INCRETIN EFFECT: SAY WHAT??

Transcription

1 Type 2 Diabetes Mediation Update: Improving Control with Inretin Agents Luia M. Novak, MSN, ANP BC, BC ADM, CDTC The Diabetes Institute Walter Reed National Military Medial Center Bethesda, MD INCRETIN EFFECT: SAY WHAT?? Faulty Dislosures I have nothing to dislose Panreas: B ell A ell Dysregulation of Gluose Homeostasis (T2D) Brain Hyperglyemia Gut: GLP 1 Liver Kidney Adipose Tissue Musle Objetives On ompletion of this ativity, partiipants should be able to: Distinguish the mehanism of ation between the two lasses of inretin agents and understand how this impats gluose ontrol. Understand the omon side effets (SE) and potential adverse reations (AR) of these agents. Determine how to hoose the agent most appropriate for your individual patient. The Inretin Effet Inreased insulin release in response to oral gluose load when ompared to IV administration of gluose Up to 60% of postprandial insulin seretion in healthy persons is attributable to the inretin effet Inretin hormones released from intestinal muosa indue insulin seretion upon GI exposure to nutrients GLP-1 (gluagon-like peptide-1) GIP (gluose-dependent insulinotropi peptide) Idris I et al. Diabetes Obes Metab. 2007;9: ; MKennon SA et al. Diabetes Edu. 2007;33:55-66.

2 Plasma Gluose (mg/dl) Inretin Effet Inreased β-ell Response to an Oral Gluose Load Oral gluose (50 g) or isoglyemi infusion C-peptide (nmol/l) Time (min) Adapted from: Nauk MA et al. J Clin Endorinol Metab. 1986;63: * * * IV gluose Oral gluose * Inretin Effet * * * stored in the L-ells of the ileum and olon, and released at mealtime in response to neurohormonal signals and the presene of food in the gut Beta ells: Enhanes insulin seretion GLP-1 Modulates Numerous Funtions in Humans Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Ata Physiol Sand. 1997;160: Data from Nauk MA, et al. Diabetologia. 1996;39: ; Data from Druker DJ. Diabetes. 1998;47: Redues appetite Alpha ells: Postprandial gluagon seretion Liver: Gluagon redues output of sugar from liver Stomah: Helps slow stomah emptying Response of Insulin and Gluagon in Persons Without Diabetes GLP-1 Seretion and Metabolism mg/dl μu/ml pg/ml Carb meal Gluose Insulin Gluagon Time (min) Panreati islet α-cells β-cells 30 MM Islet boundary Mixed Meal GLP-1 Plasma DPP-4 enzyme Rapid Inativation 2-3 minutes >80% GLP-1 Inative Renal Clearane CHO = arbohydrate Unger RH. N Engl J Med. 1971;285: Photomirograph ourtesy of Mihael Sarras, PhD, Rosalind Franklin University of Mediine and Siene. DPP-IV = dipeptidyl peptidase-iv GLP-1 Ations Adapted from Deaon CF, et al. Diabetes. 1995;44: Inappropriate Insulin and Gluagon Responses to Gluose in Patients With Type 2 Diabetes Insulin Gluagon 150 Normal Diabetes 160 Normal Diabetes Insulin (μu/ml) Gluagon (pg/ml) Time (min) OK, SO NOW WHAT? Muller WA, et al. N Engl J Med. 1970;283:

3 MOA of DPP-4 Inhibitor Mixed Meal GLP-1 DPP-IV Rapid Inativation (> 80% of pool) 2-3 Fold inrease of GLP-1 Among the pleiotrophi effets of the inretins, there are benefiial effets on ardiometaboli risk fators and early signals indiating possible ardioprotetion. Plasma Renal Clearane GLP-1 Ations DPP-IV = dipeptidyl peptidase-iv Adapted from Deaon CF, et al. Diabetes. 1995;44: MOA of GLP-1 RA Mixed Meal DPP-4 enzyme PROLONGED EXPOSURE to GLP-1 Meta-Analysis: Blood Pressure Changes With GLP-1 RAs 1 SBP 3.57 ( 5.49 to 1.66) GLP-1 Plasma + GLP-1 RA RA GLP-1 Ations RESISTANT TO DPP-4 DEGRADATION DPP-IV = dipeptidyl peptidase-iv Adapted from Deaon CF, et al. Diabetes. 1995;44: Renal Clearane DBP 1.38 ( 2.02 to 0.73) BP Change (mm Hg) Similar BP hanges were reported between groups in head to head GLP 1 RA trials Vilsbøll T, et al. BMJ. 2012;344:d Druker D, et al. DURATION-1 Study Group. Lanet. 2008;372: Buse J, et al. LEAD-6 Study Group. Lanet. 2009;374: Buse J, et al. EASD 47th Annual Meeting. 2011;75.. stored in the L-ells of the ileum and olon, and released at mealtime in response to neurohormonal signals and the presene of food in the gut Beta ells: Enhanes insulin seretion GLP-1 Modulates Numerous Funtions in Humans Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Ata Physiol Sand. 1997;160: Data from Nauk MA, et al. Diabetologia. 1996;39: ; Data from Druker DJ. Diabetes. 1998;47: Redues appetite Alpha ells: Postprandial gluagon seretion Liver: Gluagon redues output of sugar from liver Stomah: Helps slow stomah emptying b a Change from baseline. b Signifiantly different vs EXN BID. No statistial analysis. Lipid Changes: Head-to-Head GLP-1 RA Trials EXN BID LIRA EXN ER b b Druker DJ, et al. Lanet. 2008;372: Buse J, et al. Lanet. 2009;374: NCT

4 Favors GLP 1 RA GLP-RA Cardiovasular Safety in Clinial Trials Hazard or Inidene Ratio (95% CI) AC, ative omparator; INS, insulin; MACE, major adverse ardiovasular events. a Primary MACE endpoints: CV mortality, stroke, myoardial infartion, aute oronary syndrome, and revasularization. b Standardized MedDRA database query for CV death, MI, and stroke. EXN BID 1 EXN BID (n = 2316) Non EXN (PBO or INS, n = 1629) Primary MACE a HR (95% CI): 0.70 ( ) LIRA 2 LIRA (n = 4257) Non LIRA (PBO or AC, n = 2381) MACE (Broad) b IR (95% CI): 0.73 ( ) Trials in progress EXSCEL EXN ER CV risk (results expeted in 2017) 3 LEADER liraglutide CV risk in patients with pre existing CVD (results expeted in 2016) 3 Favors Non GLP 1 RA 1. Ratner R, et al. Cardiovas Diabetol. 2011;10: Marso S, et al. Diabetes Vas Dis Res. 2011;8: National Institutes of Health. DPP-4 Inhibitors: (oral) Renal Adjustment Required Sitagliptin (Januvia ) 100 mg 50 mg (<50 >30) 25 mg (<30) Saxagliptin (Onglyza ) 5 mg 2.5 mg (<50) Alogliptin (Nesina ) 25 mg 12.5 mg (<60 >30) 6.25 mg (<30) No Renal Adjustment Required Linagliptin (Tradjenta ) 5 mg POTENTIAL CARDIOPROTECTIVE EFFECTS: Independent of Changes on Gluose Control Inreased flow mediated endothelial dependent vasodilation in pts w/t2d with CAD 1 Redued infart size and improved LVEF in pts post aute MI w/ef < 40% 2 Improved LV ontratile funtion and improved LVEF, improved exerise tolerane and improved QoL sores in patients w/t2d and NYHA lass III and IV CHF 3 Less likely to have CV related event or CVD related hospitalization in pts w/t2d 4 Redued MACE and all ause mortality in pts w/t2d 5 1 Nystrom, et al. (2004). AM J Physiol Endorinol Metab, 287(6), E1209 E Nikolaidis, et al. (2004). Cirulation, 109(8), Sokos, et al. (2006). J Cardia Failure, 12, Best, et al. (2011). Diabetes Care, 34(1), Monami, et al. (2011). Exp Diabetes Res, 2011, GLP1-RA (injetions) Exendin-4 based (syntheti) Exenatide (Byetta ) 5 mg & 10 mg Twie-daily dosing Exenatide long-ating release (Bydureon ) 2 mg One-weekly dosing Human rdna Origin Liraglutide (Vitoza ) 0.6 mg (loading dose) 1.2 mg, & 1.8 mg One-daily dosing Trial/spons or ELIXA Sanofi LEADER Novo Nordisk EXSCEL Amylin/Lilly REWIND Lilly FREEDOM CVO Intaria Drug/dose Lixisenatide 20 mg daily Liraglutide 1.8 mg daily Exenatide LAR 2 mg one weekly Dulaglutide 1.5 mg one weekly CSCI Exenetide One yearly Twie yearly Primary Outome MACE + Superiority MACE Superiority MACE or MACE + Superiority MACE Superiority Subjets Eligibility Timeframe ~6000 Reent ACS (<180 days) ~ yoa with CAD or CVD, PAD, CRF, CHF 60+ w/cvd RF ~9500 No min requirement for age or CVD RF ~ w/cvd or 2+ CVD RF MACE Safety ~ w/cvd or 60+ w/t2d +1 RF JUL 2010 thru Sep 2014 AUG 201 thru JAN 2016 JUN 2010 thru MAR 2017 JUL 2011 thru APR 2019 MAR 2013 thru AUG 2018 GLP-1 RA and DPP-4 Inhibitors Differenes and Similarities Mehanism of stimulation of insulin seretion exlusively through GLP-1 effet GLP-1 RA Yes DPP-4 Inhibitors Unknown Restitution of insulin seretion Yes Yes (2 phases) Hypoglyemia No No Maintained ounter-regulation by Yes Not tested gluagon in hypoglyaemia Inhibition of gastri emptying Yes Marginal Effet on body weight Weight loss Weight neutral Side effets Nausea, vomiting, HA, sinusitis, rhinorrhea diarrhea Administration Subutaneous Oral Tribble, AL, et al., (2013). Expert Rev Endorinol Metab, 8(3), Gallwitz B. Eur Endor Dis 2006:43-46.

5 25 Inretin Therapy: Clinial Charateristis Dosing Frequeny A1C * (%) t1/2 (h) ROA GLP-1 agonists Exenatide Subutaneous Twie a day -0.4 to Exenatide ER Subutaneous One weekly -1.4 to -1.6 Continuous exposure Liraglutide Subutaneous One a day -0.6 to DPP-4 inhibitors Alogliptin Oral One a day -0.5 to Linagliptin Oral One a day -0.4 to Saxagliptin Oral One a day -0.7 to ; 3.1 for AM Sitagliptin Oral One a day -0.6 to * Administered as monotherapy or ombination with MET or other gluose-lowering agents. AM = ative metabolite; ER = extended release; ROA = route of administration. Bydureon (exenatide extended release) [pakage insert]. San Diego, CA: Amylin Pharmaeutials, LLC; 2011; Byetta (exenatide) [pakage insert]. San Diego, CA: Amylin Pharmaeutials, LLC; 2011; Januvia (sitagliptin) [pakage insert]. Whitehorse Station, NJ: Merk & Co., In.; 2010; Nesina (alogliptin) [pakage insert]. Deerfield, IL: Takeda Pharmaeutials USA, In.; 2013; Onglyza (saxagliptin) [pakage insert]. Prineton, NJ: Bristol-Myers Squibb Co; 2011; Tradjenta (linagliptin) [pakage insert]. Ridgefield, CT: Boehringer Ingelheim; 2011; Vitoza (liraglutide) [pakage insert]. Prineton, NJ: Novo Nordisk; Greater A1C Effets with Longer-Ating GLP-1 RAs in Head-to-Head Clinial Trials Trial: Size (N): Study length (week): Baseline A1C (%): a P < b P = Did not meet noninferiority riteria vs LIRA. LEAD a DURATION b DURATION a DURATION EXN BID LIRA EXN ER 1. Buse J, et al. Lanet. 2009;374: Druker DJ, et al. Lanet. 2008;372: Blevins T, et al. J Clin Endorinol Metab. 2011;96: Buse J, et al. Diabetologia. 2011;54(suppl 1):75. Weight Effets and Hypoglyemia Risks of Agents Commonly Used to Treat Hyperglyemia in T2DM Class Weight Effet Elevated Risk of Hypoglyemia? GLP-1 RA Loss No DPP-4 inhibitors Neutral No Biguanide (MET) Neutral No TZD Gain No SU Gain Yes Insulin Gain Yes Greater FPG Effets With Longer-Ating GLP-1 RAs in Head-to-Head Clinial Trials EXN BID EXN ER LIRA a a b a,b a,b Inzuhi S, et al. Diabetes Care. 2012;35: a P <.05 vs baseline. b P <.05 vs EXN BID. P =.021 vs EXN ER. 1. Buse J, et al. Lanet. 2009;374: Druker DJ, et al. Lanet. 2008;372: Blevins T, et al. J Clin Endorinol Metab. 2011;96: NCT Glyemi Control and Weight Change With Sitagliptin vs Liraglutide or Exenatide ER a SITA LIRA 1.2 mg LIRA 1.8 mg 26 week trial (N = 658) 1,b BL A1C (%): ,d 26 week trial (N = 491) 2 BL A1C (%): EXN ER Exenatide BID Redues PPG More Than Exenatide ER and Liraglutide DURATION 1 1 LEAD 6 2 b, b Self measured plasma gluose profiles Signifiantly greater postprandial dereases with EXN BID (breakfast and dinner) Estimated treatment differenes Breakfast: 24 mg/dl Dinner: 18 mg/dl a All as add-on to MET; b Results sustained over 52 weeks 3 ; P <.05 vs SITA; d P <.0013 vs LIRA 1.2 mg. 1. Pratley R, et al. Lanet. 2010;375: Bergenstal R, et al. Lanet. 2010;376: Pratley R, et al. Int J Clin Prat. 2011;65: a Data is based on meal tolerane testing (n=51). b Signifiant hange vs baseline. P =.0124 vs EXN ER. 1. Druker DJ, et al. Lanet. 2008;372: Buse J, et al. Lanet. 2009;374:39-47.

6 GLP-1 RAs Improve Glyemi Control in Combination With Commonly Used Oral Agents KM3 Gastrointestinal Effets Are Common With GLP-1 RAs 1-3 Bakground Therapy EXN BID mg BID weeks BL A1C: 7.8%-8.6% A1C (%) With GLP-1 RA LIRA mg QD weeks BL A1C: 8.2%-8.6% EXN ER 11,12 2 mg QW 26 weeks BL A1C: 8.5%-8.6% Monotherapy MET , SU TZD ± MET 0.9 a 1.5 b SU + MET 0.8 GLP 1 RA Nausea (% of patients) Vomiting (% of patients) Diarrhea (% of patients) EXN BID 1,a LIRA 2,a EXN ER 3,a MET 4,a,b a 79% on both lasses. b 100% on MET + ROSI with LIRA. BL A1C, mean baseline A1C; MET, metformin; QD, one daily; QW, one weekly; ROSI, rosiglitazone; SU, sulfonylurea; TZD, thiazolidinedione. 1. Moretto TJ, et al. Clin Ther. 2008;30: DeFronzo RA, et al. Diabetes Care. 2005;28: Buse JB, et al. Diabetes Care. 2004;27: Zinman B, et al. Ann Intern Med. 2007;30: Kendall DM, et al. Diabetes Care. 2005;28: Garber A, et al. Lanet. 2009;373: Pratley R, et al. Int J Clin Prat. 2011;65: Nauk MA, et al. Diabetes Care. 2009;32: Marre M, et al. Diabet Med. 2009;26: Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lanet. 2010;376: a Monotherapy or in ombination with other agents. b Inludes values for several speifi agents. Reported as nausea/vomiting or nausea. 1. MaConell L, et al. Diabetes Metab Syndr Obes. 2012;5: Russell-Jones D. Int J Clin Prat. 2010;64: Malone J, et al. 71st ADA Sientifi Sessions. 2011;1066-P. 4. US Food and Drug Administration. Drugs@FDA. Clinial Insights Nausea SOUNDS TOO GOOD TO BE TRUE IS IT? Most episodes of nausea are of mild to moderate intensity Generally intermittent More frequent at treatment initiation Derease over time Tolerability of DPP-4 Inhibitors Generally very well tolerated Weight neutral Nasopharyngitis, headahe, URI, ough Disuss expetations 1 Advie for Managing Nausea Assoiated With GLP-1 RAs Nausea is likely to be mild and resolve in a few weeks Nausea may atually be fullness Suggest behavioral hanges 1 Derease portion sizes Redue fat ontent of meals Keep a log to identify foods that ause nausea Titrate more slowly maintain at lower dose for a longer period Kruger D, et al. Diabetes Edu. 2010;36 (suppl 3):44S-72S. 2. Fineman M, et al. Diabetes Metab Res Rev. 2004;20: US Food and Drug Administration. Drugs@FDA Web site.

7 Slide 34 KM3 Revised title and inluded label information from metformin The EXN BID data do not seem to learly reflet lower rates with longer-ating GLP-1 RAs. Compared with MaConell data, ranges ited by Russell-Jones for EXN BID seem more onsistent (36-57% nausea, 10-17% vomiting, 8-17% diarrhea) BUT that study inludes only about 6-7 trials, and the MaConell analysis inludes 19, so I'd rather ite it... Add a statement regarding lower nausea with longer-ating agents in head-to-head trials, or leave as-is and save that information for later? (It's inluded in Talk 3.) Kim MFarland, 7/7/2012

8 Advie for Managing Nausea Assoiated With GLP-1 RAs (ont.) Be aware of severe gastrointestinal disease GLP 1 RAs slow gastri emptying and are assoiated with GI AEs 1 3 GLP 1 RAs have not been studied in patients with severe GI disease 1 3 Avoid exenatide in patients with history of severe gastrointestinal disease (eg, gastroparesis) 1 3 Be aware of severe persistent abdominal pain, whih ould indiate panreatitis 3 Panreatitis With Inretin-Based Therapies Analysis of a Large Database Cases of panreatitis with exenatide, liraglutide, and the DPP-4 inhibitor sitagliptin have led to the addition of label warnings and preautions Analysis of a large US ommerial health insurane database revealed no inreased risk of panreatitis with exenatide or sitagliptin ompared with metformin or glyburide Panreatitis ourrene 0.13% of exenatide-treated patients 0.12% of sitagliptin-treated patients EXN=exenatide; GLY=glyburide; MET=metformin; SITA=sitagliptin EXN (n=27,996) vs MET or GLY (n=27,983) SITA (n=16,267) vs MET or GLY (n=6281) Relative Risk (95% onfidene interval) 1. Kruger D, et al. Diabetes Edu. 2010;36 (suppl 3):44S-72S. 2. Fineman M, et al. Diabetes Metab Res Rev. 2004;20: US Food and Drug Administration. Drugs@FDA Web site. Byetta (exenatide) [presribing information]. Vitoza (liraglutide) [presribing information]. Januvia (sitagliptin) [presribing information]. Dore DD et al. Curr Med Res Opin. 2009;25: Reports of GLP-1 RA and Panreatitis Exenatide Liraglutide 6 ases in linial trials 7 ases in linial trials 36 postmarketing reports - 30 ases reported to FDA from launh to Otober 2007; 27 patients had 1 or more risk fators for panreatitis - After issuing the Information for Healthare Professionals in Otober 2007, the FDA reeived reports of 6 ases of hemorrhagi or nerotizing panreatitis between Otober 2007 and August postmarketing report - Patient with a history of panreatitis reeived exenatide for 4 years, then swithed to liraglutide Panreatitis risk has been added to produt drug labels around the world US FDA Website. Exenatide (Byetta). Healthare Professional Sheet text version (8/2008). Available at: Parks M, Rosebraugh C. NEJM. 2010;362: ; Lee PH et al. Ann Pharmaother. 2011;45; Anderson SL, Trujillo JM. Ann Pharmaother. 2010;44: Clinial Insights Panreatitis Ask appropriate questions about past medial history GLP-1 agonist and other potentially suspet drugs should be disontinued promptly if panreatitis is suspeted GLP-1 agonist should not be restarted if panreatitis is onfirmed Consider antidiabeti therapies other than GLP-1 agonists in patients with a history of panreatitis Inidene Rate Ratio (± 95% CI) Type 2 Diabetis:Non-Diabetis Risk of panreatitis is greater in patients with T2D than in patients without diabetes Overall Rate Ratio Overall Inidene Rate per 100,000 Person-Years (95% CI) CI=onfidene interval Noel RA et al. Diabetes Care 2009;32: Diabetes Status Inidene Rate per 100,000 Person-Years (95% CI) No Diabetes T2DM By Age and Sex Male Female Age (y) Gender Fators that ontribute to inreased risk in patients with T2DM remain unlear GLP-1 Reeptor Agonists and Thyroid Tumors Thyroid -ell tumors observed in rodents but not in nonhuman primates 1 Liraglutide No medullary thyroid arinoma; 5 ases of papillary thyroid aner in linial trials 1,2 Approvability supported regarding papillary thyroid aner risk (FDA Advisory Committee) 3 No effet on thyroid C-ell funtion 4 Label arries a blak box warning of thyroid aner risk Exenatide No thyroid aner in linial trials 2 9 ases of thyroid aner in postmarketing experiene 2 No effet on thyroid C-ell funtion 4 1. Liraglutide (injetion) NDA FDA briefing materials liraglutide. Available at: 3. Update on FDA Advisory Committee meeting on liraglutide for the treatment of type 2 diabetes. Available at attahment.pdf?sattahmentguid=187137d-806f-41b-832a-e5a74aa Buse JB et al. Lanet. 2009;374:39-47.

9 Clinial Insights Thyroid Tumors Ask the patient appropriate questions about past medial history Query the patient about personal or family history of medullary thyroid aner or multiple endorine neoplasia type 2 Drug Drug Interations With GLP-1 Agonists Does delayed gastri emptying result in linially relevant interations? None identified Oral ontraeptives Digoxin Lisinopril Warfarin Diabetes. 2008;57(suppl 1):A593,abs2144-PO; Diabetes. 2008;57(suppl1):A130,434-P; Kothare PA et al. J Clin Pharmaol. 2005;445: ; Linnebjerg H et al. Int J Clin Pharmaol Ther. 2009;47: ; Kothare PA. AAPS PharmSi. 2007;9(S2) Abstrat 554; Soon D et al. J Clin Pharmaol. 2006;46: Cliniian Considerations Regarding Risk of Aute Renal Impairment With GLP-1 RAs Renal impairment (RI) has been reported in patients taking GLP 1 RAs, sometimes requiring hemodialysis or transplantation 1 3 RI was reversed in many ases with supportive treatment and disontinuation of potentially ausative agents 1 3 Evidene does not indiate that GLP 1 RAs are diretly toxi to kidney ells 1 5 Renal impairment may our in patients who have experiened nausea, vomiting, diarrhea, dehydration 1 3, Byetta (exenatide) [presribing information]. 2. Bydureon (exenatide extended-release for injetable suspension) [presribing information]. 3. Vitoza (liraglutide) [presribing information]. 4. Pendergrass M, Chen W. ADA 70th Sientifi Sessions. 2010:11-LB; 5. Tuttle K, et al. ADA 71st Sientifi Sessions. 2011:0971-P. 6. Johansen O, Whitfield R. Br J Clin Pharmaol. 2008;66: ; 7. Weise WJ, et al. Diabetes Care. 2009;32:e22-e Ferrer-Garia JC, et al. Diabet Med. 2010;27: ; 9. López-Ruiz A, et al. Pharm World Si. 2010;32: Summary GLP-1 RAs are appropriate options for improving glyemi ontrol aross the spetrum of T2D progression, inluding Intensifiation of metformin monotherapy Use in ombination with basal insulin therapy (exept Bydureon) Additional benefits of GLP-1 RAs inlude Low risk of hypoglyemia Potential weight loss Nausea assoiated with GLP-1RA tends to be mild to moderate and will diminish with time. In head-to-head trials with exenatide BID, liraglutide and exenatide ER provided Greater glyemi ontrol benefits Similar weight loss benefits Be aware of patient medial history pertinent to thyroid aner, panreatitis, and renal funtion when presribing GLP-1 RAs GLP-1 Reeptor Agonist Use in Patients With Renal Impairment Clearane of exenatide, but not liraglutide, is signifiantly dereased with renal insuffiieny 1,2 Assess renal funtion at initiation and periodially thereafter 3 5 Renal Status Exenatide BID 3 Exenatide ER 4 Liraglutide 5 Mild impairment (CrCl ml/min) Moderate impairment (CrCl ml/min) No adjustment or reommendation Use aution when initiating or esalating doses a Use with aution a Severe impairment (CrCl < 30 ml/min) Should not be used Not reommended ESRD Renal transplant Use with aution No dose adjustment Use aution when initiating or esalating doses a HOW DO I FIGURE THIS OUT? a Hypovolemia due to nausea/vomiting may worsen renal funtion. 1. Linnebjerg H, et al. Br J Clin Pharmaol. 2007;64: Jaobsen L, et al. Br J Clin Pharmaol. 2009;68: Byetta (exenatide) [presribing information]. 4. Bydureon (exenatide extended-release for injetable suspension) [presribing information]. 5. Vitoza (liraglutide) [presribing information].

10 Panreas Sulfonylureas Glinides GLP 1 RA DPP 4 Inhibitors Metformin TZDs Liver SGLT2 Kidney Target Sites of Ation GLP 1 RA Bromoriptine Hyperglyemia Musle Alpha gluosidase Inhibitors Metformin, GLP 1 RA Colesevelam Adipose Tissue TZDs DPP 4 = dipeptidyl peptidase 4; TZDs thiazolidinediones, GLP 1RA = gluagon like peptide Reeptor Agonists, SGLT2 = sodium-gluose transporter-2 Gut Contribution of FPG and PPG to A1C in T2DM Contributions (%) (<7.3) ( ) ( ) ( ) (>10.2) A1C quintiles Postprandial Fasting Holst JJ, Ørskov C. Diabetes. 2004;53:S197 S204; Lebovitz HE. Diabetes Rev. 1999;7: ; Presribing Information for Atos (pioglitazone HCl), Amaryl (glimepiride), Avandia (rosiglitazone maleate), Glyset (miglitol tablets), Gluophage (metformin), Januvia (sitagliptin), Prandin (repaglinide), Preose (aarbose tablets). Monnier L,et al. Diabetes Care. 2003;26:881. KM4 Optional more-rapid progression of treatment ADA/EASD 2012 General Reommendations for Antihyperglyemi Therapy in T2DM Initial drug monotherapy Effiay ( A1C) Hypoglyemia Weight Major side effets Costs Two-drug ombinations Effiay ( A1C) Hypoglyemia Weight Major side effets Costs Three-drug ombinations More omplex insulin strategies Healthy eating, weight ontrol, inreased physial ativity Metformin high low risk neutral / loss GI / lati aidosis low If needed to reah individualized A1C target after 3 months, proeed to 2-drug ombination (order not meant to denote any speifi preferene): Metformin + Metformin + Metformin + Metformin + Metformin + Sulfonylurea Thiazolidinedione DPP-4 Inhibitor GLP-1 reeptor agonist Insulin (usually basal) high high intermediate high highest moderate risk low risk low risk low risk high risk gain gain neutral loss gain hypoglyemia edema, HF, Fx s rare GI hypoglyemia low high high high variable If needed to reah individualized A1C target after 3 months, proeed to 2-drug ombination (order not meant to denote any speifi preferene): Metformin + Metformin + Metformin + Metformin + Metformin + Sulfonylurea Thiazolidinedione DPP-4 Inhibitor GLP-1 reeptor agonist Insulin (usually basal) TZD SU SU SU + TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or GLP-1-RA or GLP-1-RA or or or Insulin Insulin GLP-1-RA or or Insulin Insulin If ombination therapy that inludes basal insulin has failed to ahieve A1C target after 3-6 months, proeed to a more omplex insulin strategy, usually in ombination with 1 or 2 noninsulin agents. Insulin (multiple daily doses) Inzuhi S, et al. Diabetes Care. 2012;35: Diurnal Glyemi Variation (mmol/l) in T2DM Aording to A1 Level Fasting Breakfast Morning Period Monnier L et al. Diabetes Care. 2007;30: Postprandial < Diabetes duration (years) AACE (2013). Endorine Pratie,19(2) Gluose Targets T2DM vs non-t2dm Measurement Target Normal Fasting plasma gluose mg/dl <100 mg/dl Peak postprandial apillary gluose (tested 1 2 h after the start of a meal) <180 mg/dl <140 mg/dl A1C <7% (ADA) 6.5% (AACE) 4% 6% AACE=Amerian Assoiation of Clinial Endorinologists; ADA=Amerian Diabetes Assoiation. ADA. Diabetes Care. 2011;34(suppl 1):S11-S62. AACE/ACE. Endor Prat. 2009;15:

11 Slide 50 KM4 Went with this version that was generated for ADA. Will need to reformat when new template is available. Removed footnotes beause they are not inluded in the ADA/EASD slides Animiated per onversation with EM. Please retain animation when formatting. Kim MFarland, 7/7/2012

12 Class Classes of Antihyperglyemi Agents Available for Treatment of T2D A1C Redution Fasting vs PPG Weight Change Dosing (times/day) Outome Studies Metformin 1.5% Fasting No Neutral 2 UKPDS Insulin, long-ating % Fasting Yes Gain 1, injeted DIGAMI, UKPDS, (DCCT) Insulin, rapid-ating % PPG Yes Gain 1-4, injeted DIGAMI, UKPDS, (DCCT) Sulfonylureas 1.5% Fasting Yes Gain 1 UKPDS Thiazolidinediones % Fasting No Gain 1 PROative, RECORD pending Repaglinide 1 1.5% Both Yes Gain 3 None Nateglinide % PPG Rare Gain 3 NAVIGATOR Pending α-gluosidase inhibitor % PPG No Neutral 3 ACE pending Amylin-mimetis % PPG No Loss 3, injeted None GLP-1 agonists % PPG No Loss 2, injeted None DPP-4 inhibitors % Both No Neutral 1 TECOS pending Bile aid sequestrant 0.5% Fasting No Neutral 1-2 None Bromoriptine 0.7% PPG No Neutral 1 None Patients With T2DM Who Should Use GLP-1 Agonists Aording to the ADA, patients should use lifestyle hanges, metformin, and a GLP-1 agonist as Tier 2 therapy Aording to the AACE, GLP-1 agonists an be reommended for any patients with T2DM regardless of A1C level GLP-1 agonists are espeially useful in patients who need to lose weight, have fasting or postprandial hyperglyemia, are worried about hypoglyemia, or have failed on oral agents Retail Pries for Commonly Used Antidiabeti Agents July 2012 a Drug Class Approximate Cost for 30 day Supply ($) 1 Sulfonylureas a,b Biguanides (metformin) a NPH insulin Basal insulin analogs Thiazolidinediones (pioglitazone) DPP 4 inhibitors GLP 1 RAs Co payments vary by insurane provider Hypoglyemia 1. DestinationRX. Drug Compare. July 9,2012. a Versions offered at no ost from some pharmaies Free diabetes drugs now available at some pharmaies. b Pries may be lower for larger supplies. Assuming < 30 unit total daily dose. PRACTICE MAKES PERFECT Patient attitude and expeted treatment efforts Risks potentially assoiated with hypoglyemia, other adverse events Disease duration Life expetany Important omorbidities Established vasular ompliations Resoures, support system ADA/EASD Position Statement: Approah to Goal Setting More stringent Adapted from Inzuhi SE et al. Diabetologia. 2012;55(6): Highly motivated, adherent, exellent self are apaities Low Newly diagnosed Long Absent Absent Readily available Few/mild Few/mild Less stringent Less motivated, nonadherent, poor self are apaities High Long standing Short Severe Severe Limited Case 1: Rahel 71 yo Cauasian woman 5 4, 160 lbs, BMI 27.5 T2D x 3 years; HTN, HLD; no other onerning history LABS: A1C 7.4% Sr: 1.5 mg/dl; GFR: 39 ml/min Current DM mgmt: Metformin 1000 mg/day SMBG: FBG: ~108 mg/dl 2 Hr PP: ~156 mg/dl NO INJECTIONS

13 Case 1: Rahel (ontinued) CONSIDERATIONS: Renal funtion poor WHAT DO YOU DO? GLP1 RA? DPP 4 inhibitor? Case 2: Maria (ontinued) CONSIDERATIONS: 1) Post meal BG high 2) GAINING WEIGHT 3) Good renal funtion 4) already on an injetable mediation WHAT DO YOU DO? GLP1 RA? DPP 4 inhibitor? Case 1: Rahel (ontinued) PLAN: 1) TLC 2) Stop metformin 3) START DPP 4 inhibitor appropriately dosed Safe in renal impairment No hypoglyemia Weight neutral 4) Close f/u, may need adjunt therapy Case 2: Maria (ontinued) PLAN: 1) TLC 2) ADD short ating GLP1 RA Better addresses post meal, her FBG good Low risk hypoglyemia Potential weight loss 3) May need to redue basal insulin as gluose ontrol improves 3 month f/u A1: 6.6% ( 1.2%), no hypoglyemia WEIGHT: LOSS of 2 lbs Case 2: Maria 52 yo Hispani woman 5 7, 190 lbs, BMI: 29.8 (gained at least 11 lbs in last 3 months) T2D x6 years, No HTN; No HLD; no other onerning history Labs: A1: 7.8% Sr:.99 mg/dl; GFR: 88 ml/min Current DM mgmt: Basal Insulin 30 units every night Metformin 1000 mg twie daily SMBG: FBG: ~106 mg/dl 2 hr PP: ~215 mg/dl WEIGHT GAIN, FRUSTRATED Case 3: George 39 yo AA man 5 10, 225 lbs, BMI: 32.1 T2D x 3 months, +HTN; + HLD; no other onerning history Labs: A1: 8.3% Sr: 0.95 mg/dl; GFR: 93 ml/min Current DM mgmt: Metformin 1000 mg twie daily SMBG: FBG: ~140 mg/dl 2 hr PP: ~190 mg/dl TOO HEAVY, CAN T KEEP UP WITH KIDS, UPSET STOMACH AND INTERMITTENT DIARRHEA SINCE INCREASING METFORMIN AND MISSES EVENING DOSE AT LEAST ONCE A WEEK

14 Case 3: George (ontinued) CONSIDERATIONS: 1) Both Fasting and Post meal BG high 2) WEIGHT affeting QOL 3) Good renal funtion 4) Problem tolerating urrent metformin 5) Missing meds that are > 1x daily WHAT DO YOU DO? GLP1 RA? DPP 4 inhibitor? Case 3: George (ontinued) PLAN: 1) TLC 2) ADD Long ating GLP1 RA Also addresses FBG Low risk hypoglyemia Potential weight loss One daily or one weekly 3) CHANGE metformin to metformin extended release Better tolerated, an take one daily 3 month f/u A1: 7.8% (.5%), no hypoglyemia WEIGHT: no loss/gain Taking all meds, no problem 6 month f/u A1: 6.0% ( 1.8%), no hypoglyemia WEIGHT: LOSS of 19 lbs Taking all meds, no problem Summary The inretin effet is important in both early and longer-duration T2D By preventing inativation of the inretin hormone GLP-1, Inretin agents are effetive, appropriate therapies for most patients with T2D. DPP-4 inhibitors: are assoiated with signifiant and linially relevant dereases of A1 have a favorable safety profile and a low inidene of hypoglyemia and are weight neutral. GLP-1 RA: have important effets in multiple organ systems, inluding improving the health of alpha and beta ells, reduing gastri emptying, inreasing satiety; may help with weight loss other effets inlude reduing BP and lipids There are signals of inretin mediated ardioprotetive effets Can be ombined with all other forms of urrent oral antidiabetes therapy