Patient Centric Treatment of Diabetes: The Role of GLP 1 Inhibitors

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1 1:3 2:45pm Patient-Centric Treatment of Diabetes: The Role of GLP-1 Inhibitors SPEAKER Mark Molitch, MD Presenter Disclosure Information The following relationships exist related to this presentation: Mark E Molitch, MD, is a consultant for Janssen, Merck, Bristol- Myers Squibb, Astra-Zeneca, Novo Nordisk, Eli Lilly, Novartis and Abbott. Dr. Molitch also does research for Novartis, Lilly, Novo Nordisk and Bayer. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Patient Centric Treatment of Diabetes: The Role of GLP 1 Inhibitors Mark E. Molitch, M.D. Division of Endocrinology, Metabolism & Molecular Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Design treatment regimens for patients with T2DM, incorporating evidence based guidelines and best practices. Review the mechanism of action, safety, and efficacy profiles of GLP 1 inhibitors and incorporate these agents into T2DM treatment plans. Select and sequence therapies for patients with T2DM based on individual profiles, intensifying treatment if glycemic goals are not met. Develop effective patient education and communication skills to enhance adherence, outcomes, and appropriate referrals. Diagnosed and Undiagnosed Diabetes in the United States Total: 29.1 million people, or 9.3% of the US population, have diabetes. Diagnosed: 21. million people Undiagnosed: 8.1 million people 86 million adults (37%) over age 2 with prediabetes Good Glycemic Control (Lower A1C) Reduces Complications DCCT 1 Kumamoto 2 UKPDS 3 A1C: 9 7% 9 7% 8 7% Retinopathy 76% 69% 17 21% Nephropathy 54% 7% 24 33% Neuropathy 6% Macrovascular 41% 16% Not statistically significant DCCT = Diabetes Control and Complications Trial; Kumamoto = Kumamoto University School of Medicine study; UKPDS = UK Prospective Diabetes Study. CDC National Diabetes Fact Sheet, diabetes report web.pdf 1. DCCT Research Group. N Engl J Med. 1993;329: Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28: UKPDS Group. Lancet. 1998;352:

2 Glucose Treatment Targets (after ACCORD, ADVANCE, and VADT) Large randomized trials found no significant reduction in CVD risk with more intensive glucose control. ACCORD 1 ADVANCE 2 VADT 3 No. Subjects 1,251 11,14 1,791 Mean Age HbA1c (%) Intensive vs. Standard Rx 6.4 vs. 7.5% 6.4 vs. 7.% 6.9 vs. 8.4% Primary Results & Conclusions No decrease in CVD risk with intensive control. Increased mortality risk with intensive Rx No decrease in CVD risk with intensive control. Reduced risk of nephropathy with intensive Rx No decrease in CVD risk with intensive control Significant difference between intensive and standard group; ACCORD Trial halted intensive glucose group (2/6/8) Glycemic Control: Potential Benefits, Risks, and Unanswered Questions If diabetic retinopathy or renal disease is present, glycemic control is very important. Hypoglycemia Increases with intensity of glycemic control. Risk of it precipitating injury, myocardial infarction, seizure, stroke, or death is greatest in individuals who: Are frail and older Eat erratically Are on insulin and sulfonylureas Have decreased kidney function 1. ACCORD Study Group. N Engl J Med. 28;358: ADVANCE Collaborative Group. N Engl J Med. 28;358: VADT investigators. N Engl J Med. 29;36; Control of Diabetes: Guidelines for Treatment ADA 1 AACE 2 HbA1c (%) < Preprandial glucose (mg/dl) 7 13 <11 2-hour postprandial glucose (mg/dl) <18 <14 However, both groups acknowledge that: Lower goals may be appropriate for those with long life expectancy, on oral agents, and at low risk for hypoglycemia Higher goals may be appropriate for those with shorter life expectancy, comorbidities, chronic kidney disease, and at high risk for hypoglycemia Control of Diabetes: Patient Centric Goals of Treatment Glycemic Goals Numerous studies have now shown benefits of achieving A1c goals of <7% to prevent or delay the microvascular complications of diabetes. While continued benefit occurs with an A1c <7%, the slope (rate of improvement in risk for reduction in A1c) becomes relatively flat, and the risk for hypoglycemia increases substantially. 1. ADA. Standards of medical care. Diabetes Care. 215;38(suppl 1):S1 S Mechanick JI et al. Endocr Pract. 213;19: cell function (%) Changes in Cell Function Over Time IGT Lebovitz H. Diabetes Rev. 1999;7: Postprandial hyperglycemia Time of diagnosis of type 2 diabetes Years from diagnosis Dashed line shows extrapolation forward and backward from years to 6 based on HOMA data from UKPDS. With increasing duration of treatment, clinicians may need to add more and more drugs or change to insulin to achieve adequate glycemic control. Postprandial glucose 35 3 Glucose Onset Diagnosis 25 (mg/dl) 2 15 Fasting glucose % Beta cell function Natural History of Type 2 Diabetes At risk for cell diabetes dysfunction Years R. Bergenstal and D. Kendall, International Diabetes Center. Insulin resistance Insulin level

3 Control of Diabetes: Lifestyle Change: the Cornerstone of Treatment With weight loss, insulin sensitivity improves. With exercise, insulin sensitivity improves. Lifestyle change can result in substantial improvement in insulin sensitivity, allowing the amount of insulin still being made by the pancreas to work better and be more responsive to oral agents. Major Targeted Sites of Drug Classes Liver Hepatic glucose overproduction Kidney Thiazolidinediones GLP 1 agonists DPP IV inhibitors Glucose reabsorption Pancreas Beta cell dysfunction Glucose level Glucose absorption Sulfonylureas Meglitinides GLP 1 Agonists DPP IV inhibitors Gut Muscle and fat Insulin resistance Thiazolidinediones Alpha glucosidase inhibitors GLP 1 agonists Pramlintide SGLT2 inhibitors Medications to Treat Diabetes (1) Sulfonylureas (glipizide, glyburide, glimepiride) Oldest class, potent High risk of hypoglycemia (especially with glyburide) Weight gain common Less likely to maintain control as monotherapy Meglitinides (nateglinide, repaglinide) Less potent Moderate risk of hypoglycemia Some weight gain Short acting, take TID with meals Long experience, potent GI intolerance Very rare lactic acidosis (susceptible patients); cannot use if GFR Weight neutral Generally recommend as first line oral agent, if tolerated Medications to Treat Diabetes (2) (Revised) Thiazolidinediones (rosiglitazone, pioglitazone) Moderately potent Can cause fluid retention, worsen CHF Weight gain common Fractures increased (distal arm and foot) Disaccharidase inhibitors (acarbose, miglitol) Less potent Cause increased intestinal gas poor tolerance Glucagon like peptide 1 (GLP 1) receptor agonists (exenatide, liraglutide, albiglutide, dulaglutide) DPP IV Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) Colesevelam SGLT2 Inhibitors DPP IV = dipeptidyl peptidase IV; SGLT2 = sodium glucose cotransporter 2. Medications Used to Treat Diabetes (3) GLP 1 Analogs Albiglutide Dulaglutide Lixisenatide Plasma glucose (mg/dl) 2 1 The Incretin Effect in Healthy Subjects Oral glucose Intravenous (IV) glucose Time (min) C peptide (nmol/l) Incretin effect Time (min) Approved in the EU, but not US. Nauck MA et al. J Clin Endocrinol Metab. 1986;63:

4 IR insulin, mu/l The Incretin Effect in Subjects Without and With Type 2 Diabetes Control subjects (n=8) Incretin effect 6 12 Time, min Oral glucose load Intravenous (IV) glucose infusion nmol / L IR insulin, mu/l Patients with type 2 diabetes (n=14) The incretin effect is diminished in type 2 diabetes Time, min nmol/l GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Beta cells: Enhances glucosedependent insulin secretion Brain: Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted with permission from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer Verlag. Flint A et al. J Clin Invest. 1998;11: Larsson H et al.acta Physiol Scand. 1997;16: Nauck MA et al. Diabetologia. 1996;39: Drucker DJ. Diabetes. 1998;47: GLP 1 Secretion and Metabolism GLP 1 Secretion and Metabolism Intestinal GLP 1 release Mixed meal Plasma GLP 1(7 36) active DPP IV Rapid inactivation (T 1/2 <2min) GLP 1(9 36) inactive Intestinal GLP 1 release Mixed meal Plasma GLP 1(7 36) active DPP IV inhibitors DPP IV Rapid inactivation (T 1/2 <2min) GLP 1(9 36) inactive GLP 1 actions Renal clearance GLP 1 actions Renal clearance Adapted from Deacon CE et al. Diabetes. 1995;44: Adapted from Deacon CE et al. Diabetes. 1995;44: GLP 1 Receptor Agonists: Dosing Considerations Agent Albiglutide Dulaglutide (long-acting) Dosing Considerations Subcutaneous injection once weekly Initiate at 3 mg subcutaneously once weekly; increase to 5 mg once weekly as needed Subcutaneous injection once weekly Initiate at.75 mg subcutaneously once weekly; increase to 1.5 mg once weekly as needed Subcutaneous injection once weekly Administer 2 mg once weekly Subcutaneous injection within 6 minutes of morning and evening meals (or two main meals of the day) (short-acting) Initiate at 5 mcg per dose; increase to 1 mcg twice daily after 1 month as needed Subcutaneous injection once daily Initiate at.6 mg per day for one week; increase dose to 1.2 mg after 1 week; increase to 1.8 mg as needed See prescribing information for limitations to indications and additional dosing considerations Prescribing information for albiglutide, dulaglutide, liraglutide, and exenatide. Available at: Change in HbA 1c (%) Buse JB et al. Lancet. 29;374: vs. Change in HbA 1c baseline 8.2% P<.1 baseline 8.2% Bodyweight (kg) Change in body weight Time (Weeks) Patients receiving maximally tolerated doses of metformin, sulfonylurea, or both stratified by previous oral therapy and randomized to liraglutide 1.8 mg once daily vs. exenatide 1 μg BID = Not significant

5 Effects of Once Weekly, Long Acting Over 15 Weeks Once Weekly Albiglutide vs. Once Daily in T2DM over 32 weeks (Harmony 7 Study) Albiglutide HbA 1C change (%) P <.1 Placebo EXE LAR.8mg/wk EXE LAR 2mg/wk 1.4 P < Fasting BG change (mg/dl) P < Placebo EXE LAR.8mg/wk EXE LAR 2mg/wk P < Non inferiority P=.846 for comparison with liraglutide. Injection-site reactions Albiglutide 12.9% 5.4% GI events 35.9% 49.% P<.2 EXE = exenatide; LAR = long acting release Kim D et al. Diabetes Care. 27;3: Pratley RE et al. Lancet Diab Endocrinol. 214;2: Week Prospective, Randomized Study Comparing Once Weekly Dulaglutide vs Use INSTEAD of Insulin: vs. Once Daily Insulin Glargine: 26 Week Results HbA 1c change from baseline (%, LSM+SE) Treatment difference =.6%, 95% CI.19% to.7%.2 P (non inferiority) < Dulaglutide (n= 299) (n=3) Dungan KM et al. Lancet. 214;384: HbA 1c change from baseline (mmol/mol, LSM/SE) Blood glucose (mg/dl) mcg BID A1C: Both lowered A1C from 8.2% to 7.1%. Weight: ( 2.3 kg); insulin glargine (+1.8 kg) Nausea: (57.1%); insulin glargine (8.6%) Heine RJ et al. Ann Intern Med. 25;143: Baseline (week ) Endpoint (week 26) Insulin glargine titrated to FPG <1 mg/dl Baseline (week ) Endpoint (week 26) Use INSTEAD of Insulin: Change in A1C (%) A1C 1.5 P < mg once daily Insulin glargine 1.1 Russell Jones D et al. Diabetologia.29;52: vs. Once Daily Insulin Glargine: 26 Week Results Weight change (kg) Major hypoglycemia (events/pt-year) Minor hypoglycemia (events/pt-year) Glargine Insulin Therapy in Type 2 Diabetes: Indications Significant hyperglycemia at presentation Hyperglycemia despite maximal doses of oral agents Decompensation Acute injury, stress, infection Severe hyperglycemia with ketonemia and/or ketonuria Uncontrolled weight loss Surgery Pregnancy Renal disease Allergy or serious reaction to oral agents American Diabetes Association. Medical Management of Non Insulin Dependent (Type II) Diabetes, 3rd ed. 1994:44 48.

6 The Basal/Bolus Insulin Concept Basal insulin Suppresses glucose production between meals and overnight Nearly constant levels 5% of daily needs Bolus insulin (mealtime or prandial) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 1 2% of total daily insulin requirement at each meal Basal insulin primarily improves FPG control Combination Therapy: Incretins + Insulin Glucose dependent effects of incretins can additionally benefit PPG Adding incretin to insulin Offset weight gain associated with insulin Reduce or neutralize hypoglycemia Provide additive glycemic control Adding insulin to incretin Limited evidence: GLP 1RA may continue to make a significant contribution to glucose lowering 6-2 Vora, J. Diabetes Care. 213;36(Suppl 2):S226 S232. Ahluwalia R, et al. Diabetes Ther. 211;2(3): Combination Glargine Plus : Change from Baseline in Hemoglobin A1c Hemoglobin A 1c level (%) Week 2 3 P <.1 for between group comparisons. Buse JB et al. Ann Intern Med. 211;154: Insulin glargine + placebo Insulin glargine + exenatide Combination Therapy: Incretins + Insulin Practical Considerations Complementary actions of basal insulin and incretins, regardless of sequence of introduction BP/weight/lipid reductions may be attractive for obese patients and those with CV risk/disease Note: CV outcomes are NOT established with incretins; trials are underway (e.g., LEADER trial) Insulin reductions of 15 63% when adding a GLP 1RA to insulin; unchanged with addition of DPP IV in clinical trials D/C of insulin is not advised when adding incretin; data show worsening glycemic control for 5% of patients when d/c insulin. Possible tolerability advantages of DPP 4s (e.g., oral administration, less nausea) must be weighed against GLP 1RA efficacy advantages. Review cost burden Vora, J. Diabetes Care. 213;36(Suppl 2):S226 S232. Eng C, et al. Lancet. 214;384(9961): Inzucchi SE et al. Diabetes Care. 215;38: GLP 1 RAs: Boxed Warnings GLP 1 RAs: Safety Considerations Agent Albiglutide Dulaglutide (long-acting) Boxed Warnings Thyroid C cell tumors have been observed in rodent studies with GLP 1 RAs at clinically relevant exposures. It is unknown whether these agents cause thyroid C cell tumors, including medullary thyroid carcinoma (MTC), in humans. Contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2. No current boxed warnings for short acting. Agent Albiglutide Adverse Reactions Upper respiratory tract infection, diarrhea, nausea, injection site reaction Dulaglutide Nausea, diarrhea, vomiting, abdominal pain, decreased appetite Nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, (long-acting) dizziness, headache, dyspepsia, constipation, asthenia. (short-acting) Nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Increased INR with concomitant use of warfarin, sometimes with bleeding. Headache, nausea, diarrhea, anti liraglutide antibody formation, immunogenicity related events (e.g., urticaria) Prescribing information for albiglutide, dulaglutide, liraglutide, and exenatide. Available at: Prescribing information for albiglutide, dulaglutide, liraglutide, and exenatide. Available at:

7 Other Warnings with GLP 1 Receptor Agonists Pancreatitis Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with pancreatitis history. Hypoglycemia when used with secretagogues Consider lowering dose of insulin secretagogue (eg, sulfonylurea) or insulin to reduce risk. Renal Impairment should not be used when GFR<3 ml/min; dulaglutide, albiglutide, and liraglutide can be used at any GFR. For all, use caution when initiating/escalating doses. Severe gastrointestinal disease Do not use in these patients. Acute Pancreatitis Crude Incidence Rates from Time on Drug Analysis Incidence rate/ 1, PY Current use Recent use Past use N = 25,719 Antidiabetic drugs N = 234,536 vs. Other Drugs Adjusted Rate Ratio 95% CI Current use Recent use Past use prescribing information; Rev 215. Dulaglutide prescribing information; Rev 214. Albiglutide prescribing information; Rev 214. prescribing information; Rev 215. Bloomgren G et al. Presented at ADA, 69th Scientific Sessions. 29; New Orleans, LA: (158 OR). (Presentation available online) DPP 4 Inhibitors Agents: alogliptin, linagliptin, saxagliptin, sitagliptin Increase endogenous GLP 1 and GIP by decreasing degradation Glucose dependent insulin secretion Not associated with weight gain when glycemic control improved Well tolerated with few adverse effects Doses adjusted for renal insufficiency for sitagliptin, saxagliptin and alogliptin but not necessary for linagliptin Efficacious when used in combination with other oral antidiabetic agents Clinical Effects of GLP 1 Receptor Agonists and DPP 4 Inhibitors GLP 1 Receptor Agonists HbA1c reduction:.6% to 1.5% Significant and sustained weight loss generally observed Injected therapy (BID) Most common GI adverse effects include nausea and diarrhea, particularly with initiation Low rates of hypoglycemia Multiple mechanisms of action Increased insulin secretion Decreased glucagon release Reduced food intake with weight loss Slowed gastric emptying Possible increase in pancreatitis DPP 4 Inhibitors HbA1c reduction:.5% to 1.% Weight neutral Oral administration No significant GI adverse effects Low rates of hypoglycemia Improved meal related insulin secretion Reduced glucagon release Can reduce dose and use in renal insufficiency Aschner P et al. Diabetes Care. 26;29: Charbonnel B et al. Diabetes Care. 26;29: Sitagliptin prescribing information; Rev 215. Saxagliptin prescribing information; Rev 214. Alogliptin prescribing information; Rev 213. Linagliptin prescribing information; Rev 214. Kendall et al. Am J Med. 29;122(6 Suppl 1):S37 S5. Meta Analysis for Risk of Pancreatitis in Randomized Studies of Patients Receiving DPP 4 Inhibitors vs. Comparators 25 Studies 2 events in 11,553 (.17%) patients treated with DPP 4 Inhibitors 16 events in 8,973 (.18%) patients treated with comparators Antihyperglycemic Monotherapy Maximum Therapeutic Effect on HbA1c Nateglinide Acarbose Sitagliptin Repaglinide Canagliflozin Pioglitazone Glipizide Reduction HbA1c (%) Monami M et al. Diabetes Obes Metab. 214;16: Hanefeld M et al. Diabetes Care. 2;23: Acarbose prescribing information. Wolffenbuttel BH, van Haeften TW. Drugs. 1995;5: Lebovitz HE et al. J Clin Endocrinol Metab. 21;86: Aronoff S et al. Diabetes Care. 2;23: Goldberg RB et al. Diabetes Care. 1996;19: Simonson DC et al. Diabetes Care. 1997;2: Garber AJ et al. Am J Med. 1997;13: Buse JB et al. Lancet. 29;374: Stenlöf K et al. Diab Obes Metab. 213;15:

8 ADA/EASD Position Statement: Considerations When Adding 2nd or 3rd Drug to + SU TZD DPP-4 GLP-1 SGLT2 Insulin HbA 1c High Low Low Low Low High Weight Gain Gain Neutral Loss Loss Gain Side effects Edema, CHF, Fx Rare GI Candida Hypoglycemia Hypoglycemia Hypoglycemia Cost Low Low High High High High Obesity: Special Considerations Weight gain Weight Modestneutral Significant Modest Pioglitazone SUs Glyburide Glipizide Insulin NPH Glargine Regular Aspart Lispro Glulisine SUs Glimepiride Glipizide XL Glinides Repaglinide Nateglinide Insulin Detemir Glulisine DPP-4 Inhibitors Sitagliptin Saxaglipitin Linagliptin Alogliptin a-glucosidase Inhibitors Colesevelam Bromocriptine Weight loss GLP-1 Analogs ER Albiglutide Pramlintide SGLT2 Inhibitors Inzucchi SE et al. Diabetes Care. 215;38: Mitri J, Hamdy O. Expert Opin Drug Saf. 29;8: How Do We Get Our Patient to A1c and BMI Goals? Education, adherence, monitoring, communication, motivational interviewing It is hard to keep up with lifestyle interventions, and most clinicians motivate patients to keep trying. Patients need to learn about aspects of insulin resistance and progressive islet cell failure. Measuring daily fasting blood glucose can serve to reinforce benefits of diet/exercise. Patient education and communication are key. Barriers to Diabetes Control Clinical inertia Financial Adverse effects of oral agents Fear of injections with injectible therapy (e.g., insulin, GLP 1 RA s) Insulin Fear of hypoglycemia Complexity of management Targets of treatment Need to adjust to individual patient Cultural Psychological insulin resistance Poor Adherence and Persistence Rates in Oral Antidiabetic Therapy Clinical Inertia Over 12 months: 37% of patients discontinued therapy 1.5% of patients failed to fill a second Rx for any hypoglycemic agent About 46% of patients were nonadherent. Nonadherence (%) Percentage of Adults Years Old With Nonadherence, by Therapeutic Class Physician Patient Nonadherence = Medication Possession Ratio <8% TZD=thiazolidinediones; SU=sulfonylureas; MET=metformin; AGI=a glucosidase inhibitors; MEG=meglitinides Hertz RP, et al. Clin Ther. 25;27:

9 Most Patients With T2DM May Fail to Attain A1C Goal With Conventional Treatment Paradigm Mean A1C of patients 1 9 Diet and exercise MonoRx up titration combo + basal insulin + multiple daily insulin injections Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy A1C, % 1 9 Diet and exercise MonoRx up titration combo + basal insulin + multiple daily insulin injections A1C, % 8 7 Mean A1C of patients Duration of diabetes 6 Duration of diabetes Conventional treatment Earlier, more aggressive treatment Adapted from Del Prato S et al. Int J Clin Pract. 25;59: Adapted from Del Prato S et al. Int J Clin Pract. 25;59: Factors Influencing Therapeutic Choices Medical needs and treatment goals A1C level and distance from target Postprandial glycemia Costs (immediate vs. long term savings from decreased complications) Safety (hypoglycemia) Need for flexibility in treatment program Patient issues with respect to insulin use Intellect and judgment Psychosocial and cultural considerations Physical capabilities and limitations Other medical conditions and issues relating to use of other noninsulin medications For patients with advanced diabetes complications, life limiting comorbid illness, or cognitive or functional impairment, it is reasonable to set less intensive target goals. Referral Considerations Endocrinologist/Diabetes Specialist: Individualized patient goals not met after 6 months of intensive treatment A1C 8.% for 6 months or any A1C 1.4 x upper limit of normal % Recurrent episodes of severe hypoglycemia Continuous glucose monitoring Initiation of insulin pump therapy or physiologic insulin regimen Eye care specialist Evaluate for presence of retinopathy Dietician/diabetes educator/behavioral health specialist Medical nutrition therapy Physical activity and monitoring Non adherence, motivation, coping strategies, support Ongoing education Others (e.g., nephrologist, cardiologist) as necessary Ganda, O, et al. Joslin Diabetes Center Guideline for Specialty Consultation/Referral Conclusions: Diabetes is chronic and progressive /lifestyle change: cornerstones of therapy Multi modal therapy is typically eventually needed Select therapies based on individual profiles Intensify treatment if glycemic goals are not met Not reaching goal = multifactorial Weight loss, avoidance of hypoglycemia and adherence are key to monitor throughout care Patient education, communication, and referrals, when necessary, are critical for optimal management Use what s effective AND safe for patient