Presentation on theme: "1 Advancing Our Understanding of Glycemic Control: Refocusing on Glucose Regulation in Type 2 Diabetes Joe L Reese, M.D."— Presentation transcript:
1 Advancing Our Understanding of Glycemic Control: Refocusing on Glucose Regulation in Type 2 Diabetes Joe L Reese, M.D.
2 Learning Objectives Describe the multiple factors involved in the pathogenesis of type 2 diabetes and explain their contribution over time. Explain the role of incretin hormones in maintaining normal glucose homeostasis. Discuss clinical challenges and guideline recommendations for getting patients to goal. Describe the efficacy, safety/tolerability profile, and place in therapy for sitagliptin in patients with type 2 diabetes.
3 Type 2 Diabetes: Refocusing Priorities Diabetes: a multifactorial disease Impairment of insulin secretion coupled with unsuppressed glucagon release Impairment of insulin action (ie, insulin resistance) Impairment of insulin action (ie, insulin resistance) Pancreatic islet- (alpha- and beta-) cell dysfunction: a central factor in the development of hyperglycemia and progression of type 2 diabetes Progressively reduced insulin secretion from beta cells, contributing to hepatic glucose overproduction Progressively reduced insulin secretion from beta cells, contributing to hepatic glucose overproduction Excess glucagon release from alpha cells, leading to hepatic glucose overproduction 1. Del Prato S et al. Horm Metab Res. 2004;36:775–781. 2. Porte D et al. Clin Invest Med. 1995;18:247–254. Major defect in insulin resistance already present at onset of diabetes Major defect in insulin resistance already present at onset of diabetes
4 Manifestations of Beta-Cell Dysfunction in Type 2 Diabetes Mellitus Increased proinsulin to insulin ratio 1 Abnormal pulsatile insulin response 1 Decreased beta- cell responsiveness to glucose 2,3 Decreased insulin production 4 Decreased insulin content Decreased insulin granule density 1. Buchanan TA. Clin Ther. 2003;25:B32–-B46. 2. Buse JB et al. Williams Textbook of Endocrinology. 2003:1427–1483. 3. Ward WK et al. J Clin Invest. 1984;76:1318–1328. 4. Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541. Beta-Cell Dysfunction
5 Beta-Cell Function Years From Diagnosis 40 60 20 Over a 10-year Study, Beta-Cell Function Worsened and Insulin Resistance Remained Relatively Constant %β=measure of beta-cell function; %S=measure of insulin sensitivity. Levy J et al. Diabet Med. 1998;15:290–296. Permission requested. 0 0 40 60 80 20 246 HOMA % β 0 0246 HOMA % S Insulin Sensitivity N=432 Belfast Diet Study
6 Alpha-Cell Dysfunction Contributes to Excess Hepatic Glucose Production 1. Del Prato S et al. Horm Metab Res. 2004;36:775–781. 2. Clark A et al. Diabetes Res. 1988;9:151–159. 3. Butler PC et al. Diabetes. 1991;40:73–81. Alpha-Cell Dysfunction Dysregulation of glucagon secretion during fasting Impaired suppression of glucagon secretion after a meal Fasting and postprandial hyperglycemia in type 2 diabetes
7 Fasting and Postprandial Hepatic Glucose Output in Type 2 Diabetes Meal 2 4 6 8 10 12 14 16 18 20 –300306090120150180210240270300 Time, min Endogenous Glucose Production, µmol/min/kg Subjects Without Diabetes (n=12) Subjects With Diabetes (n=18) Kelley D et al. Metabolism. 1994;43:1549–1557. Permission requested.
8 Glucoregulatory Role of Key Incretin Hormones GLP-1 Inhibits gastric emptying 1,2 Reduces food intake and body weight 2 Inhibits glucagon secretion from alpha cells in a glucose-dependent manner 1 Stimulates insulin response from beta cells in a glucose-dependent manner 1 Is released from L cells in ileum and colon 1,2 GIP Has no significant effects on satiety or body weight 2 Does not affect gastric emptying 2 Stimulates insulin response from beta cells in a glucose-dependent manner 1 Is released from K cells in duodenum 1,2 GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic peptide. 1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
9 The Incretin Effect Is Diminished in Subjects With Type 2 Diabetes Oral glucose loadIntravenous (IV) glucose infusion IR=immunoreactive. Nauck M et al. Diabetologia 1986;29:46–52. Permission requested. Time, min Control Subjects (n=8) IR Insulin, mU/L 80 60 40 20 0 180601200 Normal Incretin Effect 80 60 40 20 0 180601200 Subjects With Type 2 Diabetes (n=14) Diminished Incretin Effect Time, min IR Insulin, mU/L
10 GLP-1 and GIP Are Degraded by the DPP-4 Enzyme Intestinal GLP-1 and GIP release DPP-4 enzyme DPP-4 enzyme Active GLP-1 and GIP a Inactive metabolites Rapid inactivation a Half-lives: GLP-1 ~2 minutes; GIP ~5 minutes. 1. Deacon CF et al. Diabetes. 1995;44:1126–1131. 2. Meier JJ et al. Diabetes. 2004;53:654–662. Meal
21 ADA and AACE/ACE Guidelines: Treatment Goals for A1C, FPG, and PPG Parameter Normal 1,2 Level ADA 3 Goal AACE/ACE 2 Goal FPG, mg/dL<10090–130<110 PPG, mg/dL<140<180<140 A1C, %4–6 <7 a ≤6.5 FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology. 1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed. 2003. Permission requested. 2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68. 3. ADA. Diabetes Care. 2007;30:S4–S41. a The goal for an individual patient is to achieve an A1C as close to normal (<6%) as possible without significant hypoglycemia.
22 Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles n = 58 Monnier L et al. Diabetes Care. 2003;26:881–885. Permission requested. A1C Contribution, %
23 Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Permission requested. Published Conceptual Approach Earlier and More Aggressive Intervention May Improve Patients’ Chances of Reaching Goal 7 8 6 9 10 A1C, % Mean A1C of patients Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin
24 Case Study: Mona Female, 60 years old, obese Serum creatinine: 1.4 mg/dL A1C: 7.1% Antihypertensive therapy History of inflammatory bowel disease Recent myocardial infarction Treatment-naive for diabetes
25 Case Study: Archie Male, 54 years old, obese Serum creatinine: 0.9 mg/dL A1C: 8.0% Has been receiving metformin 1,000 mg twice a day for past 6 months
26 Case Study: Nancy Female, 55 years old, obese Serum creatinine: 1.0 mg/dL A1C: 8.5% Mild edema Antihypertensive therapy Treatment-naive for diabetes
27 Major Targets of Oral Drug Classes DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinediones. 1. DeFronzo RA. Ann Intern Med. 1999;131:281–303. 2. Buse JB et al. In: Williams Textbook of Endocrinology. 2003:1427–1483. Pancreatic Islet Cells ↓ Glucose level Muscle and Fat Liver Sulfonylureas Meglitinides Biguanides TZDs Biguanides alpha-Glucosidase inhibitors Gut DPP-4 inhibitors
29 JANUVIA™ (sitagliptin) Indication –JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Important limitations of use –JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. –JANUVIA has not been studied in combination with insulin. JANUVIA has been studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, and glimepiride plus metformin.
30 Dosage and Administration Usual Dosing for JANUVIA™ (sitagliptin) a The recommended dose of JANUVIA is 100 mg once a day Patients With Renal Insufficiency a,b 50 mg once a day25 mg once a day ModerateSevere and ESRD CrCl 30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.7–≤3.0; Women: >1.5–≤2.5) CrCl <30 mL/min (~Serum Cr levels [mg/dL] Men: >3.0; Women: >2.5; or on dialysis) a JANUVIA can be taken with or without food. b Patients with mild renal insufficiency—100 mg once a day. ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis; CrCl=creatinine clearance. Assessment of renal function is recommended before initiation of JANUVIA and periodically thereafter.
31 Contraindications/Warnings and Precautions Contraindications –History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema Warnings and Precautions –Use in patients with renal insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. Assessment of renal function is recommended prior to initiating JANUVIA™ (sitagliptin) and periodically thereafter. –Use with medications known to cause hypoglycemia: As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA was used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.
32 Contraindications/Warnings and Precautions (cont) Warnings and Precautions (cont) –Hypersensitivity reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA™ (sitagliptin). Reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.
33 Adverse Reactions The most common adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA™ (sitagliptin) as monotherapy or in combination therapy and more commonly than in patients treated with placebo are: –Upper respiratory tract infection –Nasopharyngitis –Headache. Hypoglycemia was also reported regardless of investigation assessment of causality more commonly in patients treated with the combination of JANUVIA and sulfonylurea, with or without metformin, than in patients given the combination of placebo and sulfonylurea, with or without metformin. Additional adverse reactions identified during postapproval use (reported voluntarily from a population of uncertain size) including: –Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome.
34 Initial Combination With Sitagliptin Plus Metformin Study: Design Week –2Day 1 Screening Period If on OHA: discontinue therapy Single- Blind Placebo Run-in Period Diet and Exercise Run-In Period Eligible if A1C 7.5%–11% Week 24 Patients Not Using OHA or Monotherapy or Low-Dose OHA Combination PlaceboSitagliptin 100 mg qd Metformin 500 mg bid Metformin 1,000 mg bid Sitagliptin 50 mg/ Metformin 500 mg bid Sitagliptin 50 mg/ Metformin 1,000 mg bid R OHA=oral antihyperglycemic; bid=twice a day. Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
36 Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results Mean A1C = 8.8% Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid LSM A1C Change From Baseline, % –3.5 –3.0 –2.5 –2.0 –1.5 –1.0 –0.5 0.0 0.5 178177183178175n= –0.8 –1.0 –1.3 –1.6 –2.1 Open label 117 –2.9 a a LSM change from baseline without adjustment for placebo. qd=once a day; bid=twice a day. Goldstein B et al. Diabetes Care. 2007;30:1979–1987. 24-Week Placebo-Adjusted Results
37 Initial Combination Therapy With Sitagliptin Plus Metformin Study: FPG and PPG Results 24-Week Placebo-Adjusted Results a LSM adjusted for baseline value. b Difference from placebo. Goldstein B et al. Diabetes Care. 2007;30:1979–1987. Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid LSM PPG Change, mg/dL b 2-h PPG Mean baseline level: 283–293 mg/dL –54 a –117 a –125 –100 –75 –50 –25 0 LSM FPG Change, mg/dL b FPG Mean baseline level: 197–205 mg/dL –33 a –70 a –75 –50 –25 0 –53 a n=183 –35 a n=179 n=141 –93 a n=147 –78 a n=138n=152 –23 a n=180 n=178n=179 –52 a Sitagliptin 100 mg qd n=136
38 Sitagliptin 50 mg + metformin 1,000 mg bidMetformin 1,000 mg bidSitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bidPlacebo Initial Combination Therapy With Sitagliptin Plus Metformin Study: Percentage of Patients Achieving <7% A1C at 24 Weeks a P<0.01 vs monotherapy. Goldstein B et al. Diabetes Care. 2007;30:1979–1987. A1C <6.5%A1C <7% To Goal, % 0 10 20 30 40 50 60 70 165183178175177175178165178177183178 2 22 a 10 20 9 38 23 20 9 66 a 43 a 44 a
39 Initial Combination Therapy With Sitagliptin Plus Metformin Study: Change in Body Weight and Incidence of Hypoglycemia Placebo Sita 100 MF 500 bid MF 1,000 bid Sita 50 + MF 500 bid Sita 50 + MF 1,000 bid Hypoglycemia n/N (%) 1/176 (0.6) 1/179 (0.6) 1/182 (0.5) 2/182 (1.1) 2/190 (1.1) 4/182 (2.2) LSM Change From Baseline, kg –2 –1 0 1 167184178 175 179175 Rates of Hypoglycemia in Combination With Sitagliptin Sitagliptin 50 mg + metformin 1,000 mg bidMetformin 1,000 mg bidSitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bidPlacebo Sita=sitagliptin; MF=metformin. Goldstein B et al. Diabetes Care. 2007;30:1979–1987.
40 2 weeks Single-blind placebo Sitagliptin Monotherapy Studies: Design 2 randomized, double-blind, placebo-controlled studies in patients with type 2 diabetes –18- and 24-week treatment periods (placebo or sitagliptin 100 mg or 200 mg once daily) 1,2 ScreeningDouble-blind treatmentDiet/exercise run-in Eligible if A1C 7% to 10% Therapy discontinued Randomization Eligible patients: On therapy or not on therapy ≥8 weeks 18 weeks 1 or 24 weeks 2 7 weeks Washout 1. Raz I et al. Diabetologia. 2006;49:2564–2571. 2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
41 Mean Change in A1C, % c a Compared with placebo. b Least squares mean (LSM) adjusted for prior antihyperglycemic therapy status and baseline value. c Difference from placebo. d Combined number of patients on sitagliptin or placebo. e P<0.001 overall and for treatment-by-subgroup interactions. CI, confidence interval. 1. Raz I et al. Diabetologia. 2006;49:2564–2571. 2. Aschner P et al. Diabetes Care. 2006;29:2632–2637. Mean baseline A1C: 8.0% P < 0.001 a –0.6 b –1.0 –0.8 –0.6 –0.4 –0.2 0.0 –0.8 b Placebo-Adjusted Results 24-week monotherapy study 2 (95% CI: – 1.0, – 0.6) 18-week monotherapy study 1 (95% CI: – 0.8, – 0.4) n=193 n=229 Inclusion criteria A1C: 7%–10% Overall<8 ≥8–<9 ≥ 9 Baseline A1C, % –1.4 –0.6 –0.7 –1.8 –1.6 –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 –0.2 0.0 n=411 d n=239 d n=119 d Mean Change in A1C, % Prespecified pooled analysis at 18 weeks e –0.7 n=769 d Sitagliptin Monotherapy Studies: A1C Reductions Study 021 and 023
42 Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results From Patients not on Antihyperglycemic Therapy at Study Entry LSM Change From Baseline, % Study 036 –1.1 n=88 –1.1 n=90 –1.2 n=87 –1.6 n=100 –1.9 n=86 – 2.0 – 1.8 – 1.6 – 1.4 – 1.2 – 1.0 – 0.8 – 0.6 – 0.4 –0.2 0 n=83 Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bidSitagliptin 100 mg qdPlacebo LSM=least squares mean change. Data available on request from Merck & Co., Inc.
43 Single-blind placebo Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Design Patients with type 2 diabetes (on any monotherapy or dual combination with metformin) Noninferiority design Screening Period Double-blind treatment period: glipizide or sitagliptin 100 mg qd Metformin monotherapy run-in period Week -2: Eligible if A1C 6.5% to 10% Mean baseline A1C: 7.65% Continue/start metformin monotherapy Day 1 Randomization Metformin (stable dose >1,500 mg/day) Week 52 Glipizide: 5 mg qd increased to 10 mg bid (held if premeal fingerstick glucose < 6.1 mmol/L or hypoglycemia) Glipizide dosing Mean titrated dose 10 mg/day Per protocol, glipizide was kept constant except for down-titration if needed to prevent hypoglycemia Nauck MA, et al. Diabetes Obes Metab. 2007;9:194–205.
44 Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Glycemic Parameters (Intent-to-Treat) a Sitagliptin 100 mgGlipizide A1C (%)N=576N=559 Baseline (mean)7.77.6 Change from baseline (adjusted mean b ) –0.5–0.6 FPG (mg/dL)N=583N=568 Baseline (mean)166164 Change from baseline (adjusted mean b ) –8 Glycemic Parameters at Final Visit (Week 52) a The intent-to-treat analysis used the patients' last observation in the study before discontinuation. b Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
46 Glipizide-Controlled Sitagliptin Add-on to Metformin Noninferiority Study: Weight Change and Incidence of Hypoglycemia Glipizide Sitagliptin 100 mg Incidence of Hypoglycemia at 52 Weeks Incidence, % Body Weight at 52 Weeks LSM Change From Baseline, kg n=584n=588 n=411 n=382 P<0.001 LSM=least squares mean. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
47 Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Design Stratum 1 Glimepiride (≥4 mg/day) (n=212) Placebo (n=219) Screening Period Single-blind Placebo Stratum 2 Glimepiride + Metformin ≥1500 mg/day) (n=229) Week 24 RANDOMIZATIONRANDOMIZATION Week 0 Patients with type 2 diabetes mellitus aged 18–75 years Continue/start regimen of glimepiride ± metformin Week –2 eligible if A1C 7.5%–10.5% Double-Blind Sitagliptin 100 mg once daily (n=222) Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
48 24-Week Placebo-Adjusted Results LSM A1C Change from Baseline, % –0.7 a –0.6 a –0.9 a –1.0 –0.9 –0.8 –0.7 –0.6 –0.5 –0.4 –0.3 –0.2 –0.1 0.0 Sitagliptin Add-on to Glimepiride With or Without Metformin Study: A1C Results LSM=least squares mean. a P<0.001 vs placebo. Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. Entire cohort (Sitagliptin + glimepiride ± metformin) Stratum 1 (sitagliptin + glimepiride) Stratum 2 (sitagliptin + glimepiride + metformin)
49 Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Change in Body Weight LSM=least squares mean. a Difference in LSM change from baseline 1.1 kg. Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. LSM Change From Baseline, kg Change in Body Weight at 24 Weeks a Sitagliptin + glimepiride ± metformin Placebo + glimepiride ± metformin P=0.016
50 Sitagliptin Add-on to Glimepiride With or Without Metformin Study: Incidence of Hypoglycemia As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when sitagliptin was used in combination with a sulfonylurea, the incidence of hypoglycemia was increased over that of placebo. Treatment GroupN Overall n (%) Sitagliptin + Glimepiride ± Metformin22227 (12.2) Placebo + Glimepiride ± Metformin219 4 (1.8) Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
51 Treatment Paradigm Challenge Case Studies Group Discussion
52 Case Study: Mona (cont) Female, 60 years old, obese Serum creatinine: 1.4 mg/dL A1C: 7.1% Treatment-naive for diabetes Antihypertensive therapy History of inflammatory bowel disease Recent myocardial infarction Treatment option(s): ? ?
53 Case Study: Archie (cont) Male, 54 years old, obese Serum creatinine: 0.9 mg/dL A1C: 8.0% Has been receiving metformin 1,000 mg twice a day for past 6 months Treatment option(s): ? ?
54 Case Study: Nancy (cont) Female, 55 years old, obese Serum creatinine: 1.0 mg/dL A1C: 8.5% Treatment-naive for diabetes Mild edema Antihypertensive therapy Treatment option(s): ? ?