嘉 義 長 庚 醫 院 藥 劑 科 Speaker : 翁 玟 雯

Transcription

1 The Clinical Efficacy and Safety of Sodium Glucose Cotransporter-2 (SGLT2) Inhibitors in Adults with Type 2 Diabetes Mellitus 嘉 義 長 庚 醫 院 藥 劑 科 Speaker : 翁 玟 雯

2 Diabetes Mellitus : A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both The classification of diabetes includes three clinical classes: 1) Type 1 diabetes (insulin-dependent diabetes mellitus (IDDM) 2) Type 2 diabetes (non insulin-dependent diabetes mellitus (NIDDM)) 3) Gestational diabetes (form of glucose intolerance diagnosed during pregnancy) Type 2 diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - about 90%~95% of all diagnosed cases of diabetes

3 Diabetes-Prevalence Diabetes is currently the seventh leading cause of death in the United States. The 500 million people worldwide will develop diabetes by Source: National Health and Nutrition Examination Survey: CDC, 2010

4

5 Diabetes Pathophysiology

6 Typical pathogenic features of hyperglycaemia in type 2 diabetes Lancet 2011; 378:

7 Diabetes - diagnosis Fasting Plasma Glucose NORMAL <100 mg/dl PRE-DIABETES Impaired fasting glucose (IFG) mg/dl 126 mg/dl DIABETES Oral Glucose Tolerance Test NORMAL <140 mg/dl PRE-DIABETES Impaired glucose tolerance(igt) mg/dl 200 mg/dl DIABETES HbA 1C NORMAL PRE-DIABETES DIABETES <5.7% % 6.5% DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013

8 Diabetes Risk factors Type 2 diabetes mellitus is more common in people who: Are overweight (BMI 25 kg/m2) Are 45 or older Are physically inactive Have a parent or sibling with type 2 diabetes Are African American, Native American, Hispanic American, or Pacific Islander Have abnormal cholesterol levels Have had gestational diabetes Have high blood pressure

9 Diabetes Complication Nontraumatic lowerlimb amputations Blindness and eye problems Heart disease and stroke Hypertension Kidney disease Nervous system disease

10 Important of glycemic control Effects of 1% reduction in updated mean HbA 1C On complications of type 2 diabetes Risk reduction 40% 35% 30% 25% 20% 15% 10% 5% 21% 14% 37% 21% 0% Any diabetes related complication Myocardial infarction Microvascular disease Death due to diabetes UKPDS (35). Br Med J 2010; 321(7258):

11 Diabetes treatment goals Table 1 : Summary of recommendations for glycemic, blood pressure, and lipid control for most adults with diabetes DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013

12 ADA/EASD: Antihyperglycemic therapy in type 2 diabetes: general recommendations Inzucchi SE et al, Diabetes Care, april 2012

13 ENDOCRINE PRACTICE Vol 19 No. 2 March/April 2013

14

15 In 2013, canagliflozin was the first SGLT2 inhibitor to be approved in the USA.

16 Phlorizin - a nonselective sodium glucose transport inhibitor - discovered on the root bark of an apple tree in glycosuria and weight loss - the rapid degradation and poor absorption O- glucosides C-glucosides

17 Canagliflozin New Class -Sodium glucose co-transporter 2 (SGLT2) inhibitor -Insulin independent mechanism Indication -An adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Dose and administration -Initial, 100 mg taken once daily before the first meal of the day -Increased to 300 mg once daily if estimated GFR is 60mL/min/1.73 Contraindication -Dialysis -Severe kidney impairment or end-stage renal disease

18 Mechanism of action Proximal Convoluted Tubule Loop of Henle

19 Comparison of SGLT1 and SGLT2

20 Inhibition of SGLT2 by Canagliflozin Leads to Increased Renal Glucose Excretion and Improved Glucose Homeostasis American Diabetes Association. From Diabetes R, Vol. 54, 2005;

21 Pharmacokinetics of SGLT-2 Inhibitors Pharmacokinetics do not appear to be affected by age, body weight, sex, race, administration with food. Bioavailability, oral: 65% Protein binding, albumin: 99% Renal (33%) and fecal (41.5%) excretion. Hepatic: Glucuronidation is major metabolic pathway No active metabolites

22 Pharmacodynamics of SGLT-2 Inhibitors Dose dependent decreases in RT G

23 Efficacy In clinical trials - canagliflozin improved: 1. Hemoglobin A1c levels 2. Fasting and postprandial blood glucose levels 3. Weight loss

24

25 CANTATA-M: Significant HbA 1C Reductions with Canagliflozin vs Placebo at 26 Weeks Baseline A1C in trial:8.0% Diabetes Obes Metab. 2013;15(4) :

26 CANTATA-M: Significant FPG Reductions with Canagliflozin vs Placebo at 26 Weeks Baseline FPG in trial:171.2 mg/dl (9.6 mmol/l) Diabetes Obes Metab. 2013;15(4) :

27 CANTATA-M: Significant PPG Reductions with Canagliflozin vs Placebo at 26 Weeks Diabetes Obes Metab. 2013;15(4) :

28 CANTATA-M: Significant Weight Reductions with Canagliflozin vs Placebo at 26 weeks Diabetes Obes Metab. 2013;15(4) :

29 CANTATA-M: significant reductions in systolic blood pressure vs placebo at 26 weeks Diabetes Obes Metab. 2013;15(4) :

30 CANTATA-M: Incidence of Hypoglycemia with Canagliflozin vs Placebo at 26 weeks Diabetes Obes Metab. 2013;15(4) :

31

32 Effects of canagliflozin from baseline to week 12 in subjects with type 2 diabetes on metformin: =>A1C (%) Diabetes Care; Jun 2012; 35

33 Effects of canagliflozin from baseline to week 12 in subjects with type 2 diabetes on metformin: =>FPG (mg/dl) Diabetes Care; Jun 2012; 35

34 Effects of canagliflozin from baseline to week 12 in subjects with type 2 diabetes on metformin: =>Body weight (kg)

35

36 Changes from baseline in glycated haemoglobin A1c at week 52 Baseline HbA 1C in trial:7.8% Lancet 2013;382:941-50

37 Change in FPG Baseline FPG in trial:9.2mmol/l

38 Proportion of patients with documented hypoglycaemia episodes

39 Common adverse reactions

40 Five post-marketing studies: Cardiovascular outcomes trial Pharmacovigilance program to monitormalignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, live abnormalities and adverse pregnancy outcomes Bone safety study Two pediatric studies

41 Summary Insulin independent mechanism Inhibitors of SGLT2 lower RTG and increase urinary glucose excretion, therefore reducing circulatory glucose levels Increased Glucose Excretion Increased Sodium Excretion Reduced glycemia Loss of energy calories Reduced sodium load HbA 1C Reduction Weight loss Blood pressure reduction

42 Thanks for your attention