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:
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
Major Therapeutic Targets in Type 2 Diabetes Mellitus (T2DM) 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. 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
Normal Glomerular Filtration and Renal Glucose Transport
Glomerular Filtration 125 mL of filtrate formed/min (180 L/24 h) 1 –Urine output 1.5 L/24 h 25000 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;14:782-790. 2. Mount DB, et al. In: Brenner and Rector’s The Kidney. 8th ed. Elsevier Saunders; 2007:156-200. 1.5 L/24-h volume 100 mEq Na + /24 h 0 g/24-h glucose 180 L/24 h 25000 mEq Na + /24 h Reabsorption Artery Afferent Efferent Filtration Tubular system Secretion
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.
Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. 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
With permission from Marsenic O. Am J Kidney Dis. 2009;53:875-883. 60 0 40 0 20 0 0 0 40 0 60 0 80 0 Reabsorbed ExcretedFiltered “Splay ” TmTm Plasma Glucose (mg/dL) Glucose (mg/min) Renal Glucose Handling Abbreviation: Tm, transport maximum.
Rationale for SGLT-2 Inhibition in Type 2 Diabetes
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.
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;9:551-559. 2. Wright EM. J Intern Med. 2007;261:32-43.
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;79:1510-1515. * * * * Significantly different from other groups.
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.
Oral SGLT-2 Inhibitors in Development SGLT-2 InhibitorDevelopment Phase Dapagliflozin 1 3 Canagliflozin 1 3 BI10773 2 3 ASP1941 2 3 GSK189075 1 2 R7201 1 2 TS-071 3 2 CSG452 4 2 LX4211 2 2/1 * ISIS 388626 2 1 BI 44847 2 1 GSK1614235 2 1 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 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.
SGLT-2 Inhibitors in Phase III Development Dapagliflozin
Phase III Study of Dapagliflozin in Treatment-Naive T2DM Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2-week single-blind lead-in phase: diet and exercise + placebo T2DM Age 18–77 y Tx-naive N = 591 24-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
Phase III Study of Dapagliflozin in Treatment-Naive T2DM Glycemic Control at Week 24 Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. Reduction in HbA1c (%)
Phase III Study of Dapagliflozin in Treatment-Naive T2DM Fasting Plasma Glucose Level Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. Reduction in FPG (mg/dL) HbA1c <10.1% HbA1c ≥10.1%
Phase III Study of Dapagliflozin in Treatment-Naive T2DM Effect on Body Weight at Week 24 Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. Reduction in Weight (kg)
Phase III 24-Wk Study of Dapagliflozin in T2DM Patients on Metformin Bailey CJ, et al. Lancet. 2010;375:2223-2233. 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 =.0019. † ‡ † †
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, 2010. Abstract 870. Reduction in HbA1c (%) Reduction in Postprandial OGTT (mg/dL)* Dapagliflozin groups averaged 1.18–2.26 kg weight loss N = 597
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..
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: http://www.clinicaltrials.gov. Accessed on: November 2010.
SGLT-2 Inhibitors in Phase III Development Canagliflozin
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 = 65 12-week, double-blind phase Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.
Phase IIb Study of Canagliflozin in T2DM Patients on Metformin Glycemic Control at Week 12 Rosenstock J, et al. 70th ADA; June 25-29, 2010. 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
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, 2010. Abstract 77-OR.
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, 2010. Abstract 77-OR. No safety signals in laboratory abnormalities, echocardiogram, or vital signs with canagliflozin
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: http://www.clinicaltrials.gov. Accessed on: November 2010.
Other SGLT-2 Inhibitors in Phase III Development BI10773 and ASP1941
Phase II Study of BI10773 80 patients with T2DM BI10773 10 mg QD BI10773 25 mg QD Placebo BI10773 100 mg QD 4-week, double-blind phase Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.
Phase II Study of BI10773 Effect on Glucose Levels Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P. Urinary Glucose Excretion (g) Reduction in FPG (mg/dL)
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 ASP1941 50 mg QD n = 12 ASP1941 100 mg QD n = 12 Placebo n = 13 ASP1941 200 mg QD n = 12 ASP1941 300 mg QD n = 12 28-day, double-blind phase Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P. 2-wk washout for patients already on treatment
Phase IIa Study of ASP1941 in T2DM Effects on Glucose Levels Schwartz S, et al. 70th ADA; June 25-29, 2010. 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
Most Frequent Adverse Events BI10773 1 Frequent urination Nasopharyngitis Constipation Headache ASP1941 2 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.
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: http://www.clinicaltrials.gov. Accessed on November 2010.
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: http://www.clinicaltrials.gov. Accessed on November 2010.
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?
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;43:1286-1293.
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