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2011 US Diabetes Statistics

2011 US Diabetes Statistics. Diabetes affects 25.8 million people in the US (8.3% of the U.S. population) 18.8 million diagnosed, 7.0 million undiagnosed 10.9 million (26.9%) of those aged ≥65 have diabetes 215,000 people <20

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2011 US Diabetes Statistics

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  1. 2011 US Diabetes Statistics • Diabetes affects 25.8 million people in the US (8.3% of the U.S. population) • 18.8 million diagnosed, 7.0 million undiagnosed • 10.9 million (26.9%) of those aged ≥65 have diabetes • 215,000 people <20 • 79 million US adults >20 years estimated to have had prediabetes in 2010 • 7th leading cause of death in the U.S. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

  2. 1994 2000 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% Percentage of U.S. Adults With Diagnosed Diabetes 2009 www.cdc.gov/diabetes/statistics

  3. Cost of Diabetes • Total (direct and indirect) estimated diabetes costs in the US in 2007 = $174 billion • Medical expenses for people with diabetes are more than two times higher than for people without diabetes • A 50 year old with diabetes dies, on average, 6 years earlier than someone without diabetes Emerging Risk Factors Collaboration. NEJM. 2011; www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

  4. Type 2 Diabetes Pathophysiology Inherited/acquired factors Acquired/genetic factors (obesity)1,2 Insulin deficiency, inappropriate glucagon secretion1,3 Insulin resistance1  FFA1-3  Production of glucose in the liver1,2  Glucose uptake1,2 Gluco-lipotoxicity Decreased Incretin Effect Hyperglycemia1-3 FFA=free fatty acid Type 2 DM1 1BergenstalRM, et al. Endocrinology. 2001; 2DeFronzo RA. Diabetes. 1988; 3Poitout V, et al. Endocrinology. 2002.

  5. Current Therapeutic Targets BRAIN PANCREAS LIVER Insulin GLP-1 Agonists DPP-4 Inhibitors Sulfonylureas Pramlintide (α cells only) Meglitinides Metformin Thiazolidinediones (TZD) Dopamine Analogs Pramlintide GI TRACT MUSCLE/FAT ?? KIDNEY ?? Metformin Thiazolidinediones (TZD) GLP-1 Agonists Alpha Glucosidase Inhibitors

  6. Updated ADA/EASD Consensus Algorithm STEP 1 STEP 2 STEP 3 Tier 1: Well-validated therapies Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Intensive Insulin At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea Tier 2: Less well-validated therapies Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Pioglitazone No hypoglycemia, edema/CHF, bone loss Lifestyle + Metformin + GLP-1 agonist No hypoglycemia, weight loss, nausea/vomiting Lifestyle + Metformin + Basal Insulin Nathan DM, et al. Diabetes Care. 2009.

  7. AACE/ACE Diabetes Algorithm for Glycemic Control American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at https://www.aace.com/publications.

  8. Risks of Current Therapies: Weight Gain Hypoglycemia Weight Gain Neutral Benefits Causes

  9. The Kidneys Play an Important Role in the Handling of Glucose • Total glucose stored in body ~450 g • Glucose utilization ~250 g/day • Brain ~125 g/day • Rest of body ~125 g/day • Glucose in Western diet ~180 g/day • Renal glucose production (gluconeogenesis + ~70 g/day glycogenolysis) • Renal glucose filtration and reabsorption ~180 g/day • Urinary glucose 0 g Wright EM, et al. J Intern Med. 2007.

  10. Sodium-Glucose Cotransporters Lee YJ, et al. Kidney Int Suppl. 2007.

  11. Altered Renal Glucose Control in Diabetes • Renal gluconeogenesis is increased in patients with Type 2 DM • Renal contribution to hyperglycemia • 3-fold increase relative to patients without diabetes • Glucose reabsorption • Increased SGLT2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals Marsenic O. Am J Kidney Dis. 2009; Bakris GL, et al. Kidney Int. 2009; Rahmoune H, et al. Diabetes. 2005.

  12. Rationale for SGLT2 Inhibitors The SGLT2 is a glucose transporter responsible for 90% of glucose reabsorption Selective SGLT2 inhibitors could reduce blood glucose levels due to increased renal excretion of glucose Mutations in the SGLT2 transporter linked to hereditary renal glycosuria, a relatively benign condition in humans Selective SGLT2 inhibition would cause urine loss of the calories from glucose (200-300 kcal/day), also potentially leading to weight loss Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J ClinEndocrinolMetab. 2010.

  13. Effects of SGLT2 Inhibitors • Inhibition of renal tubular Na+-glucose cotransporter • Reversal of hyperglycemia • Reduction of “glucotoxicity” • Insulin sensitivity in muscle and liver • Gluconeogenesis • Improved beta cell function Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J ClinEndocrinolMetab. 2010.

  14. SGLT2 Inhibitors in Phase 3 Development • Dapagliflozin • Canagliflozin • Empagliflozin • Ipragliflozin • Tofogliflozin

  15. Empagliflozin: Change in A1C • Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin† Change in A1C (%) Placebo N = 408 Baseline A1C = 7.9% *P<.001 vs. placebo †500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose Ferrannini E, et al. Abstract 877. EASD 2010.

  16. Empagliflozin: Change in FPG • Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin† 5 mg 10 mg 25 mg Metformin Change in FPG (mg/dl) Placebo * * * * N = 408 *P<.001 vs. placebo †500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose Ferrannini E, et al. Abstract 877. EASD 2010.

  17. Empagliflozin: Change in Weight • Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin† Placebo 5 mg 10 mg 25 mg Metformin Change in weight (%) * * * * N = 408 Baseline BMI = 29 kg/m2 *P<.001 vs. placebo †500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose Ferrannini E, et al. Abstract 877. EASD 2010.

  18. Empagliflozin: Safety Considerations • Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin† • Side effects: • Polyuria (3.3% vs. 0% in placebo), thirst (3.3% vs. 0% in placebo), and nasopharyngitis (2% vs. 1.2% in placebo) were the most frequently reported side effects • UTI 1.2% vs. 1.2% in placebo and 1.3% in metformin Ferrannini E, et al. Abstract 877. EASD 2010.

  19. Canagliflozin: Change in A1C • Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2) 7.71 8.01 7.81 7.57 7.70 7.71 7.62 Mean Baseline A1C (%) Change in A1C (%) * * * * * * N = 451 *P<.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.

  20. Canagliflozin: Change in FPG • Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2) Change in FPG (mg/dl) * * * * * * N = 451 Baseline FGP 162 mg/dl) *P<.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.

  21. Canagliflozin: Change in Weight • Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2) 85.5 87.5 87.7 87.7 87.8 86.3 87 Mean Baseline Weight (kg) Change in weight (%) * * * * * N = 451 Baseline weight 87 kg *P<.01 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.

  22. Canagliflozin: Safety Considerations • Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2) • Side effects: • Mild-to-moderate, transient • Non dose-dependent increase in symptomatic genital infections: 3-8% in canagliflozin vs. 2% in placebo and 2% in sitagliptin • UTI: 3-9% in canagliflozin (no dose-dependency) vs. 6% in placebo and 2% in sitagliptin • Hypoglycemia: 0-6% in canagliflozin (no dose dependency) vs. 2% in placebo and 5% in sitagliptin Rosenstock J, et al. Abstract 77-OR. ADA 2010.

  23. Effects of Canagliflozin on VulvovaginalCandida Colonization (VCC) • Relative to PBO/SITA, CANA treatment increased conversion to positive vaginal Candida culture and VVC events • Incidence of VVC in female subjects was 2.9% and 3.7% with PBO and SITA, respectively, and 10.4% with CANA • None of the VVC events were serious or led to discontinuation; most were treated with topical or oral antifungals, and resolved without study drug interruption Nyirjesy P, et al. Abstract 0032-LB. ADA 2011.

  24. Bacteria or UTI Incidence with Canagliflozin • At Week 12, CANA decreased A1C (0.45%-0.73% relative to PBO), lowered weight (1.3%-2.3% relative to PBO), and increased urinary glucose excretion (UGE) (35.4-61.6 mg/mg creatinine) • Conversion from negative baseline urine bacterial culture to positive culture did not differ in pooled CANA group vs pooled PBO/SITA group (4.8% vs. 3.7%, respectively) • UTI AEs (both symptomatic and positive post-baseline urine culture reported as a UTI) occurred in 16 (5.0%) in pooled CANA group and 5 (3.8%) in pooled PBO/SITA group • All UTI AEs considered mild or moderate, and none led to discontinuation Nicolle L, et al. Abstract 0043-LB. ADA 2011.

  25. Dapagliflozin Phase 3 Studies: Change in A1C Dapa 2.5mg Dapa 5mg Dapa 10mg Placebo Change in A1C (%) Baseline- Monotherapy (N=591): 8.6% Met add-on (N=546): 8% SU add-on (N=597): 8.1% Insulin add-on (N=808): 8.5% Wilding JPH, et al. Abstract 871. EASD 2010; StrojekK, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.

  26. Dapagliflozin Phase 3 Studies: Change in FPG Dapa 2.5mg Dapa 5mg Dapa 10mg Placebo Change in FPG (mg/dl) Baseline- Monotherapy (N=591): 179 mg/dl Met add-on (N=546): 163.9 mg/dl Insulin add-on (N=808): 178 mg/dl Wilding JPH, et al. Abstract 871. EASD 2010; FerranniniE, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.

  27. Dapagliflozin Phase 3 Studies: Change in Weight Dapa 5mg Dapa 2.5mg Dapa 10mg Placebo Change in weight (kg) Baseline- Monotherapy (N=591): 89.7 kg Met add-on (N=546): 85.9 kg SU add-on (N=597): 81.1 kg Insulin add-on (N=808): 94 kg Wilding JPH, et al. Abstract 871. EASD 2010; StrojekK, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.

  28. Dapagliflozin, Metformin XR, or Both as Initial Therapy DAPA+MET DAPA+MET DAPA+MET DAPA+MET DAPA5mg DAPA5mg DAPA10mg DAPA10mg MET MET MET MET DAPA+MET DAPA+MET Change in A1C Change in FPG DAPA5mg DAPA10mg MET MET Henry R, et al. Abstract 307-OR. ADA 2011. Change in Body Weight

  29. Dapagliflozin: Effect on BP and Lipids HDL (% change) • Placebo: +0.4 • Dapa 2.5mg: +1.8 • Dapa 5mg: +3.3 • Dapa 10mg: +4.4 Triglycerides (% change) • Placebo: +2.1 • Dapa 2.5mg: -2.4 • Dapa 5mg: -6.2 • Dapa 10mg: -6.2 • Systolic Blood Pressure (mmHg) • Placebo: -0.2 • Dapa 2.5mg: -2.1 • Dapa 5mg: -4.3 • Dapa 10mg: -5.1 • Diastolic Blood Pressure (mmHg) • Placebo: -0.1 • Dapa 2.5mg: -1.8 • Dapa 5mg: -2.5 • Dapa 10mg: -1.8 Bailey CJ, et al. Lancet. 2010.

  30. Dapagliflozin: Safety Considerations • Based on all trials (Monotherapy, metformin add-on, sulfonylurea add-on, and insulin add-on) • Side effects: • UTI*: 3.9-13.2% in dapagliflozin vs. 4-6.2% in placebo1-3 • Genital infections*: 3.9-12.9% in dapagliflozin vs. 0.7-5% in placebo1-4 • Hypoglycemia: 0-7.9% in dapagliflozin vs. 2.7-4.8% in placebo2-4 • *Most occurred during the first 24 weeks, were generally mild, and responded to routine management 1Wilding JPH, et al. Abstract 871. EASD 2010; 2Strojek K, et al. Abstract 870. EASD 2010; 3Ferrannini E, et al. Diabetes Care. 2010; 4Bailey CJ, et al. Lancet. 2010.

  31. Dapagliflozin:Sulfonylurea Comparator Study Randomized, double-blind, parallel-group, multicenter trial comparing dapagliflozin to glipizide as add-on to metformin Results • Average A1C: 7.72% • Change in A1C: -0.52% for dapagliflozin vs. -0.52% for glipizide • Weight change: -3.2 kg for dapagliflozin vs. +1.4 kg for glipizide • Hypoglycemic episodes: 3.5% for dapagliflozin vs. 40.8% with glipizide • Significant reductions in diastolic and systolic blood pressure and improvement in HDL with dapagliflozin vs. glipizide (P<.0001) • Side effects: • UTI: 10.8% with dapagliflozin vs. 6.4% with glipizide (actively solicited) • Genital infection: 12.3% with dapagliflozin vs. 2.7% with glipizide (actively solicited) • Renal impairment: 5.9% with dapagliflozin vs. 3.4% with glipizide Nauck MA, et al. Diabetes Care. 2011.

  32. Dapagliflozin + Insulin for 48 Weeks AE = Adverse events s/sx = signs and symptoms • A1C reductions from baseline for PLA and DAPA 2.5, 5, and 10mg at 24 weeks were maintained at 48 weeks • (−0.43%, −0.74%, −0.94%, −0.93%, respectively) • 24 week body weight reductions with DAPA were maintained at 48 weeks • −1.5kg with DAPA 10mg vs. +0.9kg with PLA • AEs, serious AEs, and discontinuations were balanced across all groups • Actively solicited s/sx suggestive of UTI and genital infections (GI) were more with DAPA vs PLA • UTI 7.9%-10.8% vs. 5.1%; GI 6.4%-10.7% vs. 2.5% • most events were reported during the first 24 weeks, were of mild/moderate intensity and responded to standard treatment Wilding J, et al. Abstract 0021-LB. ADA 2011.

  33. Dapagliflozin + Insulin for 48 Weeks:Insulin Dose 15 PLA + INS DAPA 2.5 mg + INS DAPA 5 mg + INS DAPA 10 mg + INS 10 Insulin dose (IU/day) Adjusted mean change from baseline ± SE 5 0 -5 0 4 8 12 16 20 24 28 32 36 40 44 48 Timepoint (weeks) Wilding J, et al. Abstract 0021-LB. ADA 2011.

  34. Long-Term Efficacy of Dapagliflozin + Metformin Bailey CJ, et al. Abstract 0988-P. ADA 2011.

  35. Potential SGLT2 Safety Considerations??? • Evidence Demonstrates • Urinary tract/genital infections • Questions • Hepatic toxicity? • Breast and bladder cancer?? • Intravascular volume depletion due to osmotic diuresis?? • Nephrotoxicity (AGEs)?? • Drug-drug interactions?? • Evidence Does Not Demonstrate • Electrolyte imbalance (Na+, K+, Ca++, PO4) • Increased risk for hypoglycemia • Nocturia

  36. Dapagliflozin PDUFA Date The FDA issued a Complete Response Letter to the makers of dapagliflozin on January 19, 2012 requesting additional information.

  37. SGLT2 Inhibitors: A New Era in Diabetes Treatment?? • In treatment-naive patients with newly-diagnosed Type 2 DM, SGLT2 inhibitors resulted in: • Clinically meaningful decreases in A1C and fasting plasma glucose with no increased risk of hypoglycemia • Also improved glycemic control in combination with a variety of other antihyperglycemic agents • Metformin, sulfonylureas, insulin • Side effects generally appear to be mild and transient, while avoiding increased risk of hypoglycemia or weight gain

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