Sitagliptin: A component of incretin based therapy. Rezvan Salehidoost, M.D., Endocrinologist

Transcription

1 Sitagliptin: A component of incretin based therapy Rezvan Salehidoost, M.D., Endocrinologist

2 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan study Impact of Hypoglycemia Summary

3 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan study Impact of Hypoglycemia Summary

4 Sitagliptin Enhances Active Incretin Levels Through Inhibition of DPP GI tract Sitagliptin (DPP-4 inhibitor) Ingestion of food Release of active incretins GLP-1 and GIP a Inactive GLP-1 X Inactive GIP DPP-4 enzyme Pancreas Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose-dependent Glucagon from alpha cells (GLP-1) Peripheral glucose uptake Hepatic glucose production Blood glucose in fasting and postprandial states By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. a Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer TJ et al. Endocr Rev. 1999;20(6): Ahrén B. Curr Diab Rep. 2003;3(5): Drucker DJ. Diabetes Care. 2003;26(10): , 4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):

5 Sitagliptin and Metformin Target the Core Metabolic Defects of Type 2 Diabetes Sitagliptin improves beta-cell function and increases insulin synthesis and release. 1 Beta-Cell Dysfunction Insulin Resistance Metformin has insulinsensitizing properties. 3 5 (Liver > Muscle, fat) Sitagliptin reduces HGO through suppression of glucagon from alpha cells. 2 Hepatic Glucose Overproduction (HGO) Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis Aschner P et al. Diabetes Care. 2006;29(12): Data on file. 3. Abbasi F et al. Diabetes Care. 1998;21(8): Kirpichnikov D et al. Ann Intern Med. 2002;137(1): Zhou G et al. J Clin Invest. 2001;108(8):

6 Dosing Adult,Diabetes mellitus, type 2: Oral: 100 mg once daily Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas): Reduced dose of insulin and/or insulin secretagogues may be needed. Administration Oral: Administer without regard to meals.

7 Dosing Renal Impairment CrCl 50 ml/minute: No dosage adjustment necessary. CrCl 30 to <50 ml/minute (approximate SCr of >1.7 to 3 mg/dl [males] or >1.5 to 2.5 mg/dl [females]): 50 mg once daily CrCl <30 ml/minute (approximate SCr of >3 mg/dl [males] or >2.5 mg/dl [females]): 25 mg once daily ESRD requiring hemodialysis or peritoneal dialysis: 25 mg once daily; administer without regard to timing of hemodialysis

8 Dosing Hepatic Impairment Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer s labeling (has not been studied).

9 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan study Impact of Hypoglycemia Summary

10 Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy: Study Design T2DM, aged yrs, Off OHA 4 months, HbA 1c 7.5% R Sitagliptin 50 mg bid + metformin 1000 bid a (n=626) Metformin 1000 mg bid a (n=624) Screening period Phase A Phase B 1 week 18 weeks Screening Day 1 Randomization Week weeks Week 44 a Metformin was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid. bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus. 1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5 9, Data on file, MSD.

11 HbA 1c LS Mean (±SE) Change From Baseline, % Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs Metformin Monotherapy: HbA 1c Results Over 18 Weeks 10 FAS Population 9 8 LS means difference 0.6; P< Week Sitagliptin/metformin FDC (n=560) Mean baseline HbA 1c =9.9% Metformin (n=566) Mean baseline HbA 1c =9.8% FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error. 1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5 9, Data on file, MSD.

12 Published Online in Nov. 2010

13 Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Study Design 1 Patients 18 years of age with T2DM on stable dose of metformin ( 1500 mg/day) for 12 weeks and HbA 1c 6.5% 9.0% R Sitagliptin 100 mg qd Glimepiride (started at 1 mg qd and up-titrated until week 18 as needed up to maximum dose of 6 mg qd) Continue stable dose of metformin Screening Period Single-blind Placebo Run-in Double-blind Treatment Period Week 4 Week 2 Day 1 Week 30 qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus. 1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):

14 LS Mean (±SE) HbA 1c, % HbA 1c -Lowering Efficacy of Sitagliptin at Week 30 Was Noninferior to That of Glimepiride in Patients Inadequately Controlled on Metformin 1 Per-Protocol Population Sitagliptin 100 mg + metformin (n=443) Glimepiride a + metformin (n=436) (95% CI) 0.07% ( 0.03, 0.16) Prespecified noninferiority margin = 0.40% Week LS=least squares; SE=standard error. a Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. 1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):

15 Patients With 1 Hypoglycemic Episode, % Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Clinical Assessment of Hypoglycemia Over 30 Weeks 1 APaT Population (95% CI) 15.0% ( 19.3, 10.9) (P<0.001) Sitagliptin 100 mg + metformin (n=516) Glimepiride a + metformin (n=518) APaT=all patients as treated; CI=confidence interval. a Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. 1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):

16 LS Mean Change (±SE) in Body Weight From Baseline, kg Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin: Body Weight Change from Baseline 1 APaT Population 2 Sitagliptin 100 mg + metformin Glimepiride a + metformin kg b 0 = 2.0 kg (P<0.001) kg b APaT=all patients as treated; LS=least squares; SE=standard error. Week a Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. b LS mean body weight change at 30 weeks. 1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):

17 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan study Impact of Hypoglycemia Summary

18 Objective: To assess the long-term cardiovascular safety of adding sitagliptin to usual care, as compared with usual care alone, in patients with type 2 diabetes and established cardiovascular disease N Engl J Med 2015;373:

19 TECOS CV Safety Trial: Study Design 1,2 Patients aged 50 years with T2DM, and established CVD HbA 1c 6.5% 8.0% and dose-stable for 3 months on other AHA therapy a Continue metformin and/or pioglitazone and/or sulfonylurea, and/or insulin Randomized 1:1 treatment assignment Sitagliptin (n=7,332) Placebo (n=7,339) Sitagliptin dose was 100 mg, or 50 mg if egfr was 30 and <50 ml/min/1.73 m 2. Adjusted during trial based on egfr as needed. b Additional AHA or insulin (other than GLP-1 receptor agonists and DPP-4 inhibitors) added according to usual care to target HbA 1c, according to current guidelines (eg, ADA) Study continued until 1300 patients with a confirmed event in the primary composite outcome were reached amono- or dual therapy with metformin, sulfonylurea, or pioglitazone, or insulin alone or in combination with metformin. bif egfr is 50 ml/min/1.73 m 2, dose of sitagliptin or placebo will be 100 mg/day; if egfr is 30 to <50 ml/min/1.73 m 2 at screening, dose of sitagliptin or placebo will be 50 mg/day; if egfr is <30 ml/min/1.73 m 2 during the study, dose will be reduced to 25 mg/day. TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; AHA = antihyperglycemic agent;dpp-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; ADA = American Diabetes Association; egfr = estimated glomerular filtration rate. 1. Green JB et al. Am Heart J. 2013;166: e7. 2. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: /NEJMoa

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21 Key message Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events 11/21/

22 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan Study Impact of Hypoglycemia ADA/EASD Guideline Summary

23 Background 78.8% of patients with type 2 diabetes fast during Ramadan, with a 7.5-fold increase in the incidence of severe hypoglycaemia. There is no consensus about the most appropriate oral antihyperglycaemic agent(s) for patients with type 2 diabetes to use during Ramadan. SU is typically recommended in combination with metformin because of broad clinical experience and lower cost. The ADA recommends caution when using SU during Ramadan because they are associated with an increased risk of hypoglycaemia. Sitagliptin when added to ongoing metformin monotherapy was shown to reduce the incidence of symptomatic hypoglycaemia 3- to 6-fold compared with the addition of a SU in patients with type 2 diabetes. Given the low risk of hypoglycaemia demonstrated in previous sitagliptin trials in non-fasting patients with type 2 diabetes, it was of interest to evaluate the incidence of hypoglycaemia with sitagliptin during Ramadan fasting. Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care 2004; 27: Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: Malik S, Lopez V, Chen R, Wu W, Wong ND. Undertreatment of cardiovascular risk factors among persons with diabetes in the United States. Diabetes Res Clin Pract 2007; 77: Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: Arechavaleta R, Seck T, Chen Y et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab 2011; 13: Data on file, MSD

24 Study Design Screen patient according to inclusion and exclusion criteria 1066 patients 18 yrs HbA1c <10% Fasting during Ramadan SU stable-dosesu (glimepiride, gliclazide or glibenclamide [glyburide] ± Metformin R Sitagliptin 100 mg/day ± Metformin Continue stable dose SU ± Metformin Mean age: 55 yrs Mean HbA 1c : 7.5% Mean disease duration: 5-6 yrs 4 weeks wk 1 wk 2 wk 3 wk 4 Start of Ramadan 1ry E.P: overall incidence of symptomatic hypoglycaemia recorded during Ramadan Data on file, MSD

25 Results The proportion of patients who recorded 1 symptomatic hypoglycaemic events during Ramadan was 4.8% in the sitagliptin group and 14.3% in the SU group. The proportion of patients with hypoglycaemic events (symptomatic or asymptomatic) was 8.5% in the sitagliptin group and 17.9% in the SU group Data on file, MSD

26 Conclusion In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the incidence of hypoglycaemia compared to remaining on a SU-based regimen. Data on file, MSD

27 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Impact of Hypoglycemia Summary

28 Hypoglycemia May Be a Barrier to Glycemic Control in Patients With Type 2 Diabetes Hypoglycemia is an important limiting factor in glycemic management and may be a significant barrier to treatment adherence. Fear of hypoglycemia is an additional barrier to control. A study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increased. Amiel SA et al. Diabet Med. 2008;25(3):

29 Vicious circle of hypoglycemia awareness Frequent hypoglycemias <60 mg/dl Hypoglycemic events lead hypoglycaemic events Symptoms of hypoglycemia: - weaker - appear later - change Awareness of hypoglycemia: - more difficult - less reliable Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112

30 Complications and Effects of Severe Hypoglycemia Plasma glucose level Increased Risk of Cardiac Arrhythmia 1 Abnormal prolonged cardiac repolarization QTc and QTd Sudden death Progressive Neuroglycopenia 2 Cognitive impairment Unusual behavior Seizure Coma Brain death 1 20 mmol/l 10 mg/dl 1. Landstedt-Hallin L et al. J Intern Med. 1999;246: Cryer PE. J Clin Invest. 2007;117(4):

31 Sitagliptin & Hypoglycemic events Most previous studies of sitagliptin as monotherapy or in combination with metformin or a PPARγ agonist showed: Incidence of hypoglycemia generally similar to placebo Low rate of hypoglycemia observed with sitagliptin consistent with glucose-dependent mechanism of insulin secretion and glucagon suppression PPARγ=peroxisome proliferator-activated receptor gamma. T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: , 2010.

32 Agenda Mode of Action Evidences for sitagliptine cardiovascular safety of sitagliptin Ramadan Study Impact of Hypoglycemia Summary

33 Summary Sitagliptin therapy has been shown to be effective in lowering blood glucose when administered as monotherapy or when used in combination with metformin in appropriate patients with type 2 diabetes Combination therapy with sitagliptin and metformin improves glycemic control in appropriate patients with type 2 diabetes, with a low risk of hypoglycemia and no weight gain