Targeting the Kidney. Renal Glucose Transport 11/4/2015. Non insulin Agents Available IBITORS. Chao EC, et al. Nat Rev Drug Discovery. 2010;9:

Transcription

1 SGLT-2i and DPP-IVi in the Management of Diabetes Mellitus Type 2 Abel Alfonso, D.O., F.A.C.E. Endocrinologist November 5, 2015 DIABETES: CURRENT RATES AND PROJECTIONS CDC Press Release 2010: 1 in 3 adults with DM by 2050 ADA Report: Health care costs for DM increased by 40% to $245 billion between 2007 and 2012 JAMA 2014;311(17)1778 Increase in prevalence in youth between 2001 and 2009 of T1D (20%) and T2D (30%) Diabetes prevalence in the US leveling off? Lower rates of diabetesrelated complications in the US Site of SGLT- 2i Action 5 DeFronzo RA. Diabetes. 2009;58:

2 Targeting the Kidney LT2- IBITORS Chao EC, et al. Nat Rev Drug Discovery. 2010;9: Renal Glucose Transport Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9: Non insulin Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as Glucosidase inhibitors Delay carbohydrate absorption from intestine Acarbose Miglitol Precose or generic Glyset Decrease glucagon secretion Amylin analogue Slow gastric emptying Pramlintide Symlin Increase satiety Biguanide Bile acid sequestrant Decrease HGP Increase glucose uptake in muscle Decrease HGP? Increase incretin levels? Metformin Colesevelam Glucophage or generic WelChol DPP 4 inhibitors Increase glucose dependent insulin secretion Decrease glucagon secretion Alogliptin Linagliptin Saxagliptin Sitagliptin Nesina Tradjenta Onglyza Januvia Dopamine 2 agonist Activates dopaminergic receptors Bromocriptine Cycloset Glinides Increase insulin secretion Nateglinide Repaglinide Starlix or generic Prandin 11 DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:

3 Non insulin Agents Available for T2D Effects of Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as GLP 1 receptor agonists Increase glucose dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Albiglutide Dulaglutide Exenatide Exenatide XR Liraglutide Tanzeum Trulicity Byetta Bydureon Victoza FPG lowering Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR QR SU/ Glinide Insulin Pram SU: mod marked Mild to Mod Mod Mild Mod Neutral Mild Neutral Glinide: (basal Mild mod* mild insulin or premixed) SGLT2 inhibitors Sulfonylureas Increase urinary excretion of glucose Increase insulin secretion Canagliflozin Dapagliflozin Empagliflozin Glimepiride Glipizide Glyburide Invokana Farxiga Jardiance Amaryl or generic Glucotrol or generic Dia eta, Glynase, Micronase, or generic PPG lowering Mild marked Mild Mod Mild Mod Mild Mild Mod marked (short/ rapidacting marked insulin or premixed) Increase glucose uptake in muscle and fat Pioglitazone Actos Thiazolidinediones Rosiglitazone Avandia Decrease HGP GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35: Continued from previous slide 13 AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; FPG = fasting plasma glucose; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; PPG = postprandial glucose; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Mild: albiglutide and exenatide; moderate: dulaglutide, exenatide extended release, and liraglutide. 14 Effects of Agents Available for T2D Effects of Agents Available for T2D Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR QR SU/ Glinide Insulin Pram Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR QR SU/ Glinide Insulin Pram Mild Mild Neutral Neutral Mod Neutral Neutral Neutral Neutral Neutral Neutral NAFLD benefit SU: mod to severe Hypo glycemia Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral Glinide: Neutral severe* mild to mod GI adverse effects GU infection risk May worsen fluid retention Neutral Neutral Neutral Contraindicated Renal impairment/ GU in stage 3B, 4, 5 CKD Exenatide contraindicated CrCl <30 mg/ml Dose adjustment (except linagliptin) Increased Increased risks of hypoglycemiglycemia hypo risk and fluid retention Neutral Mod Mod* Neutral Neutral* Neutral Mod Mild Mod Neutral Neutral Mod CHF Neutral Neutral Neutral Neutral Mod Neutral Neutral Neutral Neutral Neutral Neutral Weight Slight loss Loss Loss Neutral Gain Neutral Neutral Neutral Gain Gain Loss CVD Possible benefit Neutral Neutral Neutral Neutral Neutral Neutral Safe? Neutral Neutral Mod bone Bone Neutral Neutral Bone loss Neutral Neutral Neutral Neutral Neutral Neutral Neutral loss AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; NAFLD, nonalcoholic fatty liver disease; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Especially with short/ rapid-acting or premixed. 15 AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; CHF = congestive heart failure; CVD = cardiovascular disease; DPP4I = dipeptidyl peptidase 4 inhibitors; GI = gastrointestinal; GLP1RA = glucagon-like peptide 1 receptor agonists; GU = genitourinary; Met = metformin; Mod = moderate; SGLT2I = sodiumglucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Caution in labeling about pancreatitis. Caution: possibly increased CHF hospitalization risk seen in CV safety trial. 16 FDA APPROVAL March 2013 Canagliflozin (Invokana 100 mg, 300 mg, Janssen Pharmaceuticals) January 2014 Dapagliflozin (Farxiga 5 mg, 10 mg, AstraZeneca/Bristol-Myers Squibb) August 2014 Empagliflozin (Jardiance 10 mg, 25 mg, Boehringer Ingelheim/Lilly) Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes SGLT-2I mellitus INDICATIONS February Glyxambi (empagliflozin / linagliptin 10/5 mg, 25/5 mg) Other Markets: February 2014 (Japan)- Ipragliflozin (Suglat 25 mg, 50 mg, Astellas Pharma / Kotobuki Pharmaceutical) 18 3

4 Warnings for SGLT2 Inhibitors Adverse drug reactions Precautions Clinical Trials Increased urination Genital mycotic infections Urinary tract infections Nasopharyngitis (dapagliflozin) Hypotension Impairment in renal function Hyperkalemia Hypoglycemia Hypersensitivity Increase in LDL Bladder cancer (dapagliflozin) SGLT 2i studies have demonstrated improved glycemic gy control as monotherapy and with combination or add on therapy to: Metformin Sulfonylureas Thiazolidinediones Insulin Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc Farxiga [package insert]. Wilmington, DE: AstraZeneca Jardiance [package insert]. Ridgefield, CT and Indianapolis, IN: Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company INVOKANA (CANAGLIFLOZIN) 21 INVOKANA (CANAGLIFLOZIN) Monotherapy (100 and 300 mg)» A1c Reduction» 0.77% and 1.03%» Weight change» -2.5 kg and -3.4 kg» SBP» -3.3 mmhg and -5.0 mmhg» Hypoglycemia» 3.6% and 3.0% 22 FARXIGA (DAPAGLIFLOZIN) FARXIGA (DAPAGLIFLOZIN) Most common side effects among those treated with dapagliflozin are genital fungal infections and urinary-tract infections. Increase in bladder cancer was seen with dapagliflozin in one of these trials dapagliflozin is not recommended for patients with active bladder cancer or moderate to severe renal impairment

5 Dapagliflozin's safety and effectiveness were evaluated in 16 clinical trials involving FARXIGA diabetes (DAPAGLIFLOZIN) more than 9400 patients with type 2 Post-marketing Studies DECLARE-TIMI 58 More than 17,000 patients followed for 4 to 5 years to ascertain whether dapagliflozin is associated with increased risks for CV events, liver 25 problems, or malignancies Similar A1c reduction (-0.52%) by end of study Weight loss (-3.22 kg) vs gain (+1.44 kg) with SGLT2I versus SU treatment Less hypoglycemia with SGLT2I vs SU treatment GLYXAMBI (EMPAGLIFLOZIN) 29 GLYXAMBI (EMPAGLIFLOZIN) Phase III Clinical Trail RCT n= 686 T2D Metformin plus» empagliflozin / linagliptin 10 / 5 mg» empagliflozin / linagliptin 25 / 5 mg» empagliflozin 10 mg» empagliflozin 25 mg» linagliptin 5 mg 30 5

6 Baseline A1c ~ 8% Change in A1c at 24 weeks: GLYXAMBI» empagliflozin / linagliptin 10 / 5 mg 6.9% (58%) (EMPAGLIFLOZIN)» empagliflozin / linagliptin 25 / 5 mg 6.7% (62%)» empagliflozin 10 mg (28%)» empagliflozin 25 mg (33%)» linagliptin 5 mg (36%)» Weight Loss:» empagliflozin GLYXAMBI / linagliptin 10 / 5 mg 3.1%» empagliflozin (EMPAGLIFLOZIN) / linagliptin 25 / 5 mg 3.2%» empagliflozin 10 mg kg» empagliflozin 25 mg kg» linagliptin 5 mg 0.7% SGLT-2I AND BONE FRACTURES 9.4% and 6% incidence of bone fractures in patients taking dapagliflozin 10 mg and 5 mg respectively over 104 weeks of follow- up» No bone fractures reported in placebo group 30% increase in incidence of bone fractures in patients taking canagliflozin in a metaanalysis of 8 clinical trials with mean 33 duration of 68 weeks ON THE HORIZON SGLT-2i for T1D SGLT-1 / SGLT-2 co-inhibitor (LX4211) Long-term studies:» Blood pressure» Lipid profile» Cardiovascular effects» Fracture risk» Bladder cancer» Euglycemic DKA 34 6

7 A Fundamental Observation: Insulin Secretion is Greater with Oral Compared to IV Glucose Blood Glucose Plasma Insulin The Role of DPP-IV Inhibitors in the Management of Type 2 Diabetes Blood Glucose (m mg/dl) IV/IJ glucose Intravenous Intrajejunal Plasma Insulin ( pmol/l) Time (min) Time (min) Adapted from McIntyre N, et al. Lancet. 1964;41: Synthesis and Secretion of GLP-1 and GIP K-Cell (jejunum) L-Cell (ileum) ProGIP Proglucagon GLP-1 [7-37] GIP [1-42] GLP-1 [7-36NH 2 ]

8 Mixed Meal Intestinal GLP-1 Release Plasma Ac vity Incretin Enhancement DPP IV Inhibitors GLP-1 (7-36) Active DPP-IV GLP-1 Actions Rapid Inactivation (>80% of pool) GLP-1(9-36) Inactive Renal Clearance DPP-IV = Dipeptidyl peptidase-iv Deacon CF, et al. Diabetes. 1995;44: DPP-4 Inhibitors (dipeptidyl peptidase-4 ) Januvia (sitagliptin), Onglyza (saxagliptin), Tradjenta (Linaglipitin), Nesina (alogliptin), Janumet, JentaDueto MOA: dipeptidyl peptidase-4 inhibitor, blocks the breakdown of GLP-1 in small intestine increasing concentration in the bloodstream A1c % FPG mg/dl PPG mg/dl Dosing: sitagliptin 50 or 100 mg daily, saxagliptin 2.5 or 5 mg daily, linaglipitin 5 mg daily, alogliptin 6.25, 12.5 or 25 mg (Taken with or without food) Side Effects: Possible hypoglycemia when used with insulin or insulin secretagogues (e.g. sulfonylurea), nasopharyngitis, URI, headache, GIrelated side effects, UTI, peripheral edema Often added to metformin for maximum effect Major features of AACE Guidelines 1. Most Important Principle : recognition of the importance of avoiding hypoglycemia. 2. It favors the use of GLP-1 agonists and DPP-4 inhibitors with higher priorityeffectiveness and overall safety profiles. 3. It moves sulfonylureas to a lower priority because of the associated risks a. hypoglycemia b. weight gain c. glycemic control only for relatively short period (1 to 2 years in typical patients). 10 Typical A1C Reduction Approved Antidiabetic Medications in the United States Medication Route of Administration Year of Introduction or FDA Approval Efficacy as Monotherapy (% Reduction in A1C) Insulin Subcutaneously Sulfonylureas Oral Metformin* Oral Alpha-glycosidase Inhibitors Oral Thiazolidinediones Oral Glinides Oral GLP-1 Analogs Subcutaneously Amylin Analogs Subcutaneously DPP-IV Inhibitors Oral *Adapted from Nathan DM. N Engl J Med. 2007;356(5):

9 Major Differences in Incretin Therapies Properties/Effect Glucose-dependent stimulation of insulin secretion Glucose-dependent reduction of increased glucagon DPP-4 Inhibitors Yes Yes GLP-1 Receptor Agonists Yes Yes Slows gastric emptying No Yes Effect on body weight Weight neutral Weight loss Side effects Well tolerated Nausea,vomiting Hypoglycemia No No Administration Oral Once daily Subcutaneous Once, twice daily or weekly 13 3