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Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors Jaime A. Davidson, MD, FACP, MACE Clinical Professor of.

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Presentation on theme: "Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors Jaime A. Davidson, MD, FACP, MACE Clinical Professor of."— Presentation transcript:

1 Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology Touchstone Diabetes Center The University of Texas Southwestern Medical Center Dallas, Texas

2 Major Therapeutic Targets in T2DM DeFronzo RA. Ann Intern Med. 1999;131: Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB Saunders; 2003: Glucose absorption Hepatic glucose overproduction Insulin resistance Pancreas Muscle and fat Liver Metformin Thiazolidinediones GLP-1 agonists DPP-4 inhibitors Sulfonylureas Meglitinides GLP-1 agonists DPP-4 inhibitors Thiazolidinediones Metformin Alpha-glucosidase inhibitors GLP-1 agonists Gut Glucose reabsorption Kidney Beta-cell dysfunction Glucose level SGLT-2 inhibitors Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.

3 Limitations of Older Agents for T2DM Limitation Agent HypoglycemiaSecretagogues, insulin Weight gainSecretagogues, glitazones, insulin EdemaGlitazones, insulin GI side effects Metformin, alpha-glucosidase inhibitors Lactic acidosis (rare)Metformin Safety issues in elderly, renal- impaired, or CHF patients Glitazones, metformin, sulfonylureas Poor response ratesAll oral medications Lack of durable effect All oral monotherapy except glitazones Abbreviations: CHF, congestive heart failure; GI, gastrointestinal.

4 Function of Incretins in Healthy Individuals

5 Role of Incretins in Glucose Homeostasis Kieffer TJ, Habener JF. Endocr Rev. 1999;20: Ahrén B. Curr Diab Rep. 2003;2: Drucker DJ. Diabetes Care. 2003;26: Holst JJ. Diabetes Metab Res Rev. 2002;18: Ingestion of food Release of gut hormones — incretins Pancreas Glucose-dependent Increased insulin from beta cells (GLP-1 and GIP) Increased glucose uptake by muscles Decreased glucose production by liver Decreased blood glucose Glucose-dependent Decreased glucagon from alpha cells (GLP-1) GI tract Active GLP-1 and GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1.

6 Actions of GLP-1 Drucker DJ. Cell Metab. 2006;3: Grieve DJ, et al. Br J Pharmacol. 2009;157: Orskov C, et al. Endocrinology. 1988;123: Freeman JS. Cleve Clin J Med. 2009;76(suppl 5):S12-S19. Action GLP-1 Stimulation of insulin secretion √ Inhibition of glucagon secretion √ Reduction in circulating glucose √ Delayed gastric emptying √ Induction of satiety/reduction of food intake √ Potentially improved myocardial and endothelial function √ Possible neuroprotection √

7 DPP-4 Transmembrane cell surface aminopeptidase expressed in liver, lungs, kidneys, intestines, lymphocytes, and endothelial cells 1 –Active extracellular domain also circulates as free soluble DPP-4 in plasma 1 Active site is in a large “pocket” 2 –Access limited to substrates with small side chains (eg, proline, alanine) 2 –Active site cleaves to proline or alanine from 2nd aminoterminal position, inactivating its substrates 1 Key substrates: GLP-1 and GIP 2 –Rapid and efficient metabolism by DPP-4 = short half-lives (~2 minutes for GLP-1) 3 1. Drucker DJ, et al. Lancet. 2006;368: Kirby M, et al. Clin Sci (Lond). 2009;118: Chia CW, et al. Diabetes Metab Syndr Obes. 2009;2:37.

8 Incretin Dysfunction in T2DM

9 The Incretin Effect Oral glucose vs IV glucose infusion: differences in insulin secretion –Insulin secretion is significantly higher with oral glucose vs IV glucose infusion (“incretin effect”) Incretin effect is diminished in T2DM patients –Failure of insulin secretion Nauck M, et al. Diabetologia. 1986;29:46-52.

10 Postprandial GLP-1 Levels in IGT and T2DM Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86: Abbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance. NGTIGTT2DM P <.001 for T2DM vs NGT GLP-1 AUC Incremental from Basal (pmol/L 240 min)

11 2 Strategies for GLP-1 Enhancement GLP-1 analogs Chemically modified GLP-1, not susceptible to DPP-4 metabolism –Longer half-lives FDA approved: exenatide BID and qwk and liraglutide Investigational –Albiglutide –Lixisenatide –Dulaglutide Subcutaneous injection DPP-4 inhibitors Block DPP-4 so that it blunts breakdown of GLP-1 –Raise endogenous GLP-1 levels; should also raise GIP FDA approved: alogliptin, linagliptin, saxagliptin, and sitagliptin Vildagliptin (approved outside United States) Oral administration Drucker DJ, et al. Lancet. 2006;368: Gallwitz B. Pediatr Nephrol. 2010;25: ClinicalTrials.gov Accessed 12/11/13 at:

12 DPP-4 Inhibitors MOA 12 Incretin effects –Augments glucose-dependent insulin secretion –Inhibits glucagon secretion and hepatic glucose production –Improves hyperglycemia Meal Inactive GLP-1 Active GIP DPP-4 IntestinalGIPreleaseIntestinalGLP-1release DPP-4 inhibitor Inactive GIP DPP-4 inhibitor Active GLP-1 Selective inhibition of DPP-4 increases plasma GLP-1 levels, resulting in reduction in glycemia

13 DPP-4 Inhibition Improves Active GLP-1 Levels Single-Dose OGTT Study 3 arms (N = 58) –Placebo –Sitagliptin 25 mg –Sitagliptin 200 mg Increase in active GLP-1 with sitagliptin compared with placebo –Placebo: active GLP-1 increases to ~7 pM at 2−3 h –Sitagliptin: active GLP-1 increases to ~15−20 pM and remains higher than placebo for ~6 h Herman GA, et al. J Clin Endocrinol Metab. 2006;91: Abbreviation: OGTT, oral glucose tolerance test.

14 Linagliptin Pharmacodynamics Effect on GLP-1 and Glucagon Rauch T, et al. Diabetes Ther. 2012;3:10. Statistically significant differences in postprandial intact GLP-1 (increased) and glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patients Change from baseline in intact GLP-1 AUEC 0–2h : Linagliptin: 18.5 pmol/h/L Placebo: 0.4 pmol/h/L P <.0001 Change from baseline in glucagon AUEC 0–2h : Linagliptin: pg/h/L Placebo: 1.3 pg/h/L P =.0452

15 Therapeutic Effect of GLP-1 in T2DM GLP-1 significantly increased Insulin (17.4 nmol x 1 -1 x min)* C-peptide (228 nmol x 1 -1 x min)* GLP-1 significantly reduced Fasting plasma glucose (normal levels reached in all patients) Pancreatic glucagon secretion (-1418 pmol x 1 -1 x min) Plasma nonesterified fatty acids (-26.3 mmol x 1 -1 x min) Nauck MA, et al. Diabetologia. 1993;36: patients with unsatisfactory control of T2DM received infusions of GLP-1 or placebo *Decreased again after plasma glucose normalized.

16 GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on HbA1c, Glucose, and Insulin Levels

17 Exenatide Has Beneficial Effects on FPG and Insulin in T2DM Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: N = 13 Mean FPG (mg/dL) Peak Mean Incremental Serum Insulin (µU/mL) Abbreviation: FPG, fasting plasma glucose.

18 Exenatide Has Beneficial Effects on Postprandial Glucose and Glucagon in T2DM N = 24. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: Exenatide 0.1 μg/kgPlacebo Postprandial glucose, day 5 (mean) Baseline 180 min (nadir) 300 min 15.9 mg/dL mg/dL mg/dL Baseline 120 min (peak) 300 min mg/dL mg/dL mg/dL Postprandial glucagon, day 5 (mean) Baseline98.9 pg/mL <5%–6% change over 180 min Baseline 60 min 180 min 94.9 pg/mL pg/mL pg/mL

19 Klonoff DC, et al. Curr Med Res Opin. 2008:24: Exenatide at 3 Years of Therapy Provides Sustained Effects on HbA1c 217 patients randomized to placebo, 5 µg exenatide, or 10 µg exenatide during prior 30-week placebo-controlled studies were transitioned to open-label exenatide treatment All patients had a minimum of 3 years of exenatide exposure for this analysis By week 12, exenatide reduced HbA1c by 1.1% Reduction in HbA1c was sustained throughout 156 weeks of treatment –Change from baseline to week 156 = -1.0% (95% CI, -1.1 to -0.8); P < % of patients achieved HbA1c ≤7%; 30% achieved HbA1c ≤6.5%

20 Liraglutide 1-Year Monotherapy Reduces FPG and PPG TherapyΔ FPG (mg/dL) P Value for Liraglutide vs Glimepiride P Value for Liraglutide 1.8 vs 1.2 mg Glimepiride-5.2 Liraglutide 1.2 mg Liraglutide 1.8 mg Garber A, et al. Lancet. 2009;373: TherapyΔ PPG (mg/dL) P Value for Liraglutide vs Glimepiride P Value for Liraglutide 1.8 vs 1.2 mg Glimepiride-24.5 Liraglutide 1.2 mg Liraglutide 1.8 mg Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose.

21 Liraglutide 1-Year Monotherapy Improves Glycemic Control Glimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246) Δ HbA1c (%) Garber A, et al. Lancet. 2009;373: week phase III study in 746 T2DM patients previously on diet and exercise or oral antidiabetic monotherapy Baseline HbA1c was 8.3%–8.4% in all groups P <.0001 P =.0014 P =.0046

22 -1.4* -1* HbA1c Change (%) Liraglutide 1.8 mg † Glimepiride Effects of Liraglutide and Glimepiride Monotherapy on HbA1c Over 2 Years * P <.05 vs glimepiride; † 73% completed 2-year extension. (n = 54) <3 yDisease duration: ≥3 y (n = 42) (n = 60) (n = 55) Garber AJ, et al. Diabetes. 2009;58(suppl 1):162-OR. % achieving HbA1c <7% 58% with liraglutide* 37% with glimepiride Weight change -2.7 kg with liraglutide* 1.1 kg with glimepiride

23 Effects of Exenatide qwk vs Exenatide BID on Glycemic Control Drucker DJ, et al. Lancet. 2008;372: Exenatide 10 mcg BID (n = 147) Exenatide 2.0 mg qwk (n = 148) Approximately 90% of patients completed 30 weeks of treatment * HbA1c < 7.0% (% of Patients) Similar cumulative incidences of nausea Exenatide BID, 35% of patients; Exenatide qwk, 26% of patients Similar weight loss Approximately 4 kg in both groups Similar rates of minor hypoglycemia Exenatide BID, 6.1% of patients; Exenatide qwk, 5.4% of patients * HbA1c Change (%) Baseline HbA1c: 8.3% * FPG Change (mg/dL) * P <.05 vs exenatide BID.

24 Exenatide qwk Delivered Powerful HbA1c Reductions Blevins T, et al. J Clin Endocrinol Metab. 2011;96: Baseline HbA1c:8.5%8.4% Exenatide qwk (n = 129)Exenatide BID (n = 123)

25 Improvements in HbA1c with Exenatide qwk Were Sustained at 1 Year *ITT population. † 52-week evaluable population. LS mean (SE). 1. Bergenstal RM, et al. Lancet. 2010;376: Wysham C, et al. Diabet Med. 2011;28: DURATION-2 Open-Label Extension Completer Analysis Primary Endpoint: Change in HbA1c (%) Time (wk) Blinded period 1 * (N = 326) Open-label period 2† (N = 249) n = 130 n = 119 Sitagliptin Exenatide qwk

26 Exenatide qwk Percent to Goal Compared to Sitagliptin or Pioglitazone Metformin background –A significantly greater percentage of patients achieved HbA1c <7.0% and HbA1c ≤6.5% with exenatide qwk than with sitagliptin (P <.0001) or pioglitazone (P <.05) 2 1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Exenatide qwk 1 (n = 248) Sitagliptin 1 (n = 163) Pioglitazone 1 (n = 163) HbA1c <7.0%63%*43%61% HbA1c ≤6.5%49%*26%42% Diet and exercise background *P <.001 vs sitagliptin.

27 Overview of GLP-1 Receptor Agonist Safety Data Abbreviation: SU, sulfonylurea. Monami M, et al. Eur J Endocrinol. 2009;160: Event Odds Ratio (95% confidence interval)P Value Hypoglycemia *† 2.92 (1.49, 5.75).002 With SUs4.62 (1.89, 11.21).001 Without SUs1.37 (0.72, 2.63).34 Cardiovascular events0.99 (0.52, 1.91).98 Nausea3.88 (2.79, 5.42)<.001 Exenatide BID8.38 (4.27, 16.48)<.001 Liraglutide3.48 (2.29, 5.28)<.001 Vomiting4.23 (2.67, 6.13)<.001 Diarrhea2.36 (1.67, 3.33)<.001 * Odds ratio based on analysis of exenatide bid trials. † Severe hypoglycemia reported for 19 patients in exenatide BID trials and 1 patient in liraglutide trials. Meta-analysis Predominantly exenatide and liraglutide –n = 5429 receiving GLP-1 receptor agonists –n = 3053 receiving active comparators or placebo

28 Current DPP-4 Inhibitors Sitagliptin Vildagliptin (approved outside United States) Saxagliptin Alogliptin Linagliptin

29 Placebo-corrected change from baseline in HbA1c - Monotherapy Comparative Efficacies of DPP-4s Δ HbA1c (%) Alogliptin mg 25 mg 7.9% Linagliptin 2 5 mg 8.1% 8.0% Saxagliptin 3 5 mg 7%-10% 8.0% Sitagliptin mg 8.0% Vildagliptin 5 50 mg BID 50 mg 8.6% 8.4% The current DPP-4s have comparative efficacy 1.DeFronzo R, et al. Diabetes Care 2008;31: Linagliptin Prescribing Information. 3. Saxagliptin Prescribing Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics

30 Alogliptin Phase III Trials: HbA1c Change from Baseline After 26 Weeks Abbreviations: MET, metformin; PIO, pioglitazone; SU, sulfonylurea. *P <.001 vs control. 1. DeFronzo RA, et al. Diabetes Care. 2008;31: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Curr Med Res Opin. 2009;25: Rosenstock J, et al. Diabetes Obes Metab. 2009;11: LS Mean Change HbA1c from Baseline (%) Alogliptin monotherapy 1 Add-on therapy Baseline HbA1c: 8.0%

31 Linagliptin Significantly Reduced HbA1c After 24 Weeks in Patients on a Stable Insulin Dose Full analysis set (last observation carried forward). Change-from-baseline HbA1c at Week 24 is the primary endpoint. *Model includes treatment, baseline HbA1c, renal function, concomitant OADs. † Sensitivity analyses (FAS OC and PPS) revealed similar results. Yki-Järvinen H, et al. Diabetes Care. 2013;36: Baseline HbA1c (%):

32 HbA1c Reduction with Linagliptin in Elderly Patients Over 75 Years In a prespecified subgroup analysis, there was no significant interaction according to patient age group (P =.1000) The study had a high proportion of elderly patients –65−74 years: 26.1% linagliptin, 28.7% placebo –≥75 years: 5.5% linagliptin, 6.5% placebo Yki-Järvinen H, et al. Diabetes Care. 2013;36:

33 The difference in HbA1c reduction between linagliptin and placebo was maintained during a 52-week free insulin titration period starting at week 24 (out to week 76) Linagliptin Reduced HbA1c After 24 Weeks (Primary Endpoint) and Maintained it in a 52- Week Free Insulin Titration Period Stable insulin dose Baseline to week 24 Free insulin dose starting at week 24 Full analysis set (last observation carried forward). *Model includes treatment, baseline HbA1c, renal function, concomitant OADs. Yki-Järvinen H, et al. Diabetes Care. 2013;36:

34 Linagliptin Significantly Reduced FPG After 24 Weeks and Maintained it in 28-Week Free Insulin Titration Period Week 24Week 52 Change in FPG from baseline Placebo-adjusted change with linagliptin: mg/dL Placebo: mg/dL Linagliptin: mg/dL Stable insulin dose baseline to week 24 Free insulin dose starting at week 24 Full analysis set (observed case set). Yki-Järvinen H, et al. Diabetes Care. 2013;36:

35 Insulin Dose Stabilized in 1st 24 Weeks and Increased in Both Groups in 2nd 28-Week Free-Titration Period, but With Greater Extent in Placebo Group Stable insulin dose Baseline to week 24 Free insulin dose starting at week 24 Full analysis set, original analysis. Yki-Järvinen H, et al. Diabetes Care. 2013;36:

36 Safety Profile of Linagliptin Compared with Placebo After 52 Weeks The overall risk of adverse events (AEs) with linagliptin (n = 631) vs placebo (n = 630): –Patients with any AEs ■78.4% with linagliptin vs 81.4% with placebo –Patients with investigator-defined drug-related AEs ■18.7% with linagliptin vs 22.2% with placebo –Patients with AEs leading to discontinuation of trial drug ■3.3% with linagliptin vs 4.4% with placebo –Patients with serious AEs ■13.8% with linagliptin vs 13.2% with placebo Yki-Järvinen H, et al. Diabetes Care. 2013;36:

37 Linagliptin, When Added to Insulin, and Its Association with the Risk of Hypoglycemia Treated set (all patients who were treated with at least 1 dose of study medication). Yki-Järvinen H, et al. Diabetes Care. 2013;36: Week 24Week 52 Improved glycemic control with linagliptin added to insulin does not appear to increase the risk of hypoglycemia

38 Linagliptin Shows Rates of Hypoglycemia Similar to Placebo The Majority of Hypoglycemia is Nonsevere Investigator-defined hypoglycemia AEs at week 24 by category All Hypoglycemia AEs Severe PlaceboLinagliptin Yki-Järvinen H, et al. Diabetes Care. 2013;36: Documented Symptomatic (≤72 mg/dL) Documented Symptomatic (<54 mg/dL)

39 Study Summary: Linagliptin as Add-On to Insulin Efficacy and safety of linagliptin as add-on therapy to insulin in type 2 diabetes Linagliptin significantly reduced HbA1c after 24 weeks in patients on a stable insulin dose (placebo-corrected reduction after 24 weeks -0.65%) The efficacy of linagliptin was reliable in different prespecified subgroups, such as –Elderly patients age ≥75 years –Different categories of renal function HbA1c reductions were maintained over 52 weeks Linagliptin significantly reduced fasting plasma glucose after 24 weeks and maintained it in 28-week free insulin titration period Linagliptin has a safety profile comparable to placebo Incidence of hypoglycemia with linagliptin was comparable to placebo Yki-Järvinen H, et al. Diabetes Care. 2013;36:

40 Both Sitagliptin and Saxagliptin Produced Greatest Reductions in HbA1c in Patients with High Baseline HbA1c Placebo-Subtracted Δ in HbA1c (%) from Baseline to Week 12 –1.2 –1.0 –0.8 –0.6 –0.4 – mg QD 100 mg QD –1.15 –1.18 Hanefeld M, et al. Curr Med Res Opin. 2007;23: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Sitagliptin-Treated Subgroup with Baseline HbA1c >9% Open-Label Saxagliptin in 66 Patients with Baseline HbA1c >10% to ≤12% Δ HbA1c from Baseline to Week 24 (%) –0.8 –0.6 –0.4 – mg QD –1.87 –1.0 –1.2 –1.4 –1.6 –1.8 –2.0

41 Incretin-Based Therapy Improves Glycemic Control When Used in Combination Abbreviation: TZD, thiazolidinedione. *Added to thiazolidinedione plus metformin. 1. Bergenstal RM, et al. Lancet. 2010;376: DeFronzo RA, et al. Diabetes Care. 2005;28: DeFronzo RA, et al. Diabetes Care. 2010;33: Buse JB, et al. Diabetes Care. 2004;27: Buse JB, et al. Lancet. 2009;374: Zinman B, et al. Diabetes Care. 2009;32: Marre M, et al. Diabet Med. 2009;26: Pratley R, et al. ADA Abstract 1158-P. 9. Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Curr Med Res Opin. 2009;25: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Haak T, et al. Diabetes Obes Metab. 2012;14: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gomis R, et al. Diabetes Obes Metab. 2011;13: Lewin AJ, et al. Clin Ther. 2012;34: e Williams-Herman D, et al. Curr Med Res Opin. 2009;25: Charbonnel B, et al. Diabetes Care. 2006;29: Nauck M, et al. Diabetes Care. 2009;32: Derosa G, et al. Metabolism. 2010;59: Rosenstock J, et al. Clin Ther. 2006;28: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Hollander P, et al. J Clin Endocrinol Metab. 2009;94: Chacra AR, et al. Int J Clin Pract. 2009;63: With Metformin Initial Tx Added to MetforminAdded to TZD Added to Sulfonylurea Exenatide ✔ 1,2 ✔3✔3 ✔4✔4 Liraglutide ✔5✔5 ✔ 6* ✔ 5,7 Alogliptin ✔8✔8 ✔9✔9 ✔ 10 ✔ 11 Linagliptin ✔ 12 ✔ 13 ✔ 14 ✔ 15 Sitagliptin ✔ 16 ✔ 17,18 ✔ 19,20 ✔ 21 Saxagliptin ✔ 22 ✔ 23 ✔ 24 ✔ 25

42 Exenatide qwk HbA1c Reduction Compared with Sitagliptin or Pioglitazone LS Mean. ITT population. *P <.001 vs sitagliptin. † P <.0001 vs sitagliptin ‡ P <.05 vs pioglitazone. 1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: %8.5% Diet and exercise background 1 Metformin background 2 8.5%Baseline :8.5% Exenatide qwk (n = 248) Exenatide qwk (n = 160)

43 Fasting Plasma Glucose Improvement Was Greater with Exenatide qwk and Pioglitazone LS Mean. ITT population. * P <.05 exenatide qwk vs sitagliptin. 1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Metformin background 2 Diet and exercise background 1 Exenatide qwk (n = 248) Exenatide qwk (n = 160)

44 GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on Weight

45 Why Is Weight a Concern? Most patients with T2DM are overweight/obese Some currently available therapies cause weight gain –Secretagogues –Glitazones –Insulin

46 Klonoff DC, et al. Curr Med Res. 2008;24: Exenatide Open-Label Extension Study Continuous Loss of Body Weight Baseline 99.3 kg Δ Body Weight from Baseline (kg) Δ Body Weight from Baseline to Week 156 (kg) Baseline BMI (kg/m 2 ) <30

47 Exenatide qwk Weight Reduction Compared with Sitagliptin or Pioglitazone *P <.001 vs sitagliptin. † P <.001 vs pioglitazone. ‡ P =.002 vs sitagliptin. § P <.0001 vs pioglitazone. 1. Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Diet and exercise background 1 Metformin background Baseline (kg) : Exenatide qwk (n = 160) Exenatide qwk (n = 248)

48 Effect of Liraglutide vs Standard Therapy on Body Weight *P =.0001 vs glimepiride; † P <.05 vs placebo; ‡ P ≤.0001 vs placebo. Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Marre M, et al. Diabetic Med. 2009;26: Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52: Weight Change from Baseline (kg)

49 Liraglutide Delayed Gastric Emptying Comparative trial: liraglutide, glimepiride, placebo in T2DM patients (N = 46) Gastric emptying was slowed with liraglutide, mainly during the first postprandial hour –Mean estimated acetaminophen AUC 0-60 min ratios ■0.62 with liraglutide vs placebo (P <.001) ■0.67 with liraglutide vs glimepiride (P <.001) –Mean estimated percentage of acetaminophen exposure during the first postprandial hour (AUC 0-60 min /AUC min ) ■30% less with liraglutide compared with placebo (P <.001) ■29% less with liraglutide compared with glimepiride (P <.001) –Acetominophen C max ■20% lower with liraglutide compared with placebo (P ≤.006) ■15% lower with liraglutide compared with glimepiride (P ≤.006) Horowitz M, et al. Diabetes Res Clin Pract. 2012;97:

50 Neutral Effect of DPP-4 Inhibitors on Body Weight Sitagliptin produced statistically significant (P <.05) decreases of 0.5–0.8 kg in body weight from baseline at week 12 at all doses 1 –Not significantly different from weight loss seen with placebo (-0.5 kg) Saxagliptin reduced body weight by -0.1 to -1.2 kg at week 24 compared with baseline 2 –Weight loss was -1.4 kg with placebo In a comparative trial, mean weight loss after 26 weeks was kg with sitagliptin vs kg with liraglutide 1.8 mg and kg with liraglutide 1.2 mg 3 Linagliptin produced no significant difference in body weight from baseline 4 –No significant difference in body weight from baseline with placebo 1. Hanefeld M, et al. Curr Res Med Opin. 2007;23: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Pratley RE, et al. Lancet. 2010;375: Del Prato S, et al. Diabetes Obes Metab. 2011;13:

51 Effect of Alogliptin Monotherapy on Body Weight at 26 Weeks DeFronzo RA, et al. Diabetes Care. 2008;31:

52 Effect of Linagliptin on Body Weight When Added to Insulin Week 24Week 52 Yki-Järvinen H, et al. Diabetes Care. 2013;36:

53 GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on Lipids

54 Exenatide Has Beneficial Effects on Lipids Klonoff DC, et al. Curr Med Res Opin. 2008;24: Mean Δ from Baseline (mg/dL) Trigs TC HDL-C LDL-C Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; Trigs, triglycerides.

55 Effect of Exenatide qwk and Exenatide BID on Lipids Exenatide qwk (n = 106) Exenatide BID (n = 105) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL)-31.86*-30.09* VLDL-C (mg/dL)-12.74*-13.13* Non-HDL-C (mg/dL) Chiquette E, et al. Vasc Health Risk Manag. 2012;8: Change from Baseline *P <.05 from baseline. Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low- density lipoprotein cholesterol.

56 Liraglutide Reduces Triglycerides and CVD Inflammatory Biomarkers Difference from Placebo in Change from Baseline (%) *P < Vilsbøll T, et al. Diabetes Care. 2007;30: Courrèges JP, et al. Diabet Med. 2008;25: Abbreviations: BNP, B-type natriuretic peptide; CVD, cardiovascular disease; hs-CRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor 1.

57 Biomarkers of Cardiovascular Risk Were Reduced with Liraglutide vs SU Abbreviations: BNP, B-type natriuretic peptide; FFA, free fatty acids. Kaku K, et al. J Diabetes Invest. 2011;2: Treatment difference (95% CI to ) Treatment difference -8.6 (95% CI to -3.6)

58 Sitagliptin Has Mixed Effects on Lipids TC Δ from Baseline (mg/dL; mmol/L for FFA) LDL-CHDL-C Trigs FFA Abbreviation: FFA, free fatty acids. Hanefeld M, et al. Curr Res Med Opin. 2007;23: Placebo Sit 25 mg qd Sit 50 mg qd Sit 100 mg qd Sit 50 mg BID

59 Saxagliptin’s Effects on Lipids Specific data were not provided in the published phase III trial “Modest numerical improvements from baseline to week 24 in total cholesterol were demonstrated in the saxagliptin treatment groups.” “There were no clear effects of saxagliptin on fasting lipid concentrations.” Rosenstock J, et al. Curr Med Res Opin. 2009;25:

60 Effect of Linagliptin on Lipids in Patients at High Risk for Renal and CVD Post-hoc pooled analysis of T2DM patients with hypertension and microalbuminuria from 6 phase III linagliptin trials (N = 512)* No significant difference in lipid changes from baseline for linagliptin vs placebo *Study durations: 18–24 weeks. † Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications, study and treatment. Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol. von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

61 GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on Blood Pressure and CVD

62 Exenatide Reduced Systolic Blood Pressure in Clinical Trials ≥6 Months’ Duration No differences between treatments in proportion of patients reducing number, type, or intensity of antihypertensive therapy Reduction in blood pressure correlated only weakly with weight loss in exenatide-treated patients (r = 0.09; P =.002) Okerson T, et al. Am J Hypertens. 2010;23: Pooled data from 6 trials of exenatide in T2DM; N = 2171

63

64 Effect of Linagliptin on Blood Pressure in Patients at High Risk for Renal and CVD Post-hoc pooled analysis of T2DM patients with hypertension and microalbuminuria from 6 phase III linagliptin trials (N = 512)* No significant difference in blood pressure changes from baseline for linagliptin vs placebo *Study durations: 18–24 weeks. † Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications, study and treatment. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

65 CV Events with Incretin-Based Therapies Meta-analyses/Pooled Analyses Drug Name/Class Number of Studies AnalyzedNCV Events Exenatide BID (2316 exenatide BID; 1629 comparator) Risk ratio 0.70 (95% CI 0.38−1.31) Liraglutide (4257 liraglutide; 2381 comparator) Incidence ratio 0.73 (95% CI 0.38−1.41) Linagliptin (3319 linagliptin; 1920 comparator) Hazard ratio 0.34 (95% CI 0.16−0.70) Saxagliptin (3356 saxagliptin; 1251 comparator) Relative risk 0.43 (95% CI 0.23−0.80) Sitagliptin ,611 (7726 sitagliptin; 6885 comparator) Incidence ratio 0.83 (95% CI 0.53−1.30) GLP-1 receptor agonists 6 37*15,398 (8619 GLP-1 RA; 6779 comparator) Odds ratio 0.78 (95% CI 0.54−1.13) DPP-4 inhibitors 7 70 † 41,959Odds ratio 0.71 (95% CI 0.59−0.86) *25 trials reported ≥1 CV event and were included in the main analysis. † 63 trials reported ≥1 CV event and were included in the main analysis. 1. Ratner R, et al. Cardiovasc Diabetol. 2011;10: Marso SP, et al. Diab Vasc Dis Res. 2011;8: Johansen OE, et al. Cardiovasc Diabetol. 2012;11:3. 4. Frederich R, et al. Postgrad Med. 2010;122: Engel SS, et al. Cardiovasc Diabetol. 2013;12:3. 6. Monami M, et al. Diabetes Obes Metab. 2014;16: Monami M, et al. Diabetes Obes Metab. 2013;15:

66 CV Outcomes Trials with Incretin-Based Therapies Trial NameComparatorsPopulation Estimated Primary Completion Date SAVOR-TIMI 53 1 Saxagliptin vs placeboT2DM with history of CVD or CV risk Completed EXAMINE 2 Alogliptin vs placeboT2DM with recent ACSCompleted TECOS 3 Sitagliptin vs placeboT2DM with pre- existing CVD Dec 2014 ELIXA 4 Lixisenatide vs placeboT2DM with ACSJan 2015 LEADER 5 Liraglutide vs placeboT2DM with CV riskOct 2015 EXSCEL 6 Exenatide ER vs placeboT2DMDec 2017 CARMELINA 7 Linagliptin vs placeboT2DM with CV riskJan 2018 CAROLINA 8 Linagliptin vs glimepirideT2DM with CV riskSep Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease.

67 SAVOR Trial: Study Design 16,492 T2DM patients with established CVD or multiple risk factors Saxagliptin 5 mg/d (2.5 mg/d if eGFR ≤50 mL/min) Placebo Randomized 1:1 Double-blind Other therapy at the physician’s discretion Primary endpoint: composite endpoint of CV death, non-fatal MI, or non-fatal ischemic stroke Scirica BM, et al. N Engl J Med ;369:

68 SAVOR Trial: Primary Endpoint HR 1.00 (95% CI 0.80−1.12) P <.001 (noninferiority) P =.99 (superiority) Scirica BM, et al. N Engl J Med ;369:

69 EXAMINE Trial: Study Design 5380 T2DM patients with recent ACS Alogliptin (5 mg, 12.5 mg, or 6.25 mg once daily based on renal function) Placebo Randomized 1:1 Double-blind Primary endpoint: composite endpoint CV death, nonfatal Ml, or nonfatal stroke Plus standard of care White WB, et al. N Engl J Med. 2013;369:

70 EXAMINE Trial: Primary Endpoint HR 0.96 (95% CI ≤1.16) P <.001 (noninferiority) P =.32 (superiority) White WB, et al. N Engl J Med. 2013;369: Placebo (n = 2679)

71 Study Design: SAVOR and EXAMINE 71 ClinicalTrials.gov Accessed 12/31/13 at:

72 Baseline Characteristics: SAVOR and EXAMINE Scirica BM, et al. N Engl J Med ;369: White WB, et al. N Engl J Med. 2013;369: Saxagliptin (n = 8280) Mean age: 65 y Mean HbA1c: 8.0% Mean BMI: 31.1 kg/m 2 Median duration of diabetes: 10.3 y Placebo (n = 8212) Mean age: 65 y Mean HbA1c: 8.0% Mean BMI: 31.2 kg/m 2 Median duration of diabetes: 10.3 y Alogliptin (n = 2701) Mean age: 61 y Mean HbA1c: 8.0% Mean BMI: 28.7 kg/m 2 Median duration of diabetes: 7.1 y Placebo (n = 2679) Mean age: 61 y Mean HbA1c: 8.0% Mean BMI: 28.7 kg/m 2 Median duration of diabetes: 7.3 y SAVOR Trial 1 (N = 16,492) EXAMINE Trial 2 (N = 5380)

73 GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on the Renally Impaired

74 Dose Titration for Renally Impaired Patients Recommended DoseDose Adjustment for Renal Impairment Exenatide 1 5 mcg twice daily; increase to 10 mcg based on clinical response Moderate: Use with caution when initiating or escalating doses Severe/ESRD: Not recommended Exenatide qwk 2 2 mg once weeklyModerate: Use with caution Severe/ESRD: Not recommended Liraglutide mg once daily for 1 week, then 1.2 mg; can be increased to 1.8 mg Use with caution; no dose adjustment recommended for renal impairment Aloglitpin 4 25 mg once dailyModerate: 12.5 mg once daily Severe/ESRD: 6.25 mg once daily Linagliptin 5 5 mg once dailyNo dose adjustment recommended for renal impairment Saxagliptin mg or 5 mg once dailyModerate or severe/ESRD: 2.5 mg once daily Sitagliptin mg once dailyModerate: 50 mg once daily Severe/ESRD: 25 mg once daily Vildagliptin 8 50 mg twice daily as monotherapy; 50 mg once daily in combination with SU Moderate or severe/ESRD: 50 mg once daily 1. Exenatide Prescribing Information. 2. Exenatide QW Prescribing Information. 3. Liraglutide Prescribing Information. 4. Alogliptin Prescribing Information. 5. Linaglitpin Prescribing Information. 6. Saxagliptin Prescribing Information. 7. Sitagliptin Prescribing Information. 8. Vildagliptin Summary of Product Characteristics.

75 Linagliptin Added to Insulin: Renal Function vs Linagliptin’s Efficacy at Week 24 In a prespecified subgroup analysis, there was no significant interaction according to patient renal function category (P =.5784) The study had a high proportion of patients with renal impairment –Mild (EGFR 60 to <90 mL/min): 46.3% linagliptin, 44.9% placebo –Moderate (EGFR 30 to <60 mL/min): 9.4% linagliptin, 10.8% placebo –Severe to end-stage (EGFR <30 mL/min): 0.5% linagliptin, 0.6% placebo Abbreviation: EGFR, estimated glomerular filtration rate. Yki-Järvinen H, et al. Diabetes Care. 2013;36:

76 GLP-1 Receptor Agonists and DPP-4 Inhibitors Safety and Tolerability

77 Adverse Effects of GLP-1 Agonists and DPP-4 Inhibitors 1. Klonoff DC, et al. Curr Med Res Opin. 2008;24: Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: Garber A, et al. Lancet. 2009;373: Exenatide QW Prescribing Information. 5. Alogliptin Prescribing Information. 6. Linagliptin Prescribing Information. 7. Hanefeld M, et al. Curr Med Res Opin. 2007;23: Sitagliptin Prescribing Information. 9. Rosenstock J, et al. Curr Med Res Opin. 2009;25: White WB, et al. N Engl J Med. 2013;369: Scirica BM, et al. N Engl J Med ;369: Nausea/ VomitingDiarrheaHypoglycemiaPancreatitis Exenatide 1, Rare Liraglutide Rare Exenatide qwk Rare Alogliptin 5 +Rare Linagliptin 6 +Rare Sitagliptin 7,8 +Rare Saxagliptin 9 +/-+Rare In the first long-term clinical trials (EXAMINE and SAVOR), there was no difference in the rate of pancreatitis between the active drug and placebo 10,11

78 Summary GLP-1 Agonists and DPP-4 Inhibitors

79 GLP-1 Analogs vs Placebo* † DPP-4 Inhibitors vs Placebo* Achieved HbA1c <7% (risk ratio) 4.19 † (3.17 to 5.53) 2.47 (2.14 to 2.84) HbA1c reduction (weighted mean difference in change in HbA1c percentage) -0.97% (-1.13% to -0.81%) -0.74% (-0.85% to -0.62%) FPG level, mg/dL (weighted mean difference in change from baseline) -27 (-33 to -21) -18 (-22 to -14) Weight, kg (weighted mean difference in change from baseline) (-3.95 to -0.78) 0.48 (0.30 to 0.66) Incretin-Based Therapy in T2DM Meta-analysis Amori RE, et al. JAMA. 2007;298: Slide courtesy of Dr. Jaime A. Davidson. *The values in parentheses represent 95% CIs. † This value represents only exenatide vs placebo.

80 Meta-analysis –GLP-1 receptor agonists ■19 studies with exenatide BID, 7 studies with exenatide qwk, 11 studies with liraglutide –DPP-4 inhibitors ■5 studies with alogliptin, 9 studies with linagliptin, 7 studies with saxagliptin, 23 studies with sitagliptin, 6 studies with vildagliptin GLP-1 Receptor AgonistsDPP-4 Inhibitors HbA1c -1.10% to -1.59%-0.60% to -1.06% FPG (mg/dL) to to Weight (kg) to to Incretin-Based Therapy in T2DM Meta-analysis Aroda VR, et al. Clin Ther. 2012;34: e22. Mean Change from Baseline

81 Summary: DPP-4 Inhibitors and GLP-1 Receptor Agonists Characteristic DPP-4 Inhibitors GLP-1 Receptor Agonists Expected HbA1c decrease 1,2 0.5%−1.0%0.8%−1.9% How administered 1 OrallyInjected Weight effect 1,2 NeutralWeight loss Common adverse events 1-3 Headache, infectionNausea, vomiting Rare serious adverse events 1-3 Hypersensitivity/ allergic reactions Symptoms of pancreatitis Low risk of hypoglycemia? 1,2 Yes Gastrointestinal adverse events? 1,2 NoYes Improve postprandial glucose levels? 1,2 Yes Yes * Included in ADA/EASD algorithm? 1 Yes Included in AACE algorithm? 4 Yes * Greater effect for this class. Abbreviations: AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes. 1. Inzucchi SE, et al. Diabetes Care. 2012;35: Garber AJ, et al. Endocr Pract. 2013;19(suppl 2): Dicker D. Diabetes Care. 2011;34(suppl 2):S276-S Garber AJ, et al. Endocr Pract. 2013;19:

82 Benefits and Advantages of Incretin-Based Therapies GLP-1 analogs Lower HbA1c ~0.8%-1.1% from baseline Promote satiety and weight loss Beneficial effects on lipids Beneficial effects on systolic blood pressure DPP-4 inhibitors Lower HbA1c ~0.4%–0.9% from baseline Weight neutral (do not promote weight gain) Once-daily oral therapy –vs once daily, twice daily, or once weekly injections with GLP-1 analogs Minimal GI side effects

83 Investigational Incretin-Based Therapies GLP-1 analogs –Albiglutide –Lixisenatide –Dulaglutide –Semaglutide ClinicalTrials.gov Accessed 12/11/13 at: DPP-4 inhibitors –Vildagliptin (approved in Europe and Latin America) –Omarigliptin (MK- 3102) –Trelagliptin (SYR-472)

84 Conclusion Incretin-based therapies are welcome additions to treatment of T2DM Both improve glycemic control GLP-1 agonists have beneficial effects on lipids, blood pressure, and weight DPP-4 inhibitors are convenient once-daily oral therapies with a good safety and tolerability profile The first 2 long-term trials with DPP-4 inhibitors— SAVOR and EXAMINE—showed these therapies to be safe in T2DM patients at a high risk for cardiovascular disease

85 Thank you for your participation. To earn CME/CE credit, please complete the posttest and evaluation. (Click link in the navigation bar above or to the left of the slide presentation.) Your feedback is appreciated and will help us continue to provide you with clinically relevant educational activities that meet your specific needs.


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