Presentation on theme: "Jaime A. Davidson, MD, FACP, MACE"— Presentation transcript:
1 Jaime A. Davidson, MD, FACP, MACE Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 InhibitorsJaime A. Davidson, MD, FACP, MACEClinical Professor of MedicineDivision of EndocrinologyTouchstone Diabetes CenterThe University of Texas Southwestern Medical CenterDallas, Texas1
2 Major Therapeutic Targets in T2DM 4/8/2017 4:58 AMGlucose absorptionHepatic glucose overproductionInsulin resistancePancreasMuscle and fatLiverMetforminThiazolidinedionesGLP-1 agonistsDPP-4 inhibitorsSulfonylureasMeglitinidesAlpha-glucosidase inhibitorsGutGlucose reabsorptionKidneyBeta-cell dysfunctionGlucose levelSGLT-2 inhibitorsAbbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.DeFronzo RA. Ann Intern Med. 1999;131: Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB Saunders; 2003:References:1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004.3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.
3 Limitations of Older Agents for T2DM HypoglycemiaSecretagogues, insulinWeight gainSecretagogues, glitazones, insulinEdemaGlitazones, insulinGI side effectsMetformin, alpha-glucosidase inhibitorsLactic acidosis (rare)MetforminSafety issues in elderly, renal-impaired, or CHF patientsGlitazones, metformin, sulfonylureasPoor response ratesAll oral medicationsLack of durable effectAll oral monotherapy except glitazonesAbbreviations: CHF, congestive heart failure; GI, gastrointestinal.
5 Role of Incretins in Glucose Homeostasis Ingestion of foodGlucose-dependent Increased insulin from beta cells(GLP-1 and GIP)Increased glucose uptake by musclesRelease of gut hormones — incretinsGI tractDecreased blood glucosePancreasActiveGLP-1 and GIPGlucose-dependentDecreased glucagon from alpha cells(GLP-1)DPP-4 enzymeDecreased glucose production by liverInactive GLP-1Inactive GIPAbbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide;GLP-1, glucagon-like peptide-1.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;18:5
6 Actions of GLP-1 Action GLP-1 √ Stimulation of insulin secretion Inhibition of glucagon secretionReduction in circulating glucoseDelayed gastric emptyingInduction of satiety/reduction of food intakePotentially improved myocardial and endothelial functionPossible neuroprotectionDrucker 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.
7 DPP-4Transmembrane cell surface aminopeptidase expressed in liver, lungs, kidneys, intestines, lymphocytes, and endothelial cells1Active extracellular domain also circulates as free soluble DPP-4 in plasma1Active site is in a large “pocket”2Access limited to substrates with small side chains (eg, proline, alanine)2Active site cleaves to proline or alanine from 2nd aminoterminal position, inactivating its substrates1Key substrates: GLP-1 and GIP2Rapid and efficient metabolism by DPP-4 = short half-lives (~2 minutes for GLP-1)31. 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.
9 The Incretin EffectOral glucose vs IV glucose infusion: differences in insulin secretionInsulin secretion is significantly higher with oral glucose vs IV glucose infusion (“incretin effect”)Incretin effect is diminished in T2DM patientsFailure of insulin secretionNauck M, et al. Diabetologia. 1986;29:46-52.
10 Postprandial GLP-1 Levels in IGT and T2DM 25001927200015871500P <.001 for T2DM vs NGTGLP-1 AUC Incremental from Basal (pmol/L• 240 min)9071000500NGTIGTT2DMAbbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:10
11 2 Strategies for GLP-1 Enhancement GLP-1 analogsDPP-4 inhibitorsChemically modified GLP-1, not susceptible to DPP-4 metabolismLonger half-livesFDA approved: exenatide BID and qwk and liraglutideInvestigationalAlbiglutideLixisenatideDulaglutideSubcutaneous injectionBlock DPP-4 so that it blunts breakdown of GLP-1Raise endogenous GLP-1 levels; should also raise GIPFDA approved: alogliptin, linagliptin, saxagliptin, and sitagliptinVildagliptin (approved outside United States)Oral administrationDrucker DJ, et al. Lancet. 2006;368: Gallwitz B. Pediatr Nephrol. 2010;25:ClinicalTrials.gov Accessed 12/11/13 at:
12 DPP-4 Inhibitors MOA Meal Active GLP-1 Active GIP Incretin effects Augments glucose-dependent insulin secretionInhibits glucagon secretion and hepatic glucose productionImproves hyperglycemiaMealInactive GLP-1Active GIPDPP-4IntestinalGIPreleaseGLP-1DPP-4 inhibitorInactive GIPActive GLP-1Selective inhibition of DPP-4 increases plasma GLP-1levels, resulting in reduction in glycemia1212
13 DPP-4 Inhibition Improves Active GLP-1 Levels Single-Dose OGTT Study 3 arms (N = 58)PlaceboSitagliptin 25 mgSitagliptin 200 mgIncrease in active GLP-1 with sitagliptin compared with placeboPlacebo: active GLP-1 increases to ~7 pM at 2−3 hSitagliptin: active GLP-1 increases to ~15−20 pM and remains higher than placebo for ~6 hAbbreviation: OGTT, oral glucose tolerance test.Herman GA, et al. J Clin Endocrinol Metab. 2006;91:
14 Linagliptin Pharmacodynamics Effect on GLP-1 and Glucagon Change from baseline in intact GLP-1 AUEC0–2h:Linagliptin: 18.5 pmol/h/LPlacebo: 0.4 pmol/h/LP <.0001Change from baseline in glucagon AUEC0–2h:Linagliptin: pg/h/LPlacebo: 1.3 pg/h/LP = .0452Statistically significant differences in postprandial intact GLP-1 (increased) and glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patientsRauch T, et al. Diabetes Ther. 2012;3:10.
15 Therapeutic Effect of GLP-1 in T2DM 10 patients with unsatisfactory control of T2DM received infusions of GLP-1 or placeboGLP-1 significantly increasedGLP-1 significantly reducedInsulin (17.4 nmol x 1-1 x min)*C-peptide (228 nmol x 1-1 x min)*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)*Decreased again after plasma glucose normalized.Nauck MA, et al. Diabetologia. 1993;36:15
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 Mean FPG (mg/dL)Peak Mean Incremental Serum Insulin (µU/mL)Abbreviation: FPG, fasting plasma glucose.Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:
18 Exenatide Has Beneficial Effects on Postprandial Glucose and Glucagon in T2DM Exenatide 0.1 μg/kgPlaceboPostprandial glucose, day 5 (mean)Baseline180 min (nadir)300 min15.9 mg/dL126.4 mg/dL177.8 mg/dL120 min (peak)170.3 mg/dL289.0 mg/dL175.5 mg/dLPostprandial glucagon, day 5 (mean)98.9 pg/mL<5%–6% change over 180 min60 min180 min94.9 pg/mL173.9 pg/mL122.7 pg/mLN = 24.Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:
19 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 treatmentAll patients had a minimum of 3 years of exenatide exposure for this analysisBy week 12, exenatide reduced HbA1c by 1.1%Reduction in HbA1c was sustained throughout 156 weeks of treatmentChange from baseline to week 156 = -1.0% (95% CI, -1.1 to -0.8); P <.000146% of patients achieved HbA1c ≤7%; 30% achieved HbA1c ≤6.5%Klonoff DC, et al. Curr Med Res Opin. 2008:24:
20 Liraglutide 1-Year Monotherapy Reduces FPG and PPG Δ FPG (mg/dL)P Value for Liraglutide vs GlimepirideP Value for Liraglutide 1.8 vs 1.2 mgGlimepiride-5.2Liraglutide 1.2 mg-15.1.027Liraglutide 1.8 mg-25.6.0001.0223TherapyΔ PPG (mg/dL)P Value for Liraglutide vs GlimepirideP Value for Liraglutide 1.8 vs 1.2 mgGlimepiride-24.5Liraglutide 1.2 mg-30.8.1616Liraglutide 1.8 mg-37.5.0038.1319Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose.Garber A, et al. Lancet. 2009;373:20
21 Liraglutide 1-Year Monotherapy Improves Glycemic Control 52-week phase III study in 746 T2DM patients previously on diet and exercise or oral antidiabetic monotherapyBaseline HbA1c was 8.3%–8.4% in all groupsGlimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246)Δ HbA1c (%)P = .0014P = .0046P <.0001Garber A, et al. Lancet. 2009;373:21
22 Effects of Liraglutide and Glimepiride Monotherapy on HbA1c Over 2 Years Disease duration:<3 y≥3 y-1.4*-1*-0.7-0.4-1.5-1-0.5HbA1c Change (%)Liraglutide 1.8 mg†Glimepiride(n = 55)(n = 42)(n = 60)% achieving HbA1c <7%58% with liraglutide*37% with glimepirideWeight change-2.7 kg with liraglutide*1.1 kg with glimepiride(n = 54)* P <.05 vs glimepiride; † 73% completed 2-year extension.Garber AJ, et al. Diabetes. 2009;58(suppl 1):162-OR.
23 Effects of Exenatide qwk vs Exenatide BID on Glycemic Control Exenatide 10 mcg BID (n = 147) Exenatide 2.0 mg qwk (n = 148)Baseline HbA1c:8.3%-25-41*-50-40-30-20-10FPG Change (mg/dL)-0.5HbA1c Change (%)-1-1.5-1.5-2-1.9*100Similar cumulative incidences of nauseaExenatide BID, 35% of patients;Exenatide qwk, 26% of patientsSimilar weight lossApproximately 4 kg in both groupsSimilar rates of minor hypoglycemiaExenatide BID, 6.1% of patients;Exenatide qwk, 5.4% of patients77*806160HbA1c < 7.0% (% of Patients)4020Approximately 90% of patients completed 30 weeks of treatment.* P <.05 vs exenatide BID.Drucker DJ, et al. Lancet. 2008;372:23
25 Improvements in HbA1c with Exenatide qwk Were Sustained at 1 Year DURATION-2 Open-Label Extension Completer Analysis Primary Endpoint: Change in HbA1c (%)0.0Blinded period1*(N = 326)Open-label period2†(N = 249)-0.5-1.0n = 130-1.5n = 119-2.0461014182226263034404652Time (wk)Exenatide qwkSitagliptin*ITT population. †52-week evaluable population. LS mean (SE).1. Bergenstal RM, et al. Lancet. 2010;376:2. Wysham C, et al. Diabet Med. 2011;28:25
26 Exenatide qwk Percent to Goal Compared to Sitagliptin or Pioglitazone Diet and exercise backgroundExenatide qwk1(n = 248)Sitagliptin1(n = 163)Pioglitazone1HbA1c <7.0%63%*43%61%HbA1c ≤6.5%49%*26%42%*P <.001 vs sitagliptin.Metformin backgroundA 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)21. Russell-Jones D, et al. Diabetes Care. 2012;35:2. Bergenstal RM, et al. Lancet. 2010;376:26
27 Overview of GLP-1 Receptor Agonist Safety Data EventOdds Ratio(95% confidence interval)P ValueHypoglycemia*†2.92 (1.49, 5.75).002With SUs4.62 (1.89, 11.21).001Without SUs1.37 (0.72, 2.63).34Cardiovascular events0.99 (0.52, 1.91).98Nausea3.88 (2.79, 5.42)<.001Exenatide BID8.38 (4.27, 16.48)Liraglutide3.48 (2.29, 5.28)Vomiting4.23 (2.67, 6.13)Diarrhea2.36 (1.67, 3.33)Meta-analysisPredominantly exenatide and liraglutiden = 5429 receiving GLP-1 receptor agonistsn = 3053 receiving active comparators or placebo* 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.Abbreviation: SU, sulfonylurea.Monami M, et al. Eur J Endocrinol. 2009;160:
28 Current DPP-4 Inhibitors SitagliptinSaxagliptinVildagliptin(approved outside United States)AlogliptinLinagliptin
29 Comparative Efficacies of DPP-4s Placebo-corrected change from baseline in HbA1c - MonotherapyAlogliptin112.5 mg mg7.9% %Linagliptin25 mg 5 mg8.1% %Saxagliptin35 mg mg7%-10% %Sitagliptin4100 mg mg8.0% %Vildagliptin550 mg BID 50 mg8.6% %-0.1-0.2-0.3-0.4ΔHbA1c (%)-0.4-0.5-0.5-0.6-0.56-0.59-0.6-0.6-0.6-0.7-0.7-0.7-0.8-0.8-0.9-1.0-1.1The current DPP-4s have comparative efficacy-1.2DeFronzo R, et al. Diabetes Care 2008;31: Linagliptin Prescribing Information. 3. Saxagliptin PrescribingInformation. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.
30 Alogliptin Phase III Trials: HbA1c Change from Baseline After 26 Weeks Alogliptin monotherapy1Add-on therapyLS Mean Change HbA1c from Baseline (%)Baseline HbA1c: 8.0%BaselineHbA1c (%)Alogliptin 12.5 mgAloglitpin 25 mgControlAdd-on to SU28.1-0.39*-0.53*0.01Add-on to MET37.9-0.6*-0.1Add-on to PIO48.0–8.1-0.66*-0.80*-0.19Add-on to insulin59.3-0.63*-0.71*-0.13Abbreviations: 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;11:30
31 Linagliptin Significantly Reduced HbA1c After 24 Weeks in Patients on a Stable Insulin Dose Baseline HbA1c (%):8.298.31Full 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:
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 patients65−74 years: 26.1% linagliptin, 28.7% placebo≥75 years: 5.5% linagliptin, 6.5% placeboYki-Järvinen H, et al. Diabetes Care. 2013;36:
33 Linagliptin Reduced HbA1c After 24 Weeks (Primary Endpoint) and Maintained it in a 52- Week Free Insulin Titration PeriodStable insulin doseBaseline to week 24Free insulin dosestarting at week 24The 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)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 Placebo-adjusted change with linagliptin: Linagliptin Significantly Reduced FPG After 24 Weeks and Maintained it in 28-Week Free Insulin Titration PeriodStable insulin dosebaseline to week 24Free insulin dosestarting at week 24Week 24Week 52Change in FPG from baselinePlacebo-adjusted change with linagliptin:mg/dLPlacebo: mg/dLLinagliptin: mg/dLFull 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 GroupStable insulin doseBaseline to week 24Free insulin dosestarting at week 24Full 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 AEs78.4% with linagliptin vs 81.4% with placeboPatients with investigator-defined drug-related AEs18.7% with linagliptin vs 22.2% with placeboPatients with AEs leading to discontinuation of trial drug3.3% with linagliptin vs 4.4% with placeboPatients with serious AEs13.8% with linagliptin vs 13.2% with placeboYki-Järvinen H, et al. Diabetes Care. 2013;36:
37 Linagliptin, When Added to Insulin, and Its Association with the Risk of Hypoglycemia Week 24Week 52Improved glycemic control with linagliptin added to insulindoes not appear to increase the risk of hypoglycemiaTreated set (all patients who were treated with at least 1 dose of study medication).Yki-Järvinen H, et al. Diabetes Care. 2013;36:
38 Linagliptin Shows Rates of Hypoglycemia Similar to Placebo The Majority of Hypoglycemia is Nonsevere Investigator-defined hypoglycemia AEs at week 24 by categoryPlaceboLinagliptinAll Hypoglycemia AEsDocumented Symptomatic (≤72 mg/dL)Documented Symptomatic (<54 mg/dL)SevereYki-Järvinen H, et al. Diabetes Care. 2013;36:
39 Study Summary: Linagliptin as Add-On to Insulin Efficacy and safety of linagliptin as add-on therapy to insulin in type 2 diabetesLinagliptin 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 asElderly patients age ≥75 yearsDifferent categories of renal functionHbA1c reductions were maintained over 52 weeksLinagliptin significantly reduced fasting plasma glucose after 24 weeks and maintained it in 28-week free insulin titration periodLinagliptin has a safety profile comparable to placeboIncidence of hypoglycemia with linagliptin was comparable to placeboYki-Järvinen H, et al. Diabetes Care. 2013;36:
40 Both Sitagliptin and Saxagliptin Produced Greatest Reductions in HbA1c in Patients with High Baseline HbA1cSitagliptin-Treated Subgroup with Baseline HbA1c >9%Open-Label Saxagliptin in 66 Patients with Baseline HbA1c >10% to ≤12%Placebo-Subtracted Δ in HbA1c (%) from Baseline to Week 12–1.2–1.0–0.8–0.6–0.4–0.250 mg QD100 mg QD–1.15–1.18Δ HbA1c from Baseline to Week 24 (%)–0.8–0.6–0.4–0.210 mg QD–1.87–1.0–1.2–1.4–1.6–1.8–2.0Hanefeld M, et al. Curr Med Res Opin. 2007;23: Rosenstock J, et al. Curr Med Res Opin. 2009;25:
41 With Metformin Initial Tx Incretin-Based Therapy Improves Glycemic Control When Used in CombinationWith Metformin Initial TxAdded to MetforminAdded to TZDAdded to SulfonylureaExenatide✔1,2✔3✔4Liraglutide✔5✔6*✔5,7Alogliptin✔8✔9✔10✔11Linagliptin✔12✔13✔14✔15Sitagliptin✔16✔17,18✔19,20✔21Saxagliptin✔22✔23✔24✔25Abbreviation: 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:
42 Diet and exercise background1 Exenatide qwk HbA1c Reduction Compared with Sitagliptin or PioglitazoneDiet and exercise background1Metformin background2Baseline :8.5%8.5%8.5%8.6%8.5%8.5%Exenatide qwk(n = 248)Exenatide qwk(n = 160)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;376:42
43 Diet and exercise background1 Fasting Plasma Glucose Improvement Was Greater with Exenatide qwk and PioglitazoneDiet and exercise background1Metformin background2Exenatide qwk(n = 248)Exenatide qwk(n = 160)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:
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 gainSecretagoguesGlitazonesInsulin
46 Exenatide Open-Label Extension Study Continuous Loss of Body Weight Baseline 99.3 kgBaseline BMI (kg/m2)<30Δ Body Weight from Baseline to Week 156 (kg)Δ Body Weight from Baseline (kg)Klonoff DC, et al. Curr Med Res. 2008;24:46
47 Diet and exercise background1 Exenatide qwk Weight Reduction Compared with Sitagliptin or PioglitazoneDiet and exercise background1Metformin background2Baseline (kg) :87.588.786.1898788Exenatide qwk(n = 248)Exenatide qwk(n = 160)*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;376:47
48 Effect of Liraglutide vs Standard Therapy on Body Weight Weight Change from Baseline (kg)Liraglutide1.2 mg1.8 mgComparator(s)Monotherapy1-2 to -3* (approximate)1−2 with glimepiride (approximate)Add-on to metformin2-2.6†-2.8†-1.5 with placebo1.0 with glimepirideAdd-on to SU30.3†-0.2†-0.1 with placebo2.1 with rosiglitazoneAdd-on to metformin + TZD4-1‡-2‡0.6 with glimepirideAdd-on to metformin + SU5-1.8‡-0.42 with placebo1.6 with glargine*P = 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:
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 hourMean estimated acetaminophen AUC0-60 min ratios0.62 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 (AUC0-60 min/AUC0-300 min)30% less with liraglutide compared with placebo (P <.001)29% less with liraglutide compared with glimepiride (P <.001)Acetominophen Cmax20% 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 doses1Not 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 baseline2Weight loss was -1.4 kg with placeboIn 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 mg3Linagliptin produced no significant difference in body weight from baseline4No significant difference in body weight from baseline with placebo1. 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 52Yki-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 TrigsTCLDL-CHDL-CMean Δ from Baseline (mg/dL)Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; Trigs, triglycerides.Klonoff DC, et al. Curr Med Res Opin. 2008;24:54
55 Effect of Exenatide qwk and Exenatide BID on Lipids Change from BaselineExenatide qwk(n = 106)Exenatide BID(n = 105)LDL-C (mg/dL)-2.700.39HDL-C (mg/dL)1.240.19Triglycerides (mg/dL)-31.86*-30.09*VLDL-C (mg/dL)-12.74*-13.13*Non-HDL-C (mg/dL)-3.320.58*P <.05 from baseline.Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol.Chiquette E, et al. Vasc Health Risk Manag. 2012;8:
56 Liraglutide Reduces Triglycerides and CVD Inflammatory Biomarkers Difference from Placebo in Change from Baseline (%)Liraglutide mgLiraglutide mgLiraglutide mgTriglycerides1-19*-15-22*PAI-12-14-29*-25*BNP2-26-30*-38*hs-CRP2-3-12-20*P <.05.Abbreviations: BNP, B-type natriuretic peptide; CVD, cardiovascular disease; hs-CRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor 1.1. Vilsbøll T, et al. Diabetes Care. 2007;30: Courrèges JP, et al. Diabet Med. 2008;25:
57 Biomarkers of Cardiovascular Risk Were Reduced with Liraglutide vs SU Treatment difference -8.6(95% CI to -3.6)Treatment difference(95% CI to )Abbreviations: BNP, B-type natriuretic peptide; FFA, free fatty acids.Kaku K, et al. J Diabetes Invest. 2011;2:57
58 Sitagliptin Has Mixed Effects on Lipids TrigsFFAPlaceboSit 25 mg qdSit 50 mg qdSit 100 mg qdSit 50 mg BIDΔ from Baseline (mg/dL; mmol/L for FFA)TCLDL-CHDL-CAbbreviation: FFA, free fatty acids.Hanefeld M, et al. Curr Res Med Opin. 2007;23:
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 Pooled data from 6 trials of exenatide in T2DM; N = 2171Mean Change in Systolic Blood Pressure (mmHg)P ValueMean Change in Diastolic Blood Pressure (mmHg)Exenatide-2.2.0002-0.7.21Placebo+0.6-0.2-4.5<.0001-1.6.16Insulin-0.9-0.8No differences between treatments in proportion of patients reducing number, type, or intensity of antihypertensive therapyReduction 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:
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/ClassNumber of Studies AnalyzedNCV EventsExenatide BID1123945(2316 exenatide BID; 1629 comparator)Risk ratio 0.70(95% CI 0.38−1.31)Liraglutide2156638(4257 liraglutide; 2381 comparator)Incidence ratio 0.73(95% CI 0.38−1.41)Linagliptin385239(3319 linagliptin; 1920 comparator)Hazard ratio 0.34(95% CI 0.16−0.70)Saxagliptin44607(3356 saxagliptin; 1251 comparator)Relative risk 0.43(95% CI 0.23−0.80)Sitagliptin52514,611(7726 sitagliptin; 6885 comparator)Incidence ratio 0.83(95% CI 0.53−1.30)GLP-1 receptor agonists637*15,398(8619 GLP-1 RA; 6779 comparator)Odds ratio 0.78(95% CI 0.54−1.13)DPP-4 inhibitors770†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 NameComparatorsPopulationEstimated Primary Completion DateSAVOR-TIMI 531Saxagliptin vs placeboT2DM with history of CVD or CV riskCompletedEXAMINE2Alogliptin vs placeboT2DM with recent ACSTECOS3Sitagliptin vs placeboT2DM with pre-existing CVDDec 2014ELIXA4Lixisenatide vs placeboT2DM with ACSJan 2015LEADER5Liraglutide vs placeboT2DM with CV riskOct 2015EXSCEL6Exenatide ER vs placeboT2DMDec 2017CARMELINA7Linagliptin vs placeboJan 2018CAROLINA8Linagliptin vs glimepirideSep 2018Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease.
67 SAVOR Trial: Study Design 16,492 T2DM patients with established CVD or multiple risk factorsRandomized 1:1Double-blindSaxagliptin 5 mg/d (2.5 mg/d if eGFR ≤50 mL/min)Other therapy at the physician’s discretionPlaceboPrimary endpoint: composite endpoint of CV death, non-fatal MI, or non-fatal ischemic strokeScirica 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 ACSRandomized 1:1Double-blindAlogliptin (5 mg , 12.5 mg, or 6.25 mg once daily based on renal function)Plus standard of carePlaceboPrimary endpoint: composite endpoint CV death, nonfatal Ml, or nonfatal strokeWhite 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)Placebo (n = 2679)White WB, et al. N Engl J Med. 2013;369:
71 Study Design: SAVOR and EXAMINE SAVOR (N = 16,492)EXAMINE (N = 5380)Planned durationEvent-driven until the occurrence of 1040 primary eventsEvent driven with interim analyses after 80, 100, 125, 150, 550, 600, and 650 events (~5 yrs)AnalysisNoninferiority/superiorityPrevention1° or 2°2°Primary outcomesEfficacy and safety: time to confirmed CV event (composite of death, nonfatal MI, nonfatal ischemic stroke)Time to CV event (composite of CV death, nonfatal MI, nonfatal stroke)Secondary outcomesTime to first occurrence of primary outcome + hospitalization for HF, unstable angina, or coronary revascularizationAll-cause mortalityTime to occurrence of any event in the secondary MACE composite of CV death, nonfatal MI, nonfatal stroke, and urgent revascularization for unstable anginaKey inclusion≥40 years, A1C ≥6.5% and ≤12.5% within 6 monthsPre-existing CVD or high risk for CV or multiple CV risk factors≥18 years, A1C 6.5%−11.0% while receiving monotherapy or combination antihyperglycemic therapy, or from 7.0%−11.0% if the regimen includes insulinKey exclusionAcute vascular event <2 months prior to randomizationTreatment with DPP-4i or GLP-1 RA within 6 monthsType 1 diabetesTreatment with GLP-1 RA at screeningTreatment with DPP-4i within 3 months of screening or more than 14 days totalClinicalTrials.gov Accessed 12/31/13 at:7171
72 Baseline Characteristics: SAVOR and EXAMINE SAVOR Trial1(N = 16,492)EXAMINE Trial2(N = 5380)Saxagliptin (n = 8280)Mean age: 65 yMean HbA1c: 8.0%Mean BMI: 31.1 kg/m2Median duration of diabetes: 10.3 yPlacebo (n = 8212)Mean BMI: 31.2 kg/m2Alogliptin (n = 2701)Mean age: 61 yMean HbA1c: 8.0%Mean BMI: 28.7 kg/m2Median duration of diabetes: 7.1 yPlacebo (n = 2679)Median duration of diabetes: 7.3 y1. Scirica BM, et al. N Engl J Med ;369:2. White WB, et al. N Engl J Med. 2013;369:7272
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 ImpairmentExenatide15 mcg twice daily; increase to 10 mcg based on clinical responseModerate: Use with caution when initiating or escalating dosesSevere/ESRD: Not recommendedExenatide qwk22 mg once weeklyModerate: Use with cautionLiraglutide30.6 mg once daily for 1 week, then 1.2 mg; can be increased to 1.8 mgUse with caution; no dose adjustment recommended for renal impairmentAloglitpin425 mg once dailyModerate: 12.5 mg once dailySevere/ESRD: 6.25 mg once dailyLinagliptin55 mg once dailyNo dose adjustment recommended for renal impairmentSaxagliptin62.5 mg or 5 mg once dailyModerate or severe/ESRD: 2.5 mg once dailySitagliptin7100 mg once dailyModerate: 50 mg once dailySevere/ESRD: 25 mg once dailyVildagliptin850 mg twice daily as monotherapy; 50 mg once daily in combination with SUModerate or severe/ESRD: 50 mg once daily1. 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 impairmentMild (EGFR 60 to <90 mL/min): 46.3% linagliptin, 44.9% placeboModerate (EGFR 30 to <60 mL/min): 9.4% linagliptin, 10.8% placeboSevere to end-stage (EGFR <30 mL/min): 0.5% linagliptin, 0.6% placeboAbbreviation: 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 Nausea/ VomitingDiarrheaHypoglycemiaPancreatitisExenatide1,2+++++RareLiraglutide3+++Exenatide qwk4++Alogliptin5Linagliptin6Sitagliptin7,8Saxagliptin9+/-In the first long-term clinical trials (EXAMINE and SAVOR), there was no difference in the rate of pancreatitis between the active drug and placebo10,111. 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:
78 GLP-1 Agonists and DPP-4 Inhibitors SummaryGLP-1 Agonists and DPP-4 Inhibitors
79 Incretin-Based Therapy in T2DM Meta-analysis 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-2.37(-3.95 to -0.78)0.48(0.30 to 0.66)*The values in parentheses represent 95% CIs.†This value represents only exenatide vs placebo.Amori RE, et al. JAMA. 2007;298: Slide courtesy of Dr. Jaime A. Davidson.
80 Incretin-Based Therapy in T2DM Meta-analysis Mean Change from BaselineGLP-1 Receptor AgonistsDPP-4 InhibitorsHbA1c-1.10% to -1.59%-0.60% to -1.06%FPG (mg/dL)totoWeight (kg)-2.03 to -2.41-0.16 to -0.64Meta-analysisGLP-1 receptor agonists19 studies with exenatide BID, 7 studies with exenatide qwk, 11 studies with liraglutideDPP-4 inhibitors5 studies with alogliptin, 9 studies with linagliptin, 7 studies with saxagliptin, 23 studies with sitagliptin, 6 studies with vildagliptinAroda VR, et al. Clin Ther. 2012;34: e22.
81 Summary: DPP-4 Inhibitors and GLP-1 Receptor Agonists CharacteristicDPP-4 InhibitorsGLP-1 Receptor AgonistsExpected HbA1c decrease1,20.5%−1.0%0.8%−1.9%How administered1OrallyInjectedWeight effect1,2NeutralWeight lossCommon adverse events1-3Headache, infectionNausea, vomitingRare serious adverse events1-3Hypersensitivity/ allergic reactionsSymptoms of pancreatitisLow risk of hypoglycemia?1,2YesGastrointestinal adverse events?1,2NoImprove postprandial glucose levels?1,2Yes*Included in ADA/EASD algorithm?1Included in AACE algorithm?4What is your opinion about initial combination therapy?What are your thoughts on candidates for DPP-4 inhibitors vs GLP-1 agonists or mimetics (injections vs pills, weight loss vs weight neutral, etc)?*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):1-48.3. Dicker D. Diabetes Care. 2011;34(suppl 2):S276-S Garber AJ, et al. Endocr Pract. 2013;19:81
82 Benefits and Advantages of Incretin-Based Therapies GLP-1 analogsLower HbA1c ~0.8%-1.1% from baselinePromote satiety and weight lossBeneficial effects on lipidsBeneficial effects on systolic blood pressureDPP-4 inhibitorsLower HbA1c ~0.4%–0.9% from baselineWeight neutral (do not promote weight gain)Once-daily oral therapyvs once daily, twice daily, or once weekly injections with GLP-1 analogsMinimal GI side effects
83 Investigational Incretin-Based Therapies GLP-1 analogsAlbiglutideLixisenatideDulaglutideSemaglutideDPP-4 inhibitorsVildagliptin (approved in Europe and Latin America)Omarigliptin (MK-3102)Trelagliptin (SYR-472)ClinicalTrials.gov Accessed 12/11/13 at:
84 ConclusionIncretin-based therapies are welcome additions to treatment of T2DMBoth improve glycemic controlGLP-1 agonists have beneficial effects on lipids, blood pressure, and weightDPP-4 inhibitors are convenient once-daily oral therapies with a good safety and tolerability profileThe 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
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