Speaker Disclosures 6/17/ :07 AM. Management of Type 2 Diabetes: From Pathophysiology to Pharmacology

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1 Speaker Disclosures Management of Type 2 Diabetes: From Pathophysiology to Pharmacology Barry S. Horowitz, MD, FACE, FACP Clinical Research: Eli Lilly, NovoNordisk, Amgen, Pfizer, Sanofi, GSK, Lexicon, BDSI, BI, Bayer, Veracyte, vtv Theraputics. Speaker: Eli Lilly, NovoNordisk, Amgen, BI, Merck, Takeda, Astra-Zeneca, Abbvie, Janssen, Vivus. Consultant: none. Age-Adjusted Adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults 1994 Obesity (BMI 3 kg/m 2 ) Diabetes Missing Data <14.% 14.% 17.9% 18.% 21.9% 22.% 25.9% 26.% Missing data <4.5% 4.5% 5.9% 6.% 7.4% 7.5% 8.9% 9.% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at Age-Adjusted Adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults 24 Age-Adjusted Adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults 213 Obesity (BMI 3 kg/m 2 ) Diabetes Obesity (BMI 3 kg/m 2 ) Diabetes Missing Data <14.% 14.% 17.9% 18.% 21.9% 22.% 25.9% 26.% Missing data <4.5% 4.5% 5.9% 6.% 7.4% 7.5% 8.9% 9.% Missing Data <14.% 14.% 17.9% 18.% 21.9% 22.% 25.9% 26.% Missing data <4.5% 4.5% 5.9% 6.% 7.4% 7.5% 8.9% 9.% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at 1

IDF Global Projections for Number of People with Diabetes, 21-2323 Clinical Impact of Diabetes Mellitus Heart disease and stroke Account for 65% of deaths 2- to 4-fold

retinopathy causes 12, to 24, new cases of blindness/year Serves as leading cause of new cases of blindness in adults 2-74 years of age Amputations More than 6% of

http://www.diabetes.org/diabetes-basics/diabetes-statistics/ Last accessed: March 3, 29.

International Diabetes Center 29 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 28;359:1577. DCCT Research Group.

2 IDF Global Projections for Number of People with Diabetes, Clinical Impact of Diabetes Mellitus Heart disease and stroke Account for 65% of deaths 2- to 4-fold increase in cardiovascular disease death rates Kidney disease Diabetes is the leading cause of ESRD Accounted for 44% of new cases in 25 Diabetes Blindness Diabetic retinopathy causes 12, to 24, new cases of blindness/year Serves as leading cause of new cases of blindness in adults 2-74 years of age Amputations More than 6% of nontraumatic lower-limb amputations occur in people with diabetes 1-fold increase in amputation rate IDF Diabetes Atlas, 4 th ed. International Diabetes Federation, Last accessed: March 3, 29. Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 29 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 28;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 25;353:2643. Gerstein HC et al. N Engl J Med. 28;358:2545. Patel A et al. N Engl J Med 28;358:256. Duckworth W et al. N Engl J Med 29;36:129. (erratum: Moritz T. N Engl J Med 29;361:124) Initial Trial Long Term Follow-up in T1DM 2

3 Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors Update on Metformin New Basal Insulins Glargine U3 Insulin Degludec Discussion Topics Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors Update on Metformin New Basal Insulins Glargine U3 Insulin Degludec Discussion Topics Incretins Incretin Effect 18 3

Physiological Role of the Incretins in Healthy Individuals The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) IR Insulin,

Diabetologia. 1986;29:46 52. Copyright 1986 Springer-Verlag. Permission pending.

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 <.

21 Glucagon pmol/l 2 15 15 When glucose levels 1 approach normal values, 1 glucagon levels rebound. 5 5 Infusion 3 6 12 18 24 Minutes Adapted from Nauck MA et al. Diabetologia. 1993;36:741 744.

4 Physiological Role of the Incretins in Healthy Individuals The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) IR Insulin, mu/l Incretin Effect nmol / L IR Insulin, mu/l The incretin effect is diminished in type 2 diabetes nmol/l Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion Adapted from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag. Permission pending. 18 Pancreatic Islet Dysfunction Leads to Insufficient Insulin and Elevated Glucagon in Type 2 Diabetes Glucose-Dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in Patients With Type 2 Diabetes Glucose mmol/l mg/dl Placebo GLP-1 P <.5 Patients with type 2 diabetes (N=1) Insulin pmol/l mu/l When glucose levels approach normal values, insulin levels decrease. 21 Glucagon pmol/l When glucose levels 1 approach normal values, 1 glucagon levels rebound. 5 5 Infusion Minutes Adapted from Nauck MA et al. Diabetologia. 1993;36: Copyright 1993 Springer-Verlag. Permission pending 2 pmol/l Incretins Play an Important Role in Glucose Homeostasis Food ingestion GI tract Release of gut hormones Incretins 1,2 Pancreas 2,3 Active GLP-1 & GIP Inactive GLP-1 DPP-4 enzyme Inactive GIP Glucose Dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose Dependent Glucagon from alpha cells (GLP-1) Glucose uptake by peripheral tissue 2,4 Glucose production by liver Blood glucose DPP-4 INHIBITORS 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;2: Ahrén B. Curr Diab Rep. 23;2: Drucker DJ. Diabetes Care. 23;26: Holst JJ. Diabetes Metab Res Rev. 22;18:

5 FDA-Approved Agents Alogliptin Linagliptin Saxagliptin Sitagliptin DPP-4 Inhibitors DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 213;19(suppl 2):1-48. Key Features Oral administration Increase endogenous GLP-1 and GIP levels by inhibiting DPP4 Increase glucosedependent insulin secretion Suppress glucagon production No major effects on appetite or gastric emptying 25 Glucose Control with DPP-4 Inhibitors Placebo-Adjusted Change from Baseline Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin1, Sax11 Sit12, Baseline A1C (%) Placebo-adjusted A1C (%) SU + metformin. With or without metformin. Absolute change from baseline (active-controlled trial). 1. DeFronzo RA, et al. Diabetes Care. 28;31: Del Prato S, et al. Diabetes Obes Metab. 211;13: Rosenstock J, et al. Curr Med Res Opin. 29;25: Nauck MA, et al. Diabetes Obes Metab. 27;9: Nauck MA, et al. Int J Clin Pract. 29;63: Taskinen MR, et al. Diabetes Obes Metab. 211;13: DeFronzo RA, et al. Diabetes Care. 29;32: Charbonnel B, et al. Diabetes Care. 26;29: Pratley RE, et al. Diabetes Obes Metab. 29;11: Owens DR, et al. Diabet Med. 211;28: Chacra AR, et al. Int J Clin Pract. 29;63: Hermansen K, et al. Diabetes Obes Metab. 27;9: Weight Change with DPP-4 Inhibitors Absolute Change from Baseline Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin1, Sax11 Sit12, Hypoglycemia with DPP-4 Inhibitors Percentage of Patients Reporting Hypoglycemia Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin1, Sax11 Sit12, Weight (kg) NR NR Patients (%) NR, value not reported. SU + metformin. With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 28;31: Del Prato S, et al. Diabetes Obes Metab. 211;13: Rosenstock J, et al. Curr Med Res Opin. 29;25: Nauck MA, et al. Diabetes Obes Metab. 27;9: Nauck MA, et al. Int J Clin Pract. 29;63: Taskinen MR, et al. Diabetes Obes Metab. 211;13: DeFronzo RA, et al. Diabetes Care. 29;32: Charbonnel B, et al. Diabetes Care. 26;29: Pratley RE, et al. Diabetes Obes Metab. 29;11: Owens DR, et al. Diabet Med. 211;28: Chacra AR, et al. Int J Clin Pract. 29;63: Hermansen K, et al. Diabetes Obes Metab. 27;9: NR, value not reported. SU + metformin. With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 28;31: Del Prato S, et al. Diabetes Obes Metab. 211;13: Rosenstock J, et al. Curr Med Res Opin. 29;25: Nauck MA, et al. Diabetes Obes Metab. 27;9: Nauck MA, et al. Int J Clin Pract. 29;63: Taskinen MR, et al. Diabetes Obes Metab. 211;13: DeFronzo RA, et al. Diabetes Care. 29;32: Charbonnel B, et al. Diabetes Care. 26;29: Pratley RE, et al. Diabetes Obes Metab. 29;11: Owens DR, et al. Diabet Med. 211;28: Chacra AR, et al. Int J Clin Pract. 29;63: Hermansen K, et al. Diabetes Obes Metab. 27;9: Safety Considerations with DPP-4 Inhibitors DPP4s: Other Safety Issues GI adverse events Pancreatitis Pancreatic cancer Renal impairment Minimal Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >8, patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Extensive review by FDA of studies involving >8, patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Further assessments required from long duration-controlled studies or epidemiological databases Kidney function monitoring and dose reduction required for alogliptin, saxagliptin, and sitagliptin when used in patients with moderate-to-severe renal impairment Linagliptin does not require dose adjustment or periodic monitoring of drug-related kidney function Garber AJ, et al. Endocr Pract. 213;19(suppl 2):1-48. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, Saxagliptin and Alogliptan had an increase in hospitalizations for CHF in their respective CV outcomes studies, especially in patients who already had cardiovascular or renal disease New labeling reflects this Sitagliptin and Linogliptin do not have this labeling as their outcomes studies did not show this 3 5

6 GLP-1 Receptor Agonists GLP-1 RECEPTOR AGONISTS 31 FDA-Approved Agents Albiglutide Dulaglutide Exenatide Exenatide ER Liraglutide ER, extended release; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 213;19(suppl 2):1-48. Key Features Injectable administration Mimic action of native GLP-1 Increase glucosedependent insulin secretion Suppress glucagon production Slow gastric emptying Suppress Appetite 32 Glucose Control with GLP-1 Receptor Agonists Placebo-Adjusted Change from Baseline Weight Change with GLP-1 Receptor Agonists Absolute Change from Baseline Monotherapy Add-on to Metformin Add-on to SU Monotherapy Add-on to Metformin Add-on to SU Alb1 Dul2 Exe3 Exe ER 4 Lir5 Alb6 Dul7 Exe8 Exe ER 9 Lir 1 Alb 11, Exe 12 Exe Lir 14 ER 13, Alb1 Dul2 Exe3 Exe ER 4 Lir5 Alb6 Dul7 Exe8 Exe ER 9 Lir 1 Alb 11, Exe 12 Exe Lir 14 ER 13, Baseline A1C (%) Placebo-adjusted A1C (%) Weight (kg) Metformin with or without SU or TZD. Metformin with or without SU. Absolute change from baseline (active-controlled trial). Metformin with or without SU or TZD. Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 214;37: Moretto TJ, et al. Clin Ther. 28;3: Russell-Jones D, et al. Diabetes Care. 212;35: Garber A, et al. Lancet. 29;373: Ahrén B, et al. Diabetes Care. 214;37: Dungan KM, et al. Lancet. 214;384: DeFronzo RA et al. Diabetes Care. 25;28: Bergenstal RM, et al. Lancet. 21;376: Pratley RE, et al. Lancet. 21;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 214;2: Buse JB, et al. Diabetes Care. 24;27: Diamant M, et al. Lancet. 21;375: Marre M, et al. Diabet Med. 29;26: Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 214;37: Moretto TJ, et al. Clin Ther. 28;3: Russell-Jones D, et al. Diabetes Care. 212;35: Garber A, et al. Lancet. 29;373: Ahrén B, et al. Diabetes Care. 214;37: Dungan KM, et al. Lancet. 214;384: DeFronzo RA et al. Diabetes Care. 25;28: Bergenstal RM, et al. Lancet. 21;376: Pratley RE, et al. Lancet. 21;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 214;2: Buse JB, et al. Diabetes Care. 24;27: Diamant M, et al. Lancet. 21;375: Marre M, et al. Diabet Med. 29;26: Hypoglycemia with GLP-1 Receptor Agonists Percentage of Patients Reporting Hypoglycemia Monotherapy Add-on to Metformin Add-on to SU Alb1 Dul2 Exe3 Exe ER 4 Lir5 Alb6 Dul7 Exe8 Exe ER 9 Lir 1 Alb 11, Exe 12 Exe Lir 14 ER 13, GI adverse events Pancreatitis Safety Considerations with GLP1 Receptor Agonists Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >8, patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Patients (%) Pancreatic cancer Medullary thyroid cancer Extensive review by FDA of studies involving >8, patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Further assessments required from long duration-controlled studies or epidemiological databases Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking Labeling : Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid tumors Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia syndrome type 2 Metformin with or without SU or TZD. Metformin with or without SU. 1. Nauck M, et al. Diabetes. 213;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 214;37: Moretto TJ, et al. Clin Ther. 28;3: Russell-Jones D, et al. Diabetes Care. 212;35: Garber A, et al. Lancet. 29;373: Ahrén B, et al. Diabetes Care. 214;37: Dungan KM, et al. Lancet. 214;384: DeFronzo RA et al. Diabetes Care. 25;28: Bergenstal RM, et al. Lancet. 21;376: Pratley RE, et al. Lancet. 21;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 214;2: Buse JB, et al. Diabetes Care. 24;27: Diamant M, et al. Lancet. 21;375: Marre M, et al. Diabet Med. 29;26: Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, Renal or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide impairment is contraindicated in patients with severe renal insufficiency or ESRD ER, extended release. Garber AJ, et al. Endocr Pract. 213;19(suppl 2):1-48. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28,

Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2

Insulin Degludec Discussion Topics FDA-Approved Agents

Key Features Oral administration Inhibit reabsorption of

control Weight loss Blood pressure reduction SGLT2,

7 Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors Update on Metformin New Basal Insulins Glargine U3 Insulin Degludec Discussion Topics FDA-Approved Agents Canagliflozin Dapagliflozin Empagliflozin SGLT2 Inhibitors Key Features Oral administration Inhibit reabsorption of glucose into the bloodstream from the kidney Improve glycemic control Weight loss Blood pressure reduction SGLT2, sodium-glucose cotransporter 2. DeFronzo RA, et al. Diabetes Obes Metab. 212;14:

8 Glucose Control with SGLT2 Inhibitors Placebo-Adjusted Change from Baseline Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9 Weight Change with SGLT2 Inhibitors Absolute Change from Baseline Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9 Baseline A1C (%) Placebo-adjusted A1C (%) Weight (kg) Absolute change from baseline (active-controlled trial). 1. Stenlof K, et al. Diabetes Obes Metab. 213;15: Ferrannini E, et al. Diabetes Care. 21;33: Roden M, et al. Lancet Diabetes Endocrinol. 213;1: Cefalu WT, et al. Lancet. 213;382: Nauck MA, et al. Diabetes Care. 211;34: Haring HU, et al. Diabetes Care. 214;37: Yale J-F, et al. Diabetes Obes Metab. 213;15: Wilding JPH, et al. Ann Intern Med. 212;156: Rosenstock J, et al. Diabetes Care. 214;37: Stenlof K, et al. Diabetes Obes Metab. 213;15: Ferrannini E, et al. Diabetes Care. 21;33: Roden M, et al. Lancet Diabetes Endocrinol. 213;1: Cefalu WT, et al. Lancet. 213;382: Nauck MA, et al. Diabetes Care. 211;34: Haring HU, et al. Diabetes Care. 214;37: Yale J-F, et al. Diabetes Obes Metab. 213;15: Wilding JPH, et al. Ann Intern Med. 212;156: Rosenstock J, et al. Diabetes Care. 214;37: Blood Pressure Change With Canagliflozin Monotherapy 26 Weeks 1 Add-on to Metformin 12 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Metformin + SU 52 Weeks 4 Add-on to OAs +/- Insulin in CKD 26 Weeks 5 N Treatment (mg/day) PBO Can Met Sit + Met Can + Met Glim + Met Can + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs Hypoglycemia with SGLT2 Inhibitors Percentage of Patients Reporting Hypoglycemia Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9 Systolic BP (mmhg) All canagliflozin dosages shown are canaglifozin 3 mg. Patients (%) <1 Estimated glomerular filtration rate 3-5 ml/min/1.73 m 2. P<.1 vs comparator. 1. Stenlof K, et al. Diabetes Obes Metab. 213;15: Rosenstock J, et al. Diabetes Care. 212;35: Cefalu WT, et al. Lancet. 213;382: Schernthaner G, et al. Diabetes Care. 213;36: Yale J-F, et al. Diabetes Obes Metab. 213;15: Stenlof K, et al. Diabetes Obes Metab. 213;15: Ferrannini E, et al. Diabetes Care. 21;33: Roden M, et al. Lancet Diabetes Endocrinol. 213;1: Cefalu WT, et al. Lancet. 213;382: Nauck MA, et al. Diabetes Care. 211;34: Haring HU, et al. Diabetes Care. 214;37: Yale J-F, et al. Diabetes Obes Metab. 213;15: Wilding JPH, et al. Ann Intern Med. 212;156: Rosenstock J, et al. Diabetes Care. 214;37: Genitourinary infection Safety Considerations with SGLT2 Inhibitors Increased incidence; patients should be monitored and treated if necessary Increased LDL-C Small increases in LDL-C have been observed in clinical trials Bladder cancer Renal impairment Increased incidence of bladder cancers in patients receiving dapagliflozin Dapagliflozin labeling recommends not using in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer Monitor kidney function during therapy, especially in patients with GFR <6 ml/min/1.73 m 2 SGLT2s: Ketoacidosis 73 cases reported to FAERS between 3/13 and 5/15 SGLT2 inhibitors are not FDA-approved to treat patients with type 1 diabetes mellitus. Before initiating an SGLT2 inhibitor, consider factors in the patients histories that may predispose them to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. Patients treated with an SGLT2 inhibitor who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis, regardless of the presenting blood glucose levels. Ketoacidosis associated with SGLT2 inhibitors may be present even if blood glucose levels are less than 25 mg/dl. If ketoacidosis is suspected, discontinue the SGLT2 inhibitor. Evaluate the patient and institute treatment, which may include insulin, fluids, and carbohydrate replacement. Garber AJ, et al. Endocr Pract. 213;19(suppl 2):1-48. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

9 SGLT2s: Ketoacidosis cont. SGLT2s: Urosepsis and Pyelonephritis In some cases, predisposing factors for ketoacidosis were identified. These included: reduction of insulin dose, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse. In patients treated with an SGLT2 inhibitor, consider monitoring for ketoacidosis and temporarily discontinuing the drug in clinical situations known to predispose to ketoacidosis, such as prolonged fasting due to acute illness or surgery. 19 cases reported to FAERS between 3/13 and 1/14 Evaluate patients for signs and symptoms of urinary tract infections, and treat promptly if indicated. Counsel patients about the signs and symptoms of a urinary tract infection, and advise them to seek medical advice if such symptoms occur 49 5 Canagliflozin: Leg and Foot Amputations In the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS) clinical trial, the trial s independent data monitoring committee (IDMC) identified an increased risk of leg and foot amputations. The amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. An interim analysis showed that over a year s time, the risks of amputation for patients in the trial were equivalent to: 7 out of every 1, patients treated with 1 mg daily of canagliflozin 5 out of every 1, patients treated with 3 mg daily of canagliflozin 3 out of every 1, patients treated with placebo Monitor patients for the signs and symptoms and advise patients to seek medical advice if they experience them. 51 Canagliflozin and Dapagliflozin: Renal Update A search of the FDA Adverse Event Reporting System (FAERS) database from March 29, 213, to October 19, 215, identified 11 cases of acute kidney injury with sufficient detail to confirm the diagnosis and demonstrate a temporal relationship with canagliflozin (73 patients) and dapaglifozin (28 patients). 1.5 Million prescriptions were written in this time period. Hospitalization for evaluation and management of acute kidney injury was necessary in 96 of the 11 cases, and 22 cases involved admission to an intensive care unit. Four deaths occurred during hospitalization, 2 of which were cardiac-related. Fifteen patients received dialysis, and of these, 3 patients had a history of chronic kidney disease or previous acute kidney injury, and 6 reported concomitant use of both an angiotensin-converting enzyme (ACE) inhibitor and a diuretic. In 58 cases, the time to onset of acute kidney injury occurred within one month or less of initiating the drug. In the 78 cases reporting drug discontinuation, 56 cases reported improvement, demonstrating reversibility of this adverse event in a majority of cases. Eleven patients did not recover, which included the 4 deaths noted previously. Three patients recovered with sequelae upon discontinuation, suggesting that kidney injury may not be fully reversible in some situations. 52 Empagliflozin: Renal Data New data form the Empa-Reg Outcome study showed Jardiance (empagliflozin) reduced the risk for new-onset or worsening kidney disease by 39 percent versus placebo when added to standard of care in adults with type 2 diabetes with established cardiovascular disease. 55 percent reduction in the initiation of renal replacement therapy (such as dialysis) 44 percent reduction in doubling of creatinine (a waste product usually filtered by the kidneys) in the blood 38 percent reduction in progression to macroalbuminuria (very high levels of a protein called albumin in the urine) JARDIANCE also significantly slowed the decline in kidney function over time compared with placebo. Most patients in this trial were already taking the recommended standard treatment for kidney disease in type 2 diabetes, renin angiotensin aldosterone system blockade; the renal effects of JARDIANCE were apparent on top of these agents. Over a median of 3.1 years, empagliflozin significantly reduced the risk of CV death, non-fatal heart attack or non-fatal stroke by 14 percent versus placebo. Risk of CV death was reduced by 38 percent, with no significant difference in the risk of non-fatal heart attack or non-fatal stroke. 53 Canagliflozin and Dapagliflozin: Renal Update Before initiating canagliflozin or dapagliflozin, consider factors that may predispose patients to acute kidney injury. These include hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications such as diuretics, angiotensinconverting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Evaluate renal function prior to initiating canagliflozin or dapagliflozin and monitor periodically thereafter. Consider temporarily discontinuing canagliflozin or dapagliflozin in any setting of reduced oral intake such as acute illness or fasting, or with fluid losses such as gastrointestinal illness or excessive heat exposure. Monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue canagliflozin or dapagliflozin promptly and institute treatment. 54 9

10 Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors Update on Metformin New Basal Insulins Glargine U3 Insulin Degludec Discussion Topics Metformin: Updated Labelling FDA is requiring manufacturers to revise the labeling of metformin-containing drugs to indicate that these products may be safely used in patients with mild to moderate renal impairment. They are also requiring manufacturers to revise the labeling to recommend that the measure of kidney function used to determine whether a patient can receive metformin be changed from one based on a single laboratory parameter (blood creatinine concentration) to one that provides a better estimate of renal function (i.e., glomerular filtration rate estimating equation (egfr)). This is because in addition to blood creatinine concentration, the glomerular filtration rate takes into account additional parameters that are important, such as the patient s age, gender, race and/or weight. Metformin: Updated Labelling Cont. The labeling recommendations on how and when kidney function is measured in patients receiving metformin will include the following information: Before starting metformin, obtain the patient s egfr. Metformin is contraindicated in patients with an egfr below 3 ml/minute/1.73 m 2. Starting metformin in patients with an egfr between 3-45 ml/minute/1.73 m 2 is not recommended (? Dose adjustment). Obtain an egfr at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking metformin whose egfr later falls below 45 ml/minute/1.73 m 2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient s egfr later falls below 3 ml/minute/1.73 m 2. Metformin: Updated Labelling Cont. Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an egfr between 3 and 6 ml/minute/1.73 m 2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate egfr 48 hours after the imaging procedure; restart metformin if renal function is stable. Discussion Topics Incretin System DPP4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors Update on Metformin New Basal Insulins Glargine U3 Insulin Degludec GLARGINE U-3 6 1

11 Glucose Control With Glargine U-3 Weight Change With Glargine U-3 Add-on to OA, Insulin- Naive 6 Months 1 Add-on to OA, Basal Insulin Users 6 Months 2 Basal-Bolus Insulin Regimen 6 Months 3 Add-on to OA, Insulin- Naive 6 Months 1 Add-on to OA, Basal Insulin Users 6 Months 2 Basal-Bolus Insulin Regimen 6 Months 3 N Treatment Gla 1 Gla 3 Gla 1 Gla 3 Gla 1 Gla 3 N Treatment Gla 1 Gla 3 Gla 1 Gla 3 Gla 1 Gla 3 Baseline A1C (%) A1C (%) Weight (kg) 1. Bolli GB, et al. Diabetes Obes Metab. 215;17: Yki-Järvinen H, et al. Diabetes Care. 214;37: Riddle MC, et al. Diabetes Care. 214;37: Bolli GB, et al. Diabetes Obes Metab. 215;17: Yki-Järvinen H, et al. Diabetes Care. 214;37: Riddle MC, et al. Diabetes Care. 214;37: Hypoglycemia With Glargine U-3 Risk of Hypoglycemia With Glargine U-3 Add-on to OA, Insulin- Naive 6 Months 1 Add-on to OA, Basal Insulin Users 6 Months 2 Basal-Bolus Insulin Regimen 6 Months 3 N Pooled Analysis of Phase III Trials (N=2496) Favors Glargine 3 Favors Glargine 1 Treatment Gla 1 Gla 3 Gla 1 Gla 3 Gla 1 Gla 3 Hypoglycemia any time of day Relative risk (95% CI) Confirmed ( 7 mg/dl) or severe.91 ( ) Patients reporting hypoglycemia (%) Documented symptomatic ( 7 mg/dl).88 ( ) Nocturnal hypoglycemia Confirmed ( 7 mg/dl) or severe.75 ( ) Documented symptomatic ( 7 mg/dl).75 ( ) 1. Bolli GB, et al. Diabetes Obes Metab. 215;17: Yki-Järvinen H, et al. Diabetes Care. 214;37: Riddle MC, et al. Diabetes Care. 214;37: Ritzel R, et al. Diabetes Obes Metab. 215 Apr 3. doi: /dom [Epub ahead of print]. 64 Insulin Dose With Glargine U-3 Add-on to OA, Insulin- Naive 6 Months 1 Add-on to OA, Basal Insulin Users 6 Months 2 Basal-Bolus Insulin Regimen 6 Months 3 N Treatment Gla 1 Gla 3 Gla 1 Gla 3 Gla 1 Gla 3 Insulin Degludec Insulin dose (U/kg/day) Baseline dose (U/kg/day) Bolli GB, et al. Diabetes Obes Metab. 215;17: Yki-Järvinen H, et al. Diabetes Care. 214;37: Riddle MC, et al. Diabetes Care. 214;37:

Degludec Pharmacology Structure 67 Retained sequence of human

acid (hexadecanedioic acid) coupled to lysine at B29 position via

duration of action Duration of Action of Insulin Degludec Patients

waking hours upon discovering the missed dose.

12 Degludec Pharmacology Structure 67 Retained sequence of human insulin Deletion of B3 residue No amino acid substitutions Fatty acid (hexadecanedioic acid) coupled to lysine at B29 position via glutamic acid spacer This plus albumin binding gives it long duration of action Duration of Action of Insulin Degludec Patients who miss a dose of Degludec should inject their daily dose during waking hours upon discovering the missed dose. Ensure at least 8 hours between injections Insulin Degludec Action Profile Insulin Degludec U1 and U2 Pharmacokinetic Profiles at Steady State Serum Insulin degludec concentrations (percent day 1 conentration) Degludec Degludec Degludec 12

Insulin degludec Insulin degludec is an ultra long-acting insulin

flexibility in dosing; especially with missed doses 73 A1c reduction

Hypoglycemia rates comparable to glargine (studies showed lower

Algorithm American Diabetes Association Standards of Medical Care in

13 Insulin degludec Insulin degludec is an ultra long-acting insulin formulation with several advantages: True 24 hour insulin Allows flexibility in dosing; especially with missed doses 73 A1c reduction comparable to glargine with numerically lower fasting blood sugars Hypoglycemia rates comparable to glargine (studies showed lower incidence of nocturnal hypoglycemia) ADA/EASD Algorithm AACE/ACE Algorithm American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 216; 39 (Suppl. 1): SX 13

All the New Medications: What Should I. Lauren LaBryer, MD Endocrinologist Oklahoma Heart Institute

All the New Medications: What Should I Choose for NIDDM Lauren LaBryer, MD Endocrinologist Oklahoma Heart Institute None Disclosures Objectives To become familiar with the new medication classes for the