: No Statistically Significant Difference vs Placebo in CV outcome Oral Agent Failure Why does this occur? Kaplan-Meier Event Rate.2.15.1.5. N at risk: Pioglitazone Placebo HR.9 P.95 CI.8-1.2 5238 518 4786 4619 4433 4268 693 (228) Changing HbA1c goals Compliance, side effects Wrong diagnosis (LADA--latent autoimmune diabetes in adults 1%) Stress, diabetogenic medications Natural progression of the disease 6 12 18 24 3 36 Time From Randomization (mo) Adapted from Dormandy JA, et al. Lancet 25;366:1279 89; proactive-results.com Composite primary endpoint: all cause mortality, non-fatal MI (including silent MI), stroke, leg amputation, ACS, cardiac intervention, leg revascularization
Relative Contributions of Fasting and Postprandial Plasma Glucose to Total Glycemic Excursions as a Function of A1C Contribution (%) 8 6 4 2 1 (<7.3) 2 (7.3 8.4) Postprandial hyperglycemia Fasting hyperglycemia 3 (8.5 9.2) A1C (%) Quintiles 4 (9.3 1.2) 5 (>1.2) Glucose (mg/dl) Relative Function (%) Natural History of Type 2 Diabetes Obesity IFG * 35 3 25 2 15 1 5 25 2 15 1 5 *IFG = impaired fasting glucose Diabetes Uncontrolled hyperglycemia Post-meal Glucose Beta-cell failure Fasting Glucose Insulin Resistance Insulin Level` -1-5 5 1 15 2 25 3 Years of Diabetes Monnier L et al. Diabetes Care. 23;26:881-885. Glucose (mg/dl) Relative Function (%) Natural History of Type 2 Diabetes 35 3 25 2 15 1 5 25 2 15 1 5 Lifestyle Thiazolidinedione - Biguanide SU Post-meal Glucose Beta-cell failure Insulin Fasting Glucose Insulin Resistance Insulin Level -1-5 5 1 15 2 25 3 Years of Diabetes Insulin Plus Oral Agents Introduction of insulin Bedtime Intermediate/Long-acting insulins NPH, glargine 1 units Self-monitoring of blood glucose (hypoglycemia education) Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)
When to go to > 1 shot per day HgA1c >7 Glucose in AM at goal but glucose before dinner >14 Options Add premeal lispro/aspart Add bid premixed insulin 7/3, 75/25 Questions Continue metformin? Sulfonylurea,? Thiazolidinedione Function of Insulin in Regimens Meal coverage (carbohydrates) Basal insulin Correction of high blood sugar More Options Insulins Insulin Lispro (Humalog ) 96 Insulin Aspart (Novolog ) 9/ Humalog Mix 75/25 1/ Insulin Glargine (Lantus ) 4/ Novolog Mix 7/3 5/2 Insulin Glulisine (Apidra ) 4/4 Insulin Detemir (Levemir ) 6/5 Inhaled Insulin (Exubera ) 1/6 Insulin delivery devices and glucose meters Insulin Dose Adjustment 1-2 unit for every 3-5 mg/dl above or below target 1 unit for every 15 gram carbohydrate Err on conservative side 1% change in total daily dose 3-day adjustments
Type 2 Diabetes: Unanswered Questions When should insulin be started? What insulin should you use in Type 2? What insulin regimen is best? Which, if any, oral agents should be continued? Insulin and Oral Agents Adding insulin to sulfonylureas is associated with improved glycemic control, lower insulin daily dose and no adverse effect on body weight. Adding insulin to metformin is associated with improved glycemic control with minimal weight gain and least risk of hypogycemic episodes Insulin and Oral Agents Thiazolidinediones added to insulin treatment significantly improves glycemic control. May also be prevent further beta cell decline Thiazolidinediones in combination with insulin increases risk of heart failure Limited data on triple and quadruple drug combinations with insulin Insulin tactics Minimize weight gain metformin Minimize risk of hypoglycemia insulin analogs, optimize self management skills Minimize insulin resistance thiazolidinediones and metformin Use oral agents to limit number of injections
More Options Incretin mimetics Exenatide (Byetta ) 4/5 Sitagliptin (Januvia ) 6/6 Amylinomimetics (amylin analog) Pramlintide (Symlin ) 3/5 INCRETINS Gut factors that promote insulin secretion in response to nutrients Major incretins: GLP-1, CCK, GIP Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a Role for Incretins GLP Agonists Exenatide Liraglutide CJC-1131 AVE-1 Albugon Glp-1-transferin Exenatide Lar Incretin Drugs DPP IV Inhibitors Vildagliptin Sitagliptin Saxagliptin PSN=931 Takeda-Syrrx
Exenatide (Byetta) Synthetic Exendin-4, or exenatide Exendin-4 originally isolated from Gila monster s (Heloderma suspectum) saliva; lizard in Arizona Analog of GLP-1 39 amino acid peptide >5% overlap with human GLP-1 Resistant to DPP-IV degradation Similar binding affinity at GLP-1 receptors Exenatide (Byetta) Indications: adults with type 2 DM who are taking metformin, sulfonylurea or combination Peak concentration post injection achieved in 2.1 hr (injected SQ twice daily within 6 minutes of meal) Metabolized primarily by kidneys Not recommended in Cl cr <3 ml/min OK in hepatic impairment A1C (%) Effect (change from baseline) Placebo BID 5 mcg exenatide BID 1 mcg exenatide BID MET.1 -.4 -.8 SFU.1 -.5 -.9 MET+SFU.2 -.6 -.8 Changes in A1C from baseline vs placebo statistically significant
Weight (change from baseline) & Hypoglycemia Side Effects Weight (kg) Hypoglycemia (%) MET SFU MET + SFU Placebo BID -1.4 5.3 3.3 1.26 5 mcg exenatide BID -3.1 4.5 14.4 19.2 1 mcg exenatide BID -4.2 5.3 35.7 27.8 GI Nausea (44% vs 18% with placebo); incidence lessens over time; 3% dropout rate due to nausea Vomiting (13% vs 4%) Diarrhea (13% vs 6%) Headache (9% vs 6%) Hypoglycemia (see previous slide) Open-label extension study to 9 weeks: persistence in weight loss and A1C Exenatide Linked to Pancreatitis FDA Alert (1/7): 3 postmarketing reports of acute pancreatitis in patients taking Exenatide An association is suspected DPP-4 inhibitors Suppress postprandial glucagon Increase endogenous GLP1 and GIP Low risk of hypoglycemia Effective as monotherapy; combination with metformin, sulfonylureas, thiazolidinediones Improvement in HbA1c range from.5 to 1.6 %
DPP-4 inhibitors: Sitagliptin Sitagliptin 1mg daily Improvements in HbA 1C With Initial Co-administration of Sitagliptin and Metformin Mean Baseline HbA 1C = 8.8% N=191 5mg daily for creatinine clearance 3 to 5 -.5 Placebo Sita 1 mg QD 25 mg daily for creatinine less than 3. Approved as monotherapy or in combination with metformin or thiazolidinediones HbA 1C (%)* -1. -1.5-2. -2.5 -.8-1. -1.3-1.6-2.1 Met 5 mg BID Met 1 mg BID Sita 5 mg BID + Met 5 mg BID Sita 5 mg BID + Met 1 mg BID * Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42 nd Annual Meeting; 14-17 September 26; Copenhagen. Monotherapy Nasopharyngitis + pioglitazone Upper resp. infection Number of patients (%) Sitagliptin n = 443 23 (5.2) n = 175 11 (6.3) Placebo n = 363 12 (3.3) n = 178 6 (3.4) Small increase in WBC neutrophil count higher by 2 on Sitagliptin No nausea or vomiting Sitagliptin adverse reactions Sitagliptin linked to hypersensitivity reactions October 27 MERCK announces post marketing reports of anaphylaxis, angioedema, and exfoliative skin conditions (including Stevens-Johnson) MERCK concludes not possible to establish causality No weight loss
Beta-Cell Deficiency in Diabetes: Insulin and Amylin Amylin 37-amino acid peptide Co-located with insulin in secretory granules Co-secreted with insulin from pancreatic β-cells Absent in type 1 diabetes Impaired in type 2 diabetes Insulin Generally absent in type 1 diabetes Impaired in type 2 diabetes Amylin Effects on Post-Prandial Blood Glucose Suppresses postprandial glucagon secretion Glucagon suppresses hepatic glucose production Glucagon is abnormally elevated postprandially in diabetes Slows gastric emptying Regulates food intake through centrally mediated effect; effect on satiety Insulin and amylin are secreted proportionally 3 Meal Meal Meal Pramlintide (Symlin) Injectable synthetic analog of amylin with 3 amino acid changes Plasma Amylin (pm) 25 2 15 1 5 Control Subjects (n=6) 7 AM Noon 5 PM Midnight Time 6 4 2 Plasma Insulin (pm) Insulin Amylin Indications: adults with type 1 and type 2 DM on insulin therapy Peak concentration post injection achieved in 2 minutes (injected SQ immediately prior to a meal) ph of solution is 4.; must be injected separately Metabolized primarily by kidneys; OK in hepatic impairment
Clinical Data: Pramlintide in DM1 Clinical Data: Pramlintide in DM2 Pooled analysis of 3 long-term trials A1C: decreased.3% Weight: decreased 1.8 kg Hypoglycemia (events/patient-yr exposure): 1.4 pramlintide vs 1.86 placebo RCT of 656 DM2 patients on insulin (~3% on metformin and/or sulfonylurea) A1C: Decreased.68% at 26 wks and.62% at 52 wks (p<.5) A1C <7% better with pramlintide (12.2% vs. 4.1%) Ratner R. Exp Clin Endocrinol Diabetes. 25;113:199-24 Hollander P et al. Diabetes Care. 23;26:784-9. Using Pramlintide (Symlin) Use in patients with diabetes who are not controlled despite optimal insulin regimen Type 2 diabetes : start at 6 ug and titrate up to 12 Reduce bolus insulins (or premixed) by 5 % Do not use in patients with gastroparesis Pramlintide Side Effects Hypoglycemia GI: minimized with dose titration; subsides after ~4 weeks Nausea (3-5%) Vomiting (~1%) Anorexia (9-17%) Headache (>1%)
Natural History of Type 2 Diabetes Incretins Thiazolidinedione - Biguanide Drug Cost Comparison Drug and Dose Cost/month Glucose (mg/dl) Relative Function (%) 35 3 25 2 15 1 5 25 2 15 1 5 Lifestyle SU Post-meal Glucose Beta-cell failure Insulin Fasting Glucose Insulin Resistance Insulin Level -1-5 5 1 15 2 25 3 Years of Diabetes Sulfonylurea Generic $4-14 Brand $34 Rapaglinide 2 mg tid $111 Acarbose 1 mg tid $75 Metformin 1 bid Generic $ 4-6 Brand $14 Rosiglitazone 8 mg qd $175 Pioglitazone 45 mg/d $18 Sitagliptin $146 Exenatide 5mcg $185 1mcg $29 Glargine, 45 U/d $118 24 hour fitness Center $4 YMCA $6 Diet, lifestyle + metformin Step 1 Diet, lifestyle + metformin Step 1 Basal insulin Sulfonylurea Thiazolidinedione Step 2 Basal insulin Sulfonylurea Pioglitazone Exenatide Sitagliptin Step 2 Intensive Insulin Rx Thiazolidinedione or basal insulin Sulfonylurea or basal insulin Step 3 Intensive Insulin Rx Pioglitazone or Exenatide or basal insulin Sulfonylurea Sulfonylurea or or Exenatide Pioglitazone or Sitagliptin or basal insulin or basal insulin Step 3 Sulfonylurea or Pioglitazone or basal insulin Add basal insulin Or intensify insulin Rx Consensus algorithm ADA. Diabetes Care (26) Aug. 29:1963 Step 4 Add basal insulin or intensify insulin Rx (or add third oral agent or Exenatide) Step 4
48 yo woman with DM, BMI 33, on diet and exercise. HbA1C is 9.2. Your next best step is: 1. Begin metformin 2. Begin a sulfonylurea 3. Begin a thiazolidinedione 4. Begin insulin 5. Begin exenatide 48 yo woman with DM, BMI 33, on diet and exercise and metformin. HbA1C is now 8.. Your next best step is: 1. Continue current therapy 2. Begin a sulfonylurea (my choice) 3. Begin a thiazolidinedione 4. Begin insulin 5. Begin exenatide