Ambrish Mithal MD, DM

Transcription

1 Ambrish Mithal MD, DM Chairman, Division of Endocrinology and Diabetes Medanta The Medicity Padma Bhushan Awardee 2015, Member Governing Council, Indian Council of Medical Research (ICMR) Dr Mithal is Editor in Chief of Indian Journal of Endocrinology and Metabolism, Past President, Endocrine Society of India. He is a Board member of the International Osteoporosis Foundation He has been the recipient of the Fogarty Fellowship (Harvard Medical School), Japan International Cooperation Agency Fellowship, Boy Frame award of the ASBMR, IOF Amgen Health Professionals Award and the Springer citation prize for his paper on Global Vitamin D tatus 2013.

2 Novel oral anti diabetics: Focus on SGLT2 inhibitors Ambrish Mithal MD, DM Chairman, Endocrinology and Diabetes Medanta, the Medicity

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5 Normal glucose 1,2 homeostasis Net balance ~0 g/day Glucose input ~250 g/day: + Dietary intake ~180 g/day Glucose production ~70 g/day The kidney filters circulating glucose Glucose filtered ~180 g/day 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Gerich, JE. Diabetes Obes Metab 2000;2: Glucose uptake ~250 g/day: Brain ~125 g/day Rest of the body ~125 g/day The kidney reabsorbs and recirculates glucose Glucose reabsorbed ~180 g/day

6 Glucose handling in Type 2 diabetes1,2 Glucose input >280 g/day: Dietary intake >180 g/day Glucose production ~100 g/day + Average BG- 150 mg/dl Kidney filters all glucose Glucose filtered ~270 g/day *Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis.2 1. Gerich JE. Diabet Med 2010;27:136 42; 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14: Glucose uptake >250 g/day: Brain ~125 g/day Rest of the body >125 g/day Increased reabsorption and recirculation of glucose Above the renal threshold for glucose (~200 mg/dl), (glucosuria)

7 Normal renal glucose handling1 3 Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule SGLT2 Glucose Glucose filtration Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion 7 SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21.

8 Increased renal SGLT2/GLUT2 expression leads to increased glucose re-absorption in T2DM Primary cultured proximal tubule epithelial cells from healthy patients and patients with T2DM 6 Transporter Protein Expression p<0.05 Healthy T2DM AMG Uptake (CPM) Normalized Levels 7 p< Cellular Glucose Uptake p< SGLT2 GLUT2 Healthy T2DM In a hyperglycemic environment, HEPTECs (Human Exfoliated Proximal Tubular Epithelial Cells) isolated from patients with type 2 diabetes expressed significantly more SGLT2 and the facilitative glucose transporter GLUT2 than cells from healthy individuals. The increase in the SGLT2/ GLUT2 level of expression in the type 2 diabetic HEPTECs was also accompanied by a threefold increase in glucose uptake Rahmoune et al. Diabetes.2005;54:

9 SGLTs are found throughout the body, but SGLT2 is specific to the kidney Transporter Major site of action SGLT1 Small intestine, heart, trachea and kidney Function Co-transports sodium, glucose and galactose across the brush border of the intestine and proximal tubule of the kidney Co-transports sodium and glucose in the S1 segment of the proximal tubule of the kidney SGLT2 Kidney SGLT3 Small intestine, uterus, lungs, Transports sodium (not glucose) thyroid and testis SGLT4 Small intestine, kidney, liver, stomach and lung Transports glucose and mannose Kidney Unknown SGLT, sodium-glucose co-transporter. Bays H. Curr Med Res Opin 2009;25: SGLT5 9

10 SGLT and GLUT transporters facilitate insulin independent reabsorption of filtered glucose in the proximal tubule S1 proximal tubule lumen (filtrate) Tissue reabsorption SGLT2 Low affinity High capacity ATPase SGLT 2 Glucose 1 Na+ GLUT 2 S3 proximal tubule lumen (filtrate) Tissue reabsorption SGLT 1 Glucose ATPase 2 Na+ GLUT 1 GLUT, glucose transporter; SGLT, sodium-glucose co-transporter. Adapted from: Wright EM. Am J Physiol Renal Physiol 2001;280:F SGLT1 High affinity Low capacity

11 Paradigm shift From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus Bays H. Curr Med Res Opin. 2009;25:

12 Phlorizin Isolated from apple tree bark (1835) Glycosuric effect (1886) Renal actions identified in rats (1903) and man (1933) Antidiabetic effect discovered (1987) Inhibitor of SGLT1 and SGLT2 SGLT, sodium-glucose co-transporter. Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:31 8.

13 tudy the past if you would define the future. Confucius

14 Structure of phlorizin and candidate SGLT2 inhibitors 14

15 SGLT2i: A novel insulin-independent approach to remove excess glucose1 3 Reduced glucose reabsorption Dapagliflozin SGLT2 Proximal tubule Dapagliflozin SGLT2 Glucose Glucose filtration Increased urinary excretion of excess glucose (~70 g/day, corresponding to 280 kcal/day*) *Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy subjects and patients with Type diabetes. SGLT2, sodium-glucose co-transporter Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21; 4. FORXIGA. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

16 Pharmacokinetics of SGLT2i

17 Glycemic Efficacy of SGLT2i

18 Consistent decreases in fasting plasma glucose (FPG) at week 24 across dapagliflozin studies Monotherapy1 Add-on to Met2 Add-on to Ins3 Add-on to Pio4 FPG adjusted mean change from baseline mmol/l mg/dl Ferrannini E, et al. Diabetes Care 2010;33: ; 2Bailey CJ, et al. Lancet 2010;375: ; 3Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21 A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, June, 2011 [Abstract 0986-P];

19 Adjusted mean change in 2-h PPG levels (mg/dl) PPG reduction with SGLT2iadded to SU 0 Dapagliflozin mg/d Placebo weeks 10

20 Consistent decreases in HbA1c from baseline at week 24 across a variety of treatment settings Monotherapy 1 Primary endpoint for 24-week adjusted from baseline HbA1c (%) Baselin e HbA1c 7.92 Add-on to Glim3 Add-on to Pio4 Add-on to Ins5 Dapa + Met XR * * * * -0.9 * Ferrannini E, Add-on to Met2 *p <0.001 compared with placebo * et al. Diabetes Care 2010;33: Bailey CJ, et al. Lancet 2010;375: Strojek K, et al. Diabetes Obes Metab 2011;13: , 24Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego4-28 June, 2011 Abstract 0986-P. 5Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21A22. Abstract 0078-OR. 6Henry R, et al. 71st ADA Scientific Sessions, San Diego, June, 2011 Abstract 307-OR.

21 Change in HbA1c in the Overall Population and Indian Subgroup Indian Data Overall population Baseline (%) 0.2 n Indian subgroup ,1 91 1,4 04 1, LS mean change (±SE) from baseline (%) % (95% CI: 0.75, 0.63) 0.83% (95% CI: 0.89, 0.77) LS, least squares; SE, standard error; CI, confidence interval. PBO % (95% CI: 1.18, 0.74) 0.87% (95% CI: 1.10, 0.65) et al.300 Poster CANA 100 mgkumarcana mg presented at IDF 2014

22 Canagliflozin had Hypoglycemia comparable to Placebo Hypoglycemia Percentage of Subject Placebo Canagliflozin 100 Stenlof et al. Diabetes Obes Metab. 2013

23 Dapa: Change in body weight at Week 24 Mean change in body weight (kg) Monotherapy1Add-on to metformin2 Add-on to a SU3 Add-on to insulin * 2.9* 3.2 Baseline: kg Baseline: kg Baseline: kg Baseline: kg Dapa 10 mg Placebo 23 *Statistically significant versus placebo by hierarchical testing rule: p<0.001; Statistically significant versus placebo: p<0.0001). Adjusted mean change from baseline using analysis of covariance, excluding data after rescue (last observation carried forward). SU, sulphonylurea. 1. Ferrannini E, et al. Diabetes Care 2010;33: ; 2. Bailey CJ, et al. Lancet 2010;375: ; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928 38; 4. Dapa. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2013.

24 Statistically Significant Weight Reduction vs Metformin XR N (LOCF) BL (kg) Dapa 10 mg MET XR 2000 mg Dapa 10 mg + MET XR Body Weight kg with 95% CI * -3.3* *Significantly superior to Metformin XR monotherapy (P-Value <0.0001) Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF)

25 Pooled analysis: Changes in blood pressure over 24 weeks Pooled analysis of phase 3 studies Dapagliflozin 10 mg Placebo Mean systolic blood pressure 131 Mean diastolic blood pressure 0.5 mmhg mmhg 130 (95% CI: 0.0, -1.0) (95% CI: -0.1, -1.7) 79 (n=1096) (n=1096) mmhg (95% CI: -3.5, -5.3) 127 (n=949) -2.1 mmhg (95% CI: -1.6, -2.6) (n=949) Weeks Weeks Dapagliflozin 10 mg Placebo Weeks Number of patients Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS Available from: (Accessed February 2012); Pool of placebo-controlled, short-term treatment studies. FDA BRIEFING DOCUMENT. NDA DAPAGLIFLOZIN BRISTOL-MYERS SQUIBB. ADVISORY COMMITTEE MEETING JULY 19,

26 Safety and tolerability data from a comprehensive clinical programme System organ class Very common ( 10%) Infections and infestations Metabolism and nutrition disorders Common* ( 1% to <10%) Vulvovaginitis, balanitis and related genital infections UTIs Hypoglycaemia (when used with a SU or insulin) Uncommon ( 0.1% to <1%) Vulvovaginal pruritus Volume depletion Thirst Gastrointestinal disorders Constipation Skin and subcutaneous tissue disorders Hyperhidrosis Musculoskeletal and connective tissue disorders Back pain Renal and urinary disorders Dysuria Polyuria Nocturia Investigations Dyslipidaemia Haematocrit increased Blood creatinine increased Blood urea increased

27 Genital infections - summary of pooled data up to 24 weeks The rate of genital infection was higher in the Dapagliflozin group than placebo More frequently experienced by women than by men All events were mild to moderate in intensity Most events did not recur with time Most events responded to the initial course of standard therapy 10 Percentage of subjects with clinical diagnosis of genital infection Placebo DAPA 10 mg Total Women Men List J, et al. 71st ADA Scientific Sessions, San Diego, June, 2011 [Poster # 985-P].

28 Urinary tract infections - summary of pooled data up to 24 weeks Most events did not recur with time Most events responded to the initial course of standard therapy Upper UTI was rare and balanced between groups 12 Placebo DAPA 10 mg 10 Percentage of subjects with clinical diagnosis of UTI All events were mild to moderate in intensity Total Parikh SJ, et al. 71st ADA Scientific Sessions, San Diego, June 24-28, 2011 [abstract 984-P]. Women Men

29 Cardiovascular Safety

30 11,531 >97 % >99 % pts screened completed trial vital status available 7020 pts randomized Patients with T2D at high CV risk Efforts were made to track outcomes and vital status for all patients, including those who discontinued trial medication Placebo Empagliflozin 10 mg Randomisation Target: 691 CV events CV, cardiovascular. Empagliflozin 25 mg On top of standard of care

31 Key inclusion and exclusion criteria Key inclusion criteria Adults with type 2 diabetes BMI 45 kg/m2 Pre-specified primary and key secondary outcomes Primary outcome 3-point MACE: Time to first occurrence of CV death, nonfatal MI or non-fatal stroke HbA1c 7 10%* Established cardiovascular disease Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease Key exclusion criteria Key secondary outcome 4-point MACE: Time to first occurrence of CV death, nonfatal MI, non-fatal stroke or hospitalisation for unstable angina egfr <30 ml/min/1.73m2 (MDRD) BMI, body mass index; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for 12 weeks prior to randomisation or no change in dose for 12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation. CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event 31

32 CV death HR 0.62 (95% CI 0.49, 0.77) p< Cumulative incidence function. HR, hazard ratio 32

33 CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) point MACE Favours empagliflozin Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI Favours placebo 33

34 Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p= Cumulative incidence function. HR, hazard ratio 34

35 In the wake of recent FDA safety issues with Diabetic Ketoacidosis, how safe are SGLT2inhibitors?

36 Multiple Mechanisms Contribute to DKA/EKA with SGLT2i Role of Insulin Fasting glucose can be maintained despite very low portal insulin because of urinary glucose loses This may predispose to ketosis and may uncouple ketosis from the finding of severe hyperglycemia. Role of Glucagon Glucagon may increase the severity of Diabetic Ketoacidosis Glucagon increases with SGLT2i Other Factors Changes in Insulin: Glucagon ratio Role of acute illness Reduced per-oral intake of Food Reduced Carbohydrate Intake Müller WA, Faloona GR, Unger RH. Am J Med Jan;54(1):52-7. Merovci A et al. J Clin Invest Feb;124(2): DKA: Diabetic Ketoacidosis, EKA: Euglycemic Diabetic Ketoacidosis

37 Mechanisms of ketosis in T1DM on SGLT2i J Clin Endocrinol Metab Aug;100(8):

38 Rare concern of DKA with SGLT2i Risk of DKA in patients with type 2 diabetes on SGLT2 inhibitors is quite low, probably numbering less than one in 1000 to one in 10,000 Evidence suggests, the two concerns include patients having surgery and those with type 1 diabetes receiving SGLT2 inhibitors off label. Peters et al: doi: /dc Diabetes Care June 15, 2015

39 Measures to Prevent DKA with SGLT2i Do Not Use SGLT2i in Type 1 Diabetes Mellitus Stop SGLT2i 3 days before surgery Recognize Early Signs & Symptoms of DKA Reduce Fluid loss Use Like Metformin. Stop Before Acute Illness Do Not Stop Insulin Encourage Adequate Carbohydrate Intake Peters A et al. Diabetes Care Jun 15 DKA: Diabetic Ketoacidosis

40 What about bones?

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42 In what kind of patients do I use SGLT2i? Overweight/obese Type 2 diabetes uncontrolled on 2-3 drugs Occasionally after metformin alone With insulin- but usually not MSII

43 Patient Populations where I do not use SGLT2 inhibitors Type 1 diabetes. Type 2 diabetes predominantly on insulin (MSII) Patients >75 years Patients with egfr <45mL/min Pregnant and/or nursing women Patients with Recurrent UTI / GUI Patients with history of volume depletion, dehydration

44 MEDANTA ENDOCRINOLOGY Consultants