Optimizing Treatment Strategies to Improve Patient Outcomes in the Management of Type 2 Diabetes Philip Raskin, MD Professor of Medicine The University of Texas, Southwestern Medical Center NAMCP Spring Managed Care Forum Orlando, Florida April 25, 214 Type 2 Diabetes is a Disease of Progressive Beta Cell Failure!!! 1
TYPE 2 DIABETES PATHOPHYSIOLOGICAL DEFECTS Impaired -cell function qualitative and quantitative Impaired Insulin Action decreased insulin sensitivity (insulin resistance) Glucagon Excess 2
Effect of Glyburide, Metformin, or Rosiglitazone Monotherapy or Glycemic Durability in Type 2 Diabetes (The Adopt Study) 8. HbA1c % 7.6 7.2 6.8 6.4 6. Rosiglitazone vs. Metformin p=.2 Rosiglitazone vs. Glyburide p<.1 1 2 3 4 5 Years Glyburide Metformin Rosiglitazone Kahn,et al NEJM 355: 2427, 26 Inzucchi May 212 Diabetes C 3
Current Control and Targets Treatment Guidelines for Diabetes American Diabetes Association A1C <7.% Preprandial BG 9-13 mg/dl (5.-7.2 mmol/l) Postprandial BG <18 mg/dl (<1 mmol/l) American Association of Clinical Endocrinologists A1C 6.5% Preprandial BG <11 mg/dl (<6.1 mmol/l) Postprandial BG <14 mg/dl (<7.8 mmol/l) International Diabetes Federation A1C <6.5% Preprandial BG <1 mg/dl (<5.5 mmol/l) Postprandial BG <14 mg/dl (<7.8 mmol/l) 4
Current Treatment Targets Are Not Being Achieved!! Current Control And Targets Percentage of patients reaching HbA 1c < 7.% The Proportion Of Patients Reaching HbA 1c Targets 6 5 4 3 2 1 44.5% NHANES 1988 1994 35.8% NHANES 1999 2 56.8% NHANES 23-24 Ford et al. Diabetes Care 31:12, 28 Koro et al. Diabetes Care 27:17, 24 5
Insulin Use in the US Remains Low Despite Poor Control NHANES 1988-1994 NHANES 23 Patients (%) 7 6 5 4 3 2 1 27.4 15. Diet only 45.4 57. Oral agents Patients treated with insulin 12. 3.1 Oral agents + insulin 24.2 16. Insulin only Koro CE et al. Diabetes Care 27:17, 24 Clinical Inertia 6
Current Control And Targets Glycemic Control Is Poor Even Among Insulin-using Type 2 Diabetic Patients Number of patients 5 4 3 2 1 Mean = 8.4% Median = 8.1% N=3,658 Insulin-users In 78.% 7.% UK And Germany 32.3% 9.% 18.2% 1.% 5. 7.5 1. 12.5 15. HbA 1c Gough et al. ADA Abstract 26. Insulin Resistance Starts in the Doctor s Office 7
GLP-1 Receptor Agonists Definition of an Incretin Released during nutrient absorption Augments insulin secretion at physiologic concentrations Insulinotropic effects are glucose dependent Creutzfeldt Wl. Diabetologia. 1979;16:75-85. 8
The Incretins GLP-1: Glucagon-Like Peptide 1 H A E G T F T S D V S S Y L E G Q A A K L A I F K G R G V W E GIP: Glucose-Dependent Insulinotropic Peptide Y A E G T F I K W D N K K H N I T Q G K S D Y S Q A L I L A M D K W N V F I D H Q Q Amino acids shown in green are homologous with the structure of glucagon Measurement of the Incretin Effect 2 15 OGTT and Matched IV Infusion Glucose (mg/dl) Insulin (pmol/l) 4 Oral 3 IV 1 2 5 1-3 3 6 9 12 15 18 21 Time (min) -3 3 6 9 12 15 18 21 Time (min) Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8. 9
GLP-1 Suppresses Glucagon Secretion 75 Meal Glucagon, pg/ml 5 25 Infusion Saline GLP-1 3 6 9 12 Time, minutes Ahrén et al Diabetes Care. 23;26:286 2864. Decreased Postprandial Levels of GLP-1 in Patients With Type 2 Diabetes * * * * * * * (1-15) Meal Meal Started Finished *P<.5, Type 2 diabetes vs NGT. Toft-Nielsen MB et al. J Clin Endocrinol Metab. 86: 3717, 21 1
Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes Glucose mmol/l 15. 12.5 1. 7.5 5. 2.5 * * * * * * * 25 2 15 1 5 mg/dl Placebo GLP-1 *P <.5 Patients with type 2 diabetes (N=1) Insulin pmol/l 25 2 15 1 5 * * * * * * * * 4 3 2 1 mu/l When glucose levels approach normal values, insulin levels decreases. Glucagon pmol/l 2 15 1 5 3 2 15 * * * * 1 5 Infusion 6 12 18 24 Minutes pmol/l When glucose levels approach normal values, glucagon levels rebound. Nauck MA et al. Diabetologia. 1993;36:741 744. Comparison of Physiology of GLP-1 and GIP Site of production GLP-1 L-cells in ileum and colon GIP K-cells in duodenum and jejunum Response to stimuli Indirect/neuronal Direct Inhibits glucagon Yes No Slows gastric emptying Yes No Stimulation of -cell growth/mass Yes Yes Major target tissues -cell, -cell, stomach, nervous system -cell, adipose tissue Antagonist Exendin [9-39] GIP [7-3] 11
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Meal Intestinal GIP and GLP-1 release DPP-4 Enzyme GIP-(1 42) GLP-1(7 36) Intact GIP and GLP-1 Actions Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes GIP-(3 42) GLP-1(9 36) Metabolites GLP-1 Receptor Agonists Glycemic Effects In general, liraglutide 1.8 mg once daily provides greater glycemic control vs exenatide 1 mcg twice daily (LEAD-6) 1 - Mean A1C reductions with liraglutide: 1.1%-1.6% (mono- and combination therapy) 2 - Mean A1C reductions with exenatide twice daily:.7%-1.% (mono- and combination therapy) 2 Exenatide long-acting release provides greater glycemic control vs exenatide twice daily (-1.6 ±.1% vs -.9 ±.1%, DURATION-5) 3 DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly; LEAD = Liraglutide Effect and Action in Diabetes. 1. Buse JB, et al. Lancet. 29;374:39-47; 2. Mundil D. Diab Vasc Dis Res. 212;9:95-18; 3. Blevins T, et al. J Clin Endocrinol Metab. 211;96:131-131. 12
Nonglycemic Effects GLP-1Rs are not restricted to the pancreas; therefore, GLP-1 RAs cause additional nonglycemic effects: Improvements in beta-cell function Reduction in Food intake Renal, GI, neuroprotective Improvements in markers of cardiovascular risk? Cardiovascular biomarkers (PAI-1, BNP, hs-crp) Reduction in oxidative stress Weight, SBP, lipids BNP = B-type natriuretic peptide; hs-crp = high-sensitivity C-reactive protein; PAI-1 = plasminogen activator inhibitor-1; SBP = systolic blood pressure. Vilsbøll T, Garber AJ. Diabetes Obes Metab. 212;14:41-49. GLP-1 Receptor Agonists Mechanisms of action Causes increased insulin secretion by increasing first phase secretion Decreases glucagon secretion Slows gastric emptying Decreases food intake (mediated through CNS) 1. Fehse F, et al. J Clin Endocrinol Metab. 25;9:5991-5997. 2. Kolterman OG, et al. J Clin Endocrinol Metab. 23;88:382-389. 3. Maekawa F, et al. J Neuroendocrinol. 26;18:748-756. 4. Rachman J, et al. Diabetes. 1996;45:1524-153. 13
Overview of GLP-1 Receptor Agonists Drug Exenatide Liraglutide Half Life 2 4 hours 12 14 hours Administration and Dosage 5 or 1 mcg twice/day 1.2 or 1.8 mg once/day FDA approved with basal insulin Yes Yes Exenatide LAR > 1 week 2. mg once/week No Weight Reduction With GLP-1 RAs: Summary of Clinical Trial Data Change in Weight (lb). -1. -2. -3. -4. -5. -6. -7. -8. -9. + None 1,2,a + SU 1 + MET 1 + SU/MET 1 + TZD ± MET 1 + MET ± SU 1-4. -5.1-5.5-3.5 -.4-8.1 a Background oral antihyperglycemic agent(s). MET = metformin. -6.2-6.2-5.1-3.5-4. -5.7-3.9-4.4-7. Exenatide 1 mcg twice daily Liraglutide 1.8 mg once daily Exenatide 2 mg every week 1. Mundil D. Diab Vasc Dis Res. 212;9:95-18 2. Poon T, et al. Diabetes Technol Ther. 25;7:467-477. 14
Long-Term Effects on Cardiovascular Risk Factors With GLP-1 RAs a HDL-C, mg/dl 1 TG, mg/dl TC, mg/dl +8.5 LDL-C, mg/dl SBP, mm Hg Diastolic BP, mm Hg Lipid and BP Changes From Baseline (%) -1-2 -3-4 * -1.8 * -11.8 * -3.5 * -3.3-5 * -44.4 a 217 patients with T2DM treated with GLP-1 RA daily for at least 3 years; * = p<.5 Klonoff, et al Current Medical Res Opin 24: 274, 28 GLP 1 Receptor Agonists: Place in Therapy At any time when target A1C is not being achieved As monotherapy As combination therapy In 2 drug combinations with metformin In 3 drug combinations In combination with basal insulin (Exenatide and Liraglutide) When certain goals are preferred When hypoglycemia is particularly undesirable When minimizing weight gain/weight reduction is an important consideration When actions complement those of other antihyperglycemic agents Inzucchi SE, et al. Diabetes Care. 212;35:1364-1379. 15
Insulin Therapy Points to Consider When Implementing Insulin Therapy Address patient concerns about insulin therapy Initial anxiety Provide education and support Feelings of personal failure Inform patient that type 2 diabetes is a progressive disease Fear of hypoglycemia Education about signs and symptoms as well as prevention and treatment Fear of injections Advise of availability of fine needles and injection devices Weight gain Adjust diet and exercise as needed Communicate benefits of insulin therapy Insulin therapy is safe, effective and flexible; it can reduce the risk of diabetes complications and improve quality of life 16
Indications To Initiate Insulin Therapy in Type 2 Diabetes Significant hyperglycemia at presentation Hyperglycemia despite diet, exercise and maximal doses of oral agents Significant Hyperglycemia At Presentation Two daily injections of a mix of intermediate and short acting insulin Often 7/3 insulin for starters Metformin (unless specific contraindication) Add pioglitazone as needed to achieve target Change insulin dose / type / number of injections as needed 17
Insulin As Initial Therapy in Type 2 Diabetes Study Design 63 treatment naive individuals with Type 2 diabetes for less than 2 months Ages 21 to 7 Years old Initiation of treatment with 7/3 twice daily (.2U/kg) plus metformin 5 mg per daily Insulin dose titrated upward based on targets ( FPG 7-11mg/dl, PPG <14 mg/dl) Weekly dose escalations of metformin of 5mg to target of 1 mg BID Study duration was 3 months Lingvay et al, J. Investigative Medicine 55: 62, 27 Initial Insulin Treatment in Type 2 Diabetes HbA1c Results (%) A1C 11 1 9 8 7 6 5 1.8 Baseline * 5.9 12 weeks * P<.1 vs baseline Lingvay et al. J Investigative Med. 55:62, 27 18
Initial Insulin Treatment in Type 2 Diabetes HbA1c Results % HbA1c 12 11.2% 1 8 6 4 2 6.4% 3 2 4 6 9 12 15 18 21 24 27 3 33 36 42 Time (months) Harrison, et al, et al Diabetes Care, 35:146, 212 Indications To Initiate Insulin Therapy in Type 2 Diabetes Significant hyperglycemia at presentation Hyperglycemia despite diet, exercise and maximal doses of oral agents 19
Hyperglycemia Despite Maximal Oral Treatment Begin at.4-.7 units/kg/day Continue insulin sensitizers especially metformin but often the thiazolidinedione Discontinue secretagogues and ά-glucosidase inhibitors Bedtime Insulin ( glargine, detemir or NPH) Two daily injections of a mixture of intermediate and short acting Insulin Often 7/3 for starters Change insulin dose/ type/ number of injections as needed to achieve glycemic targets Insulin is Better Than No Insulin! 2
What To Do When There is Basal Insulin Failure In No Particular Order Intensify using two or even three daily injections of Pre-mixed ( 7/3, 75/25) insulin Add a GLP-1 agonist Use a stepwise approach using pre-meal insulin before the largest meal. If that doesn t work, add insulin before the second largest meal. When all else fails add pre-meal insulin before all meals Switch to basal bolus therapy 21
How Often is There Basal Insulin Failure??? In studies with either insulin glargine or insulin detemir 5%-6% of subjects achieve a HbA1c of < than 7. % when a single daily injection of basal insulin is added to oral hypoglycemic agents Thus, there is close to a 5% basal insulin failure rate Two Shots of Insulin are Better Than One! 22
Comparison of Glargine + Metformin vs BID Analog Premix 75/25 + Metformin Study Design 91 individuals with poorly controlled Type 2 diabetes on tablets Age 3 to 8 years HbA1c between 1.3 and 2. times upper level of normal ( average 8.7%) 8 week lead in with metformin titrated to 15 255 mg plus NPH insulin at bed (FBG target 9 126mg/dl) Random assignment to metformin plus either Lispro 75/25 twice daily or glargine once daily Treatment crossover after 16 weeks FBG target 1 mg/dl Malone JK. Diab Med. 25;22:374 381. Comparison of Glargine + Metformin vs BID Insulin Lispro 75/25 + Metformin 8.8 Mean A1C (%) 8.6 8.4 8.2 8 7.8 7.6 Glargine Glargine * * * X 7.4 Premix Premix 7.2 4 8 12 16 2 24 28 32 Weeks on Study Malone JK. Diab Med. 25;22:374 381. 23
The Initiate Study Study Design 233 subjects with Type 2 diabetes with inadequate glycemic control on oral hypoglycemic agents HbA1c 8.% BMI 4 kg/m 2 Four week run-in: stop secretagogues and alpha glucosidase inhibitors, optimize metformin 15 mg/day, switch rosiglitazone to 3 mg pioglitazone Random assignment to either glargine 1 or 12 U at bed or 7/3 pre-breakfast (5 or 6 U) and pre-supper (5 or 6 U) Follow insulin titration schedule Study duration 28 weeks Raskin, et al Diabetes Care 28: 26, 25 INITIATE HbA1c % Reduction BIAsp 3 Glargine p-value All Subjects -2.79 ±.11-2.36 ±.11.57 Subjects with: HbA1c 8.5% -3.13 ± 1.63-2.6 ± 1.5.26 HbA1c <8.5% -1.4 ±.55-1.42 ±.59 >.5 Raskin, et al Diabetes Care 28: 26, 25 24
Phase 1 QD Phase 2 BID Phase 3 TID 1 2 3 Study Study Design Pre-dinner x 16 wks Start with 12 U at dinner Pre-breakfast & dinner x 16 wks Add 3 U at breakfast if FPG 11 Add 6 U at breakfast if FPG > 11 TID x 16 wks Add 3 U at lunch A1C 6.5% If A1C > 6.5%, go to BID, d/c secretagogues A1C 6.5% If A1C > 6.5%, go to TID End of Study End of Study Garber AJ et al, Diabetes Obes Metab. 26; 8: 58-66 1 Shot of Insulin Is Good, 2 Are Better ITT Population a (n = 1); Biphasic Insulin Aspart 7/3 Subjects (Cumulative %) 1 8 6 4 2 Mean baseline A1C level: 8.6% 77 7 41 <7.% (ADA) Rates of minor hypoglycemia Once Daily Twice Daily 3 Times Daily 15.4 22.4 12. a All patients enrolled in the trial. ITT = intention to treat. Garber AJ, et al. Diabetes Obes Metab. 8:58, 26 25
Stepwise Approach to Insulin Therapy in Patients with Type 2 Diabetes and Basal Insulin Failure Insulin glulisine 1x/d (n=115) Screening (N=1232) Run-in (n=785) A1C > 7.% Insulin glulisine 2x/d (n=113) +2 or 3 OADs + Insulin glargine + 2 or 3 OADs Randomization Insulin glulisine 3x/d (n=115) + Insulin glargine + Sensitizer(s) Discontinue SU Davidson, Raskin et al, Endocrine Practice 17:395, 211 Stepwise Approach to Insulin Therapy in Patients with Type 2 Diabetes and Basal Insulin Failure 46% * Patients (%) Achieving A1C <7.% at Week 24 3% 33% * = P<.5 vs 1 and 2 injections Davidson MB, Raskin P, et al. Endocr Pract 17:395 211. 26
GLP-1 Agonists Added to Basal Insulin A New Idea!!!! Addition of Exenatide to Basal Insulin Treated Patients with Type 2 Diabetes Study Design 259 type 2 diabetic individuals receiving insulin glargine alone or in combination with metformin and/or pioglitazone HbA1c between 7.1and 1.5% Random assignment to receive either exenatide or placebo injections, twice daily Insulin glargine could be titrated upwards using an algorithm designed to have the FBG <1 mg/dl after the first 5 weeks Prospective randomized masked trial Study duration was 3 weeks Buse, et al Ann In. Med 154:13. 211 27
Addition of Exenatide to Basal Insulin-Treated Patients with Type 2 Diabetes 7.1% * * 6.5% * = p <.1 vs. Placebo Buse et al, Ann Int Med 154:13,211 Effect of Metformin, Liraglutide, Plus Basal Insulin in Patients with Type 2 Diabetes Study Design Screening Run-In Period 12 Weeks Randomization Randomized Period 26 Weeks Metformin + Liraglutide (1.8 mg)* Metformin ± Sulfonylurea A1c 7% Randomized Treatment Group Metformin + Liraglutide 1.8 mg + Insulin Detemir Randomized Control Group Metformin + Liraglutide 1.8 mg -12 26 Time (Weeks) * Liraglutide initiated at.6 mg/day and titrated in weekly increments of.6 mg/day to final dose of 1.8 mg/day. DeVries, et al, Diabetes Care 35:1446,212 28
Basal Insulin Added to GLP 1 RAs in T2DM Change in A1C Level at 26 Weeks.2 MET + Lira 1.8 mg control (n = 157) MET + Lira + IDet (n = 162) Hypoglycemia Liraglutide plus insulin detemir Minor hypoglycemia 9.2% of liraglutide + insulin detemir group vs 1.3% of control group No major hypoglycemia P <.1 -.51 IDet = insulin detemir; Lira = liraglutide. Devries J, et al. Diabetes Care 35:1446, 212 Insulin Analog Insulin produced by technology that uses recombinant DNA to produce an insulin molecule that is slightly different from human insulin in structure as well as pharmacokinetic/ pharmacodynamic properties. 29
Time Action Profiles of Insulin Products Insulin Aspart, Insulin Glulisine, Insulin Lispro 4 6 hours Regular 6-8 hours NPH 12 2 hours Plasma Insulin Levels Insulin Glargine, Insulin Detemir up to 24 hours 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 24 Hours Skyler JS. Insulin treatment. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 3rd ed. Alexandria, Va: American Diabetes Association; 1998:186 23. Burge MR. Endocrinol Metab Clin North Am. 1997;26:575 598. Basal Bolus Therapy 3
Basal/Bolus Using Analog Insulin 75 Breakfast Lunch Supper Lispro/Aspart/Glulisine Insulin uu/ml 5 25 Bed Less potential for nocturnal hypoglycemia; improved FPG Glargine/Detemir Basal Insulin 4: 8: 12: 16: 2: 24: 4: Time Insulin Pumps 31
Basal/Bolus Using an Insulin Pump 75 Breakfast Lunch Supper Lispro Aspart Glulisine 5 Insulin U/mL 25 Basal Insulin 4: 8: 12: 16: 2: 24: 4: Time Comparison of Insulin Pump and Multiple Daily injection Treatment in Type 2 Diabetes Results CSII MDI Baseline 6 Months Baseline 6 months HbA1c 8.2 ± 1.4 7.6 ± 1.2 8. ± 1.1 7.5 ± 1.2 HbA1c (%) -----.62 ± 1.1 -----.46 ±.9 Body Weight(Kg) 96.4 ± 17 98.1 ± 18.1 96.9 ± 17. 9 97.6 ± 19.2 Hypoglycemic (% of subjects) ----- 54 ----- 59 Rate (episode/subject) -----.8 ± 1.6 ----- 1.2 ± 3.1 Nocturnal (% of subjects) 16 ----- 22 Raskin, et al, Diabetes Care 26:2598, 23 32
Conclusions Type 2 diabetes is a disease of progressive beta cell failure which explains frequent and early oral therapy failure After oral agent failure, injectable treatment with either GLP-1 agonists and/or insulin is indicated GlP-1 receptor analogs have reasonable HbA1c lowering effects with the risk of hypoglycemia or weight gain However, insulin treatment is usually inevitable and should be started sooner rather than later and treatment should be intensified as needed to meet HbA1c targets Basal insulin is a simple, reasonable starting place but basal insulin alone is successful only 5% of the time in achieving HbA1c targets Premixed insulin is a simple ( for the patient and the health care provider) therapy and is effective in having patients achieve their targets 6 to 7% of the time Multiple daily injection therapies and perhaps insulin pumps can be used when targets are not being achieved with less complicated regimens Brodee Thank You!! Any Questions? 33