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Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors Mark E. Molitch, MD Professor of Medicine Division of Endocrinology, Metabolism, and.

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Presentation on theme: "Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors Mark E. Molitch, MD Professor of Medicine Division of Endocrinology, Metabolism, and."— Presentation transcript:

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2 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

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

4 Normal Glomerular Filtration and Renal Glucose Transport

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

6 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: Marsenic O. Am J Kidney Dis. 2009;53:

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

8 With permission from Marsenic O. Am J Kidney Dis. 2009;53:  Reabsorbed ExcretedFiltered “Splay ” TmTm Plasma Glucose (mg/dL) Glucose (mg/min) Renal Glucose Handling Abbreviation: Tm, transport maximum.

9 Rationale for SGLT-2 Inhibition in Type 2 Diabetes

10 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:

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

12 Phlorizin as Proof-of-Concept for SGLT Inhibition 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 Response to Meal Tolerance Test Rossetti L, et al. J Clin Invest. 1987;79: * * * * Significantly different from other groups.

13 SGLT-2 Inhibition Is Safe 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.

14 SGLT-2 Inhibitors in Development

15 Oral SGLT-2 Inhibitors in Development SGLT-2 InhibitorDevelopment Phase Dapagliflozin 1 3 Canagliflozin 1 3 BI ASP GSK R TS CSG LX /1 * ISIS BI GSK Patel AK, et al. Curr Diab Rep. 2010;10: ClinicalTrials.gov. Available at: Accessed on: October Kakinuma H, et al. J Med Chem. 2010;53: JAPIC Clinical Trials Information. Available at: Accessed on: November 8, Astellas pipeline. Available at: Accessed on: November 9, 2010 Discontinued: YM543, 5 AVE2268, 1 T-1095, 1 TS-033, 1 remogliflozin, 1 sergliflozin 1 * LX4211 phase II efficacy study completed; phase I dosage forms study ongoing.

16 SGLT-2 Inhibitors in Phase III Development Dapagliflozin

17 Phase III Study of Dapagliflozin in Treatment-Naive T2DM Ferrannini E, et al. Diabetes Care. 2010;33: week single-blind lead-in phase: diet and exercise + placebo T2DM Age 18–77 y Tx-naive N = week, double-blind phase 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 Placebo n = 75 Dapagliflozin 10 mg QD PM n = 76 Dapagliflozin 2.5 mg QD AM n = 65 Dapagliflozin 10 mg QD AM n = 70 Dapagliflozin 5 mg QD AM n = 64 Dapagliflozin 2.5 mg QD PM n = 67 Dapagliflozin 5 mg QD PM n = 68 HbA1c 7%–10% n = 485 HbA1c 10.1%–12% n = 74 n = 35 n = 39

18 Phase III Study of Dapagliflozin in Treatment-Naive T2DM Glycemic Control at Week 24 Ferrannini E, et al. Diabetes Care. 2010;33: Reduction in HbA1c (%)

19 Phase III Study of Dapagliflozin in Treatment-Naive T2DM Fasting Plasma Glucose Level Ferrannini E, et al. Diabetes Care. 2010;33: Reduction in FPG (mg/dL) HbA1c <10.1% HbA1c ≥10.1%

20 Phase III Study of Dapagliflozin in Treatment-Naive T2DM Effect on Body Weight at Week 24 Ferrannini E, et al. Diabetes Care. 2010;33: Reduction in Weight (kg)

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

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

23 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: Bailey CJ, et al. Lancet. 2010;375: Strojek K, et al. 46th EASD; Sept 20-24, Abstract 870..

24 Additional Phase III Trials of Dapagliflozin Results 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: Accessed on: November 2010.

25 SGLT-2 Inhibitors in Phase III Development Canagliflozin

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

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

28 Phase IIb Study of Canagliflozin in T2DM Patients on Metformin Effect 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, Abstract 77-OR.

29 Canagliflozin Added to Metformin Adverse Effects Canagliflozin (All Doses) SitagliptinPlacebo Genital infections3%–8%2% Urinary tract infections 3%–9%2%6% Hypoglycemia0%–6%5%2% Rosenstock J, et al. 70th ADA; June 25-29, Abstract 77-OR. No safety signals in laboratory abnormalities, echocardiogram, or vital signs with canagliflozin

30 Phase III Trials of Canagliflozin Results 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: Accessed on: November 2010.

31 Other SGLT-2 Inhibitors in Phase III Development BI10773 and ASP1941

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

33 Phase II Study of BI10773 Effect on Glucose Levels Heise T, et al. 70th ADA; June 25-29, Abstract 629-P. Urinary Glucose Excretion (g) Reduction in FPG (mg/dL)

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

35 Phase IIa Study of ASP1941 in T2DM Effects on Glucose Levels Schwartz S, et al. 70th ADA; June 25-29, Abstract 0566-P. 24-h Urinary Glucose Excretion (mmol) Reduction in FPG (mg/dL) * * * † *P <.001; † P <.005. Weight loss: 3.2–4.2 kg with ASP1941, 1.8 kg with placebo

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

37 BI10773 Phase III Studies Results 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: Accessed on November 2010.

38 Phase III Trials of ASP1941 Results 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: Accessed on November 2010.

39 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?

40 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 of 200–300 kcal/d, associated with weight loss SGLT-2 inhibitors are generally well tolerated Brooks AM, et al. Ann Pharmacother. 2009;43:

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