1 / 38

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

laith-welch
Download Presentation

2011 US Diabetes Statistics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related