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Dapagliflozin
This document discusses SGLT2 inhibitors as a treatment option for type 2 diabetes mellitus. It provides background on normal glucose homeostasis and the pathophysiology of hyperglycemia in diabetes. SGLT2 inhibitors work by inhibiting glucose reabsorption in the kidneys, causing it to be excreted in the urine. Clinical trial data shows SGLT2 inhibitors like dapagliflozin provide glycemic control as monotherapy or add-on therapy with other oral agents or insulin, with additional benefits of weight loss and blood pressure reduction. Long-term studies over 4 years show sustained glycemic control with dapagliflozin compared to other oral antidiabetic drugs.
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Dapagliflozin
- 1. 1 SGLT2 Inhibitors- ATherapeutic Option Across the Continuum of T2DM Aizikovich Alex MD
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- 3. 3 SGLT2 Inhibitors- ATherapeutic Option Across the Continuum of T2DM
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- 6. CORE - 6 SGLT2 Inhibitors TZDs Metformin Siteof Action: Oral Antidiabetic Agents Increased HGP Hyperglycemia ETIOLOGY OF T2DM DEFN75-3/99 Decreased Glucose Uptake Impaired Insulin Secretion Increased Lipolysis HYPERGLYCEMIA Metformin TZDs GLP-1 RA GLP-1 RA TZDs DPP4i SU GLP-1 RA GLP-1 RA DPP4i GLP-1 RA AGIs TZDs GLP-1 RA TZDs DPP4i SU GLP-1 RA AGIs TZDs
- 7. 7 Multiple pathophysiological failurescontribute to hyperglycaemia - The "Ominous Octet" Adapted from: DeFronzo RA. Diabetes 2009;58:773–95. Wolters Kluwer Health Islet α-cell Increased lipolysis Increased glucose reabsorption Increased glucagon secretion Increased hepatic glucose production Neurotransmitter dysfunction Decreased glucose uptake Islet β-cell Decreased incretin effect Impaired insulin secretion Hyper- glycaemia
- 8. 8 Normal glucose homeostasis1,2 1.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18. 2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50. • Brain ~125 g/day • Rest of the body ~125 g/day Glucose uptake ~250 g/day: • Dietary intake ~180 g/day • Glucose production ~70 g/day • Gluconeogenesis • Glycogenolysis + − Net balance ~0 g/day Glucose input ~250 g/day: The kidney reabsorbs and recirculates glucose Glucose reabsorbed ~180 g/day Glucose filtered ~180 g/day The kidney filters circulating glucose
- 9. 9 Glucose handling inType 2 diabetes1,2 *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;14:782–90. • Dietary intake >180 g/day • Glucose production ~100 g/day • Gluconeogenesis* • Glycogenolysis Glucose input >280 g/day: • Brain ~125 g/day • Rest of the body >125 g/day Glucose uptake >250 g/day: −Increased reabsorption and recirculation of glucose Average blood glucose concentration 150 mg/dL Kidney filters all circulating glucose Above the renal threshold for glucose (~200 mg/dL), glucose is excreted in the urine (glucosuria) + Glucose filtered ~270 g/day
- 10. The kidneys filterand reabsorb 180 g of glucose per day in the nephrons by active transport 10Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246; Washburn WN. J Med Chem 2009;52(7):1785‐1794 Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys SGLT1 10% Proximal tubule S1 Glomerulus Distal tubule Loop of Henle Collecting duct Glucose filtration Glucose reabsorption S3 ~10% of glucose is reabsorbed from the S3 segment 180 g glucose filtered each day Up to ~90% of glucose is reabsorbed from the S1 segments Minimal glucose excretion SGLT2 90% Volume of plasma kidneys filter/day = 180 L Normal glucose concentracion = 1000 mg/L (100 mg/dl) Glucose filtered/day = (180 L/day) (1000 mg/L) = 180 G
- 11. The kidneys filterand reabsorb 180 g of glucose per day in the nephrons by active transport 11Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246; Washburn WN. J Med Chem 2009;52(7):1785‐1794 Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys SGLT1 10% Proximal tubule S1 Glomerulus Distal tubule Loop of Henle Collecting duct Glucose filtration Glucose reabsorption S3 ~10% of glucose is reabsorbed from the S3 segment 180 g glucose filtered each day Up to ~90% of glucose is reabsorbed from the S1 segments GLUCOSE SGLT2 90% Volume of plasma kidneys filter/day = 180 L Normal glucose concentracion = 1000 mg/L (100 mg/dl) Glucose filtered/day = (180 L/day) (1000 mg/L) = 180 G SGLT2i
- 13. SLGT2 Inhibitors -Regulatory Status •Dapagliflozin, Canagliflozin and Empagliflzoin are EMA and FDA approved •Dapagliflozin FORXIGA is approved in MEUHEDET
- 16. 16 A Thorough andExtensive Clinical Development Program: 11,801 Patients Treated Mono- therapy Add-on to Oral agents Add-on to Insulin Active Comparator Overweight/ Obesity CVD Dapagliflozin Clinical Development Program 92-012 Japan Open Label N=728 009 Add-on to Insulin N=75 045 Insulin Sensitivity N=44 035 Renal Function N=75 054 China MonoTx N=393 92-006 Japan MonoTx N=261 008 MonoTx N=389 018 Pts with CVD+HTN N=922 019 Pts with CVD N=965 013 MonoTx N=558 032 Low dose N=282 014 Add-on to Metformin N=546 90-005 Add-on to SU N=596 030 Add-on to TZD N=420 010 Add-on to DPP4i N=451 90-006 Add-on to Insulin N=807 92-005 Japan MonoTx N=279 Glycemic Efficacy MoA Phase 2b/ Dosing Relevant Co-morbidities Regional Studies 073 HTN ACEi/ARB N=944 077 HTN ACEi/ARB +add’l anti-HTN N=582 034 Dapa 10mg Init Comb with Met and vs Met N=638 021 Dapa 5mg Init Comb with Met N=598 004 Add-on to Met vs SU N=814 Renal Impairment 029 Moderate Renal Impairment N=252 90-012 DXA / Body Composition N=182 Hypertension Study D1691C00003 not included as it was not completed on time for the submission. Study MB102-072 not included as it was studying a different indication.
- 17. Consistent reductions inHbA1c across a broad range of commonly prescribed treatments *Statistically significant versus placebo using Dunnett’s correction (p<0.0001); †Statistically significant versus placebo (p<0.0001); ‡p<0.001. OAD, oral antidiabetic drug. 1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928–38; 4. Jabbour SA, et al. Diabetes Care 2014;37:740–50; 5. Wilding JPH, et al. Ann Intern Med 2012;156:405–15. Dapagliflozin Placebo (24 weeks)
- 18. Consistent reductions inHbA1c across a broad range of treatments in patients with baseline HbA1c ≥9% NR, not reported. 1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Katz A, et al. Diabetes 2014;63(Suppl. 1):A284. (24 weeks) Dapagliflozin Placebo
- 19. FORXIGA delivers theadditional benefit of weight loss across a broad range of treatments *Statistically significant versus placebo using Dunnett’s correction (p<0.0001); †Statistically significant versus placebo after sequential testing procedure (p<0.0001); ‡Statistically significant versus placebo (p<0.0001); §p<0.001. Adjusted mean change from baseline using analysis of covariance, excluding data after rescue (last observation carried forward). 1. Ferrannini E, et al. Diabetes Care 2010;33:2217–24; 2. Bailey CJ, et al. Lancet 2010;375:2223–33; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:928–38; 4. Jabbour SA, et al. Diabetes Care 2014;37:740–50; 5. Wilding JPH, et al. Ann Intern Med 2012;156:405–15; 6. FORXIGA®. Summary of product characteristics, 2014. FORXIGA is not indicated for the management of obesity.6 Weight change was a secondary endpoint in clinical trials.2,6 (24 weeks) Dapagliflozin Placebo
- 20. 20 Significant Systolic BloodPressure Reduction at Week 12 SourceTopline73/77.pptx–Slide35/41;Table7.2.1-1 -10.4 -7.3 -14 -12 -10 -8 -6 -4 -2 0 -11.9 -7.6 -14 -12 -10 -8 -6 -4 -2 0 AdjustedMean∆SeatedSBP (mmHg)with95%CI AdjustedMean∆SeatedSBP (mmHg)with95%CI Studies in Hypertensive Patients with Diabetes, -073 and -077 •Significant P-value. Repeated measures mixed model analysis Weber, et al. Circulation 2013;128:A13144. Weber, et al. Circulation 2013;128:A13165 Placebo N=224 151.0 151.3 Study 073 Study 077 Dapa 10mg N=225 BL (mmHg) 149.8 149.5 + ACEi/ARB +add’l anti-HTN Placebo N=311 Dapa 10mg N=302 + ACEi/ARB Diff vs Pbo (95% CI) -3.1 (-4.9, -1.2) -4.3 (-6.5, -2.0) P-value 0.0010* 0.0002*
- 21. 21 BL 4 812 16 20 24 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 ∆HbA1cwith95%CI Study Week BL 4 8 12 16 20 24 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 MET XR 2000mg Dapa 10mg Dapa 10mg + MET XR Dapa 10mg MET XR 2000mg Dapa 10mg + MET XR N 216 203 202 BL HbA1c (%) 9.03 9.03 9.10 Dapa + Metformin Superior to Individual Monotherapies Dapa 10mg Initial Combination with Met and vs Met, -034 -1.98 -1.45 -1.44 Combination vs Monotherapies * Significantly superior to monotherapy. Adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF) Henry et al. Int J Clin Pract, May 2012, 66, 5, 446–456. R:CSR-034final -0.53* -0.54*
- 22. 22 Dif. −0.30% (95% CI:−0.51, −0.09) Dapagliflozin: glycaemic control over 4 years vs glipizide 0.2 −1.0 −0.4 0.0 −0.6 −0.8 −0.2 0.4 ChangeinHbA1C(%)* 0 6 12 18 28 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208 Study week Rescue therapy availableRescue therapy NOT available Sample size (including data after rescue), n DAPA + MET 400 321 233 79 GLIP + MET 401 315 208 71 DAPA + MET GLIP + MET 0.20% (95% CI: 0.05, 0.36) −0.10% (95% CI: −0.25, 0.05) Week 208 values Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA; 21–25 June 2013: Abstract 62-LB. DAPA, dapagliflozin; GLIP, glipizide; MET, metformin. *Data are adjusted mean change from baseline ± 95% CI derived from a longitudinal repeated-measures mixed model. Add-on to Metformin Compared to SU (Glipizide) Plus Metformin, -004
- 23. 23 1 4 812 16 20 24 32 40 48 52 65 78 91 104 -8 -4 0 4 8 12 16 20 24 ∆MeanInsulinDose(IU/day)with95%CI Study Week Dapa 10mg + INS Placebo + INS BL Dapa + MET Pbo + MET Insulin Doses Remain Stable on Dapa Over 2 Years Source:Study006Figure4,Table11.2.6.1.1 Add-on to Insulin, 90-006 Sample Size Per Time Point Dapa 10mg+INS 189 185 180 177 175 173 166 145 146 144 142 140 Placebo+INS 185 176 170 168 164 158 157 121 118 114 110 104 Difference vs comparator -19.2 ( -25.5, -12.9) Repeated measures mixed model analysis, including data after insulin up-titration. Wilding et al. Diabetes, Obesity and Metabolism16: 124–136, 2014 Baseline Insulin dose 77 IU/day
- 24. 24 Low Intrinsic Propensityto Cause Hypoglycemia n / N (%) of Patients Placebo-controlled studies Dapa 10mg Placebo Total Patients with Event* 309 / 2360 (13.1) 242 / 2295 (10.5) Major Episode* 2 / 2360 (0.1) 1 / 2295 (<0.1) Monotherapy 2 / 70 (2.9) 2 / 75 (2.7) Add-on to Met 5 / 135 (3.7) 4 / 137 (2.9) Add-on to TZD 0 / 140 (0.0) 1 / 139 (0.7) Add-on to DPP4i 5 / 225 (2.2) 3 / 226 (1.3) Add-on to SU 11 / 151 (7.3) 7 / 146 (4.8) Add-on to Insulin 83 / 196 (42.3) 69 / 197 (35.0) n / N (%) of Patients Active comparator studies Dapa 10mg Control Dapa vs. SU (Add-on to Met) 14 / 406 (3.5)** 162 / 408 (40.8)** Dapa vs. Met 2 / 219 (0.9) 6 / 208 (2.9) * Placebo-controlled Pool ** Adjusted percent using modified logistic regression analysis Source:30MUTable37;CSR004Table30;CSR034Table8.6.1 ST – 30MU
- 25. 25 Urinary Tract andGenital Infections* Source:rl-ae-saeutilt23,30MUTables38,41,42 Number (%) of Patients Dapa 10mg N=2360 Placebo N=2295 Infections of the Urinary Tract 110 (4.7) 81 (3.5) Genital Infections 130 (5.5) 14 (0.6) Dapa Total N=5936 Control N=3403 Pyelonephritis 7 (0.1) 7 (0.2) Infections of the Urinary Tract SAEs 8 (0.1) 6 (0.2) Genital Infection SAEs 1 (<0.1) 0 Placebo-controlled Pool, ST All Phase 2b/3 Pool, ST + LT 30MU *Based on prespecified lists of Preferred Terms
- 26. 26 Renal Function: StableOver Time Placebo-controlled Pool, ST + LT – 30MU Source:rt-lb-gfrchgltplac,30MUAppendix273 MDRD = Modification of Diet in Renal Disease Ptaszynska et al. Presented at the 74th Scientific Sessions of the American Diabetes Association (ADA), San Francisco, CA, USA, June 13–17, 2014 Number of Patients Dapa 10mg 2026 1697 1655 1777 1600 1663 712 692 656 627 Placebo 1955 1629 1570 1671 1513 1558 605 585 551 521 Change in Estimated GFR (by MDRD) BL 1 4 8 16 24 37 50 63 76 89 102 -15 -10 -5 0 5 10 15 eGFR(mL/min/1.73m2) MeanChangefromBaseline Dapa 10mg Placebo Baseline Mean 81.0 80.7 (mL/min/1.73m2)
- 27. Dapagliflozin is notassociated with an increased of risk CV events • A meta-analysis of CV events among 21 Phase IIb/III trials, showed no increase in the primary CV composite endpoint of CV death, stroke, MI and hospitalisation for unstable angina with FORXIGA1,2 CV events were adjudicated by an independent committee. CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; UA, unstable angina. 1. EMDAC background document. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Last accessed September 2014; 2. FORXIGA®. Summary of product characteristics, 2014. Dapagliflozin Control
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- 31. 31 Dapagliflozin: Indication Indication Forxiga isindicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. Add-on combination therapy In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control Limitations of use • Based on its mechanism of action, dapagliflozin is not recommended to be initiated in patients with moderate renal impairment (eGFR <60 mL/min/1.73m2) Dosing 10mg, orally once daily Dapagliflozin is currently approved in 44 countries including the European Union (since Oct 2012), Australia and the United States (since Dec 2013)