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Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors

Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors. Mark E. Molitch, MD Professor of Medicine Division of Endocrinology, Metabolism, and Molecular Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois.

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Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors

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  1. Emerging Type 2Diabetes Treatment:Novel TherapySGLT-2 Inhibitors Mark E. Molitch, MD Professor of Medicine Division of Endocrinology, Metabolism,and Molecular Medicine Northwestern UniversityFeinberg School of Medicine Chicago, Illinois

  2. Major Therapeutic Targets in Type 2 Diabetes Mellitus (T2DM) Pancreas Sulfonylureas Meglitinides GLP-1 agonists DPP-4 inhibitors Liver Beta-celldysfunction Hepatic glucoseoverproduction Muscle and fat Metformin Thiazolidinediones GLP-1 agonists DPP-4 inhibitors Insulinresistance Glucose level Thiazolidinediones Metformin Kidney Gut Glucose reabsorption Glucose absorption Alpha-glucosidase inhibitors GLP-1 agonists SGLT-2 inhibitors DeFronzo RA. Ann Intern Med. 1999;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB Saunders; 2003:1427-1483.

  3. Normal Glomerular Filtration and Renal Glucose Transport

  4. 125 mL of filtrate formed/min (180 L/24 h)1 Urine output 1.5 L/24 h 25000 mEq of Na+ filtered2 Urine Na+ excretion 100 mEq/L 162 g glucose filtered/24 h1 Urine glucose excretion = 0 because reabsorptionoccurs Glomerular Filtration Artery 180 L/24 h 25000 mEq Na+/24 h Efferent Afferent Filtration Tubular system Secretion Reabsorption 1.5 L/24-h volume 100 mEq Na+/24 h 0 g/24-h glucose 1. Abdul-Ghani M, et al. Endocr Pract. 2008;14:782-790. 2. Mount DB, et al. In: Brenner and Rector’s The Kidney.8th ed. Elsevier Saunders; 2007:156-200.

  5. Renal Glucose Transport • GLUTs • Facilitative or passive transporters, work along a glucose gradient • Expressed in all cells—GLUT2 in kidney • SGLTs • Active transport across membranes on lumenal side of cell using the Na+ gradient produced by Na+/K+ ATPase pumps • SGLT-2 • S1 and S2 segments of proximal convoluted tubule • Low affinity but high capacity for glucose • Responsible for 90% of tubular reabsorption of glucose • SGLT-1 • S3 segment of proximal convoluted tubule • Responsible for 10% of tubular reabsorption of glucose Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Marsenic O. Am J Kidney Dis. 2009;53:875-883.

  6. Active (SGLT-2) and Passive (GLUT2) Glucose Transport in S1 Renal Proximal Tubule Cells Apical membrane Basolateral membrane ATPase pump K+ Na+ Na+ SGLT-2 Glucose Glucose GLUT2 Interstitium Tubular lumen ATPase pump K+ Na+ Na+ Glucose SGLT-2 GLUT2 Glucose Abbreviations: GLUT2, glucose transporter 2; SGLT-2, sodium glucose cotransporter 2. Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Lee YJ, et al. Kidney Int. 2007;72:S27-S35.

  7. Renal Glucose Handling 600 Filtered Excreted  400 “Splay” Reabsorbed Glucose (mg/min) 200 Tm 0 800 400 600 0 200 Plasma Glucose (mg/dL) Abbreviation: Tm, transport maximum. With permission from Marsenic O. Am J Kidney Dis. 2009;53:875-883.

  8. Rationale for SGLT-2 Inhibition in Type 2 Diabetes

  9. SGLT-2 Expression and Glucose Uptake Are Increased in T2DM • Human exfoliated proximal tubular epithelial cells (HEPTECs) • Can be isolated from urine • Express a variety of proximal tubular markers, including SGLT-2 • In HEPTECs isolated from individuals with T2DM • SGLT-2 levels are 3-fold higher than in individuals with normal glucose tolerance (NGT) • Renal glucose uptake is also 3-fold higher than with NGT • Increases in renal glucose transport expression and activity seem to be associated with T2DM Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

  10. Phlorizin • Nonselective SGLT-2 inhibitor1 • Development deterred by its other activities • SGLT-1 inhibition—associated with GI effects/diarrhea2 • GLUT1 inhibition by active metabolite (phloretin)—may affect glucose uptake in the GI tract1 • Effect in rodent diabetes model provided proof-of-concept for SGLT as a therapeutic target in diabetes1 1. Chao EC, et al. Nat Rev. 2010;9:551-559. 2. Wright EM. J Intern Med. 2007;261:32-43.

  11. Phlorizin also restored fasting plasma glucose, fed plasma glucose, and glucose uptake in pancreatectomized rats Glucosuria: 8–9 g/dL in phlorizin vs 0.7–0.8 g/dL in pancreatectomy groups Phlorizin as Proof-of-Concept for SGLT Inhibition Response to Meal Tolerance Test * * * *Significantly different from other groups. Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

  12. SGLT-2 Inhibition IsSafe and Well Tolerated • Familial renal glucosuria • Rare kidney disorder associated with SGLT-2 gene mutations • Absence of glucose reabsorption indicated by higher urinary glucose excretion (1–170 g/d) • Benign, with no corresponding kidney complications • Intestinal glucose-galactose malabsorption • Due to SGLT-1 gene mutations • Severe diarrhea • Suggests major role for SGLT-1 in intestinal reabsorption • Corrected by removing glucose, galactose, and lactose from the diet • Mild glucosuria consistent with minor SGLT-1 role in renal reabsorption Wright EM. J Intern Med. 2007;261:32-43.

  13. SGLT-2 Inhibitors in Development

  14. Oral SGLT-2 Inhibitors in Development Discontinued: YM543,5 AVE2268,1 T-1095,1 TS-033,1 remogliflozin,1 sergliflozin1 *LX4211 phase II efficacy study completed; phase I dosage forms study ongoing. 1. Patel AK, et al. Curr Diab Rep. 2010;10:101-107. 2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on: October 2010. 3. Kakinuma H, et al. J Med Chem. 2010;53:3247-3261.4. JAPIC Clinical Trials Information. Available at: http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-090859. Accessed on: November 8, 2010. 5. Astellas pipeline. Available at: http://www.astellas.com/en/ir/library/pdf/4q2009_rd_en.pdf. Accessed on: November 9, 2010

  15. SGLT-2 Inhibitors in Phase III DevelopmentDapagliflozin

  16. Phase III Study of Dapagliflozin in Treatment-Naive T2DM • T2DM Age 18–77 y • Tx-naive N = 591 2-week single-blind lead-in phase: diet and exercise + placebo 24-week, double-blind phase Dapagliflozin 2.5 mg QDamn= 65 HbA1c 10.1%–12% n = 74 Dapagliflozin 5 mg QDamn= 64 n = 35 Dapagliflozin 10 mg QDamn= 70 n = 39 HbA1c 7%–10% n = 485 Dapagliflozin 2.5 mg QDpmn = 67 Dapagliflozin 5 mg QDpmn= 68 Dapagliflozin 10 mg QDpmn= 76 Placebo n = 75 Open-label metformin was allowed for patients with fasting plasma glucose >270 mg/dL at week 4, >240 mg/dL at week 8, or >200 mg/dL at weeks 12–24 Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.

  17. Phase III Study of Dapagliflozin in Treatment-Naive T2DMGlycemic Control at Week 24 Reduction in HbA1c (%) Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.

  18. Phase III Study of Dapagliflozin in Treatment-Naive T2DMFasting Plasma Glucose Level HbA1c <10.1% HbA1c ≥10.1% Reduction in FPG (mg/dL) Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.

  19. Phase III Study of Dapagliflozin in Treatment-Naive T2DMEffect on Body Weight at Week 24 Reduction in Weight (kg) Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.

  20. Phase III 24-Wk Study of Dapagliflozin in T2DM Patients on Metformin N = 534 † † † * † ‡ Reduction in HbA1c (%) Reduction in FPG (mg/dL) Dapagliflozin groups averaged 2.2–3.0 kg weight loss *P <.0002; †P <.0001; ‡P = .0019. Bailey CJ, et al. Lancet. 2010;375:2223-2233.

  21. Phase III 24-Wk Study of Dapagliflozin in T2DM Patients on Glimepiride N = 597 Reduction in HbA1c (%) Reduction in Postprandial OGTT (mg/dL)* Dapagliflozin groups averaged 1.18–2.26 kg weight loss *Measured 2 h after ingestion of 75 g glucose Strojek K, et al. 46th EASD; Sept 20-24, 2010. Abstract 870.

  22. Dapagliflozin Adverse Events • Nasopharyngitis (~3%–12%) • Diarrhea (~1%–10%) • Headache (~3%–15%) • Hypoglycemia (0%–3% in treatment-naive; ~2%–4% in patients on metformin, ~7%–8% in patients on glimepiride) • Urinary tract infection (~4%–15%) • Genital infection (~3%–18%) • Hypotensive events (0%–5%) Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. Bailey CJ, et al. Lancet. 2010;375:2223-2233. Strojek K, et al. 46th EASD; Sept 20-24, 2010. Abstract 870. .

  23. Additional Phase III Trials of DapagliflozinResults Pending • Add-on therapy • To thiazolidinedione • To DPP-4 inhibitor • To insulin • Special populations; patients with T2DM and • CVD • CVD + hypertension • Hypertension inadequately controlled on ACE inhibitor or ARB • Moderate renal impairment Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on: November 2010.

  24. SGLT-2 Inhibitors in Phase III DevelopmentCanagliflozin

  25. Phase IIb Study of Canagliflozin Added to Metformin in Patients with T2DM 12-week, double-blind phase Canagliflozin 50 mg QD n = 64 Canagliflozin 100 mg QD n = 64 451 patients with T2DM inadequately controlled on metformin Canagliflozin 200 mg QD n = 65 Canagliflozin 300 mg QD n = 64 Canagliflozin 300 mg BID n = 64 Sitagliptin 100 mg QD n = 65 Placebo n = 65 Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.

  26. Phase IIb Study of Canagliflozin in T2DM Patients on MetforminGlycemic Control at Week 12 P vs placebo ≤.001 for all groups P vs placebo ≤.001 for all groups Placebo-Adjusted Reduction in FPG (mg/dL) vs Baseline Placebo-Adjusted Reduction in HbA1c (%) vs Baseline Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.

  27. Phase IIb Study of Canagliflozin in T2DM Patients on MetforminEffect on Body Weight at Week 12 • Placebo-adjusted change in body weight • Canagliflozin groups lost 1.3–2.3 kg (dose-dependent effect) • Significant differences at all doses vs placebo • Sitagliptin group gained 0.4 kg Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.

  28. Canagliflozin Added to Metformin Adverse Effects No safety signals in laboratory abnormalities, echocardiogram, or vital signs with canagliflozin Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.

  29. Phase III Trials of CanagliflozinResults Pending • Monotherapy • Add-on to metformin • Add-on to metformin and sulphonylurea • Add-on to metformin and pioglitazone • Patients with cardiovascular risk factors • Elderly patients • Patients with moderate renal impairment ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on: November 2010.

  30. Other SGLT-2 Inhibitors in Phase III DevelopmentBI10773 and ASP1941

  31. Phase II Study of BI10773 4-week, double-blind phase BI10773 10 mg QD BI10773 25 mg QD 80 patients with T2DM BI10773 100 mg QD Placebo Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.

  32. Phase II Study of BI10773Effect on Glucose Levels Reduction in FPG (mg/dL) Urinary Glucose Excretion (g) Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.

  33. Phase IIa Study of ASP1941 in T2DM 28-day, double-blind phase ASP1941 50 mg QD n = 12 61 patients with T2DM: either tx naive, on monotherapy, or on low-dose combination therapy 2-wk washout for patients already on treatment ASP1941 100 mg QD n = 12 ASP1941 200 mg QD n = 12 ASP1941 300 mg QD n = 12 Placebo n = 13 Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.

  34. Phase IIa Study of ASP1941 in T2DMEffects on Glucose Levels * * * † Reduction in FPG (mg/dL) 24-h Urinary Glucose Excretion (mmol) Weight loss: 3.2–4.2 kg with ASP1941, 1.8 kg with placebo *P <.001; †P <.005. Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.

  35. Most Frequent Adverse Events BI107731 • Frequent urination • Nasopharyngitis • Constipation • Headache ASP19412 • Constipation • Nausea • Xerosis • Headache 1. Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P. 2. Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.

  36. BI10773 Phase III StudiesResults Pending • Monotherapy in treatment-naive T2DM • Monotherapy in T2DM pretreated with metformin • Add-on to metformin or metformin/sulfonylurea • Add-on to pioglitazone or pioglitazone/metformin • Add-on to usual care in patients at high cardiovascular risk • Add-on to pre-existing therapy in patients with renal impairment ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on November 2010.

  37. Phase III Trials of ASP1941Results Pending • Monotherapy in Japanese patients with T2DM • Add-on to metformin • Add-on to thiazolidinedione • Add-on to sulfonylurea • Add-on to DPP-4 inhibitor • Add-on to alpha-glucosidase inhibitor ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on November 2010.

  38. Where Will SGLT-2 Inhibitor Therapy Fit? • Combination therapy • Novel mechanism of action • Complementary to available agents • Second-line therapy • Monotherapy • Possibly in cases of metformin intolerance • Use in T1DM and T2DM?

  39. Summary • SGLT-2 is a low-affinity high-capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption • Mutations in SGLT-2 transporter linked to hereditary renal glycosuria, a benign condition • Oral selective SGLT-2 inhibitors in development reduce blood glucose levels by increasing renal excretion of glucose • Selective SGLT-2 inhibition results in loss of200–300 kcal/d, associated with weight loss • SGLT-2 inhibitors are generally well tolerated Brooks AM, et al. Ann Pharmacother. 2009;43:1286-1293.

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