Early treatment for patients with Type 2 Diabetes

Israel Society of Internal Medicine Kibutz Hagoshrim, June 22, 2012 Early treatment for patients with Type 2 Diabetes Eduard Montanya Hospital Universitari Bellvitge-IDIBELL CIBERDEM University of Barcelona

Agenda Guidelines recommendations in initial treatment Incretin-based therapies as second-line agents after metformin failure. Head to head RCT - Incretin based therapies vs SU - GLP-1 receptor agonists vs. DPP-4 inhibitors Liraglutide vs. sitagliptin (1860) Exenatide OW vs. sitagliptin (DURATION-2) - GLP-1 receptor agonists Conclusions Liraglutide vs. exenatide BID (LEAD-6) Exenatide OW vs. liraglutide (DURATION-6)

2012 ACP guidelines for treatment of type 2 diabetes Recommendation 1 Add oral pharmacologic therapy when diet, exercise, and weight loss have failed to improve hyperglycaemia Recommendation 2 Prescribe monotherapy with metformin for initial pharmacotherapy to treat most patients with type 2 diabetes Recommendation 3 Add a second agent to metformin to treat patients with persistent hyperglycaemia when monotherapy with metformin and lifestyle fail to control it ACP, American College of Physicians Qaseem et al. Ann Int Med 2012;156:218 31

ADA/EASD position statement 2012 Healthy eating, weight control, increased physical activity Initial monotherapy METFORMIN Not at target A 1c after ~3 months Two-drug combinations SU TZD DPP-4i GLP-1RA INSULIN Not at target A 1c after ~3 months Three-drug combinations Not at target A 1c after 3 6 months combination therapy with insulin TZD DPP-4i GLP-1RA INSULIN SU DPP-4i GLP-1RA INSULIN SU TZD INSULIN SU TZD INSULIN TZD DPP-4i GLP-1RA More complex strategies INSULIN (MDI) MDI, multiple daily injections; SU, sulfonylurea; TZD, thiazolidinedione Inzucchi et al. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print);

Traditional oral agents after metformin failure Oral agent Advantages Disadvantages Sulphonylureas Can reduce HbA 1c by 1% Inexpensive Meglitinides Reduction postprandial glucose excursion Dosing flexibility Thiazolidinediones Can reduce HbA 1c by 1% Some benefits in lipid composition No hypoglycaemia Alpha-Glucosidase Inhibitors Reduction postprandial glucose excursion No hypoglycemia Non systemic Hypoglycaemia Weight gain Hypoglycaemia Weight gain Frequent dosing schedule Weight gain Peripheral oedema Heart failure Skeletal fractures Link to bladder cancer with pioglitazone Expensive Modest HbA 1c efficacy Gastrointestinal side effects Frequent dosing schedule

GLP-1 receptor agonists and DPP-4 inhibitors: launched products GLP-1 receptor agonists Exenatide Eli Lilly/Amylin Liraglutide Novo Nordisk Exenatide once weekly Eli Lilly/Amylin DPP-4 inhibitors Sitagliptin Merck & Co. Vildagliptin Novartis Saxagliptin Bristol-Myers Squibb Linagliptin Boehringer Ingelheim Alogliptin (Japan) Takeda

Sitagliptin as add-on to metformin (vs glipizide) Outcome Sitagliptin 100 mg/day (n=588) Glipizide 5 mg/day (n=584) HbA 1c change from baseline (%) -0.67-0.67 HbA 1c <7.0% (% patients) 63% 59% Weight change from baseline (kg) -1.5 kg * +1.1 kg Hypoglycaemia (%) 4.9 32 *Significant vs. glipizide Nauck et al. Diabetes Obes Metab 2007;9:194 205

Liraglutide as add-on to metformin (vs glimepiride) LEAD-2 trial Outcome Liraglutide 1.2 mg (n=241) Liraglutide 1.8 mg (n=242) Glimepiride 4 mg (n=244) Placebo (n=122) HbA 1c change from baseline (%) 1.0* 1.0* 1.0 +0.1 HbA 1c <7.0% (% patients) 35.3* 42.4* 36.3 10.8 Weight change from baseline (kg) 2.8** 2.6** +1.0 1.5 Major hypoglycaemia (events/patient/year) Minor hypoglycaemia (events/patient/year) 0 0 0 0 0.03 0.09 1.23 0.13 *Significant vs. placebo; Significant vs. glimepiride and placebo Nauck et al. Diabetes Care 2009;32:84 90 (LEAD-2)

Incretin-based therapies vs SU as add-on to metformin Similar reductions in HbA 1c Weight differences in favor of incretin therapies Very low risk of hypoglycemia (6-10 times lower than SU)

Liraglutide vs. Sitagliptin (1860 trial) Main study: 26 weeks Extension 1: 26 weeks Extension 2: 26 weeks Adults 18 80 years with T2D HbA 1c : 7.5 10.0% Liraglutide 1.8 mg (n=221) Liraglutide 1.8 mg (n=176) Liraglutide 1.8 mg (n=218) BMI: 45 kg/m 2 1.8 mg OD Metformin 1500 mg for over 3 months Liraglutide 1.2 mg (n=225) Liraglutide 1.2 mg (n=155) Liraglutide 1.2 mg (n=201) Randomised, open-label study in 11 European countries, Canada and USA Sitagliptin 100 mg (n=219) Sitagliptin 100 mg (n=166) Liraglutide 1.2 mg OD 1 week Liraglutide 0.6 mg OD 1 week Metformin 1500 mg/day Pratley et al. Lancet 2010;375:1447 56; Pratley et al. Int J Clin Pract 2011; 65:397 407

HbA 1c (%) Mean HbA 1c by week 9.0 8.5 Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg 8.0 7.5 7.0 0.88 1.29 1.51 both p<0.0001 0.0 6.5-2 0 4 10 16 22 28 34 40 46 52 Time (weeks) Mean (1.96 SE); data are from the FAS LOCF. Pratley et al. Int J Clin Pract 2011;65:397 407

Patients reaching target (%) Patients reaching target (%) Patients achieving HbA 1c targets at Week 52 p<0.0001 p=0.0119 p<0.0001 70 63.3 70 NS 60 50 50.3 60 50 p=0.0012 p<0.0001 40 40 40.4 30 27.1 30 24.3 20 20 16.8 10 10 0 HbA 1c <7.0% 0 HbA 1c 6.5% Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg Pratley et al. Int J Clin Pract 2011;65:397 407

Change in body weight (kg) Mean body weight change by week Time (weeks) -2 0 4 10 16 22 28 34 40 46 52 0,0-0,5-1,0 0.96 1.16-1,5-2,0-2,5-3,0-3,5 2.86 3.38 Both p<0.0001 2.78 3.68 Both p<0.0001-4,0-4,5 Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg Mean (1.96 SE); data are from the FAS LOCF. Pratley et al. Lancet 2010;375:1447 56; Pratley et al. Int J Clin Pract 2011;65:397 407

Minor hypoglycaemic events/patient-year Rates of hypoglycaemia: Weeks 0 52 Rates of minor hypoglycaemia 0,35 0,30 n=18 (8.3%) 0,25 0,20 0,15 0,10 0,05 n=18 (8.1%) n=14 (6.4%) 0,00 Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg One major episode with 1.2 mg liraglutide+metformin: non-serious event in main phase of study 39-year-old woman, BMI 37 kg/m 2, blood glucose 3.6 mmol/l Dose was not changed, patient recovered, no recurrence N, number of patients; %, proportion of patients. Data are from the safety analysis set for Weeks 0 52, and exclude one outlier (who experienced 23 minor hypoglycaemic episodes). Pratley et al. Int J Clin Pract 2011;65:397 407

Patients (%) Frequency of nausea over 26 weeks 16 14 12 10 8 6 4 2 0 Time (weeks) Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Higher, but transient, initial nausea with liraglutide Data are from the safety analysis set Pratley et al. Lancet 2010;375:1447 56

IMPROVEMENT Change in DTSQ score Overall treatment satisfaction (DTSQs): change from baseline to Week 52 5 p=0.03 4 3 2 1 0 Liraglutide 1.2 mg Liraglutide 1.8 mg Sitagliptin 100 mg Mean data are from the PRO analysis set PRO, patient-reported outcome Pratley et al. Int J Clin Pract 2011;65:397 407

Exenatide once weekly vs. sitagliptin (DURATION-2: trial design) Patients with T2D stable on metformin Randomised, double-blind, doubledummy design Mean baseline values: HbA 1c 8.5±1.1% FPG 9.1±2.6 mmol/l Body weight 88.0±20.1 kg Exenatide OW 2 mg (n=160) Sitagliptin 100 mg (n=166) Pioglitazone 45 mg (n=165) Weeks: 0 26 Bergenstal et al. Lancet 2010;376:431 9

HbA 1c change over 26 weeks 0 0.5 Exenatide OW (n=160) Sitagliptin (n=166) Pioglitazone (n=165) Change in HbA 1c 1 * 1.5 * * 2.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) Superiority in HbA 1c reduction achieved with exenatide OW by Week 4 vs. pioglitazone * and Week 6 vs. sitagliptin Change in HbA 1c over 26 weeks; *p<0.05 for exenatide vs. pioglitazone; p<0.0001 for exenatide vs. pioglitazone; p<0.05 for exenatide vs. sitagliptin; p<0.0001 for exenatide vs. sitagliptin; p<0.001 for exenatide vs. pioglitazone Bergenstal et al. Lancet 2010;376:431 9

Proportion of patients (%) Patients achieving HbA 1c targets at Week 26 70 60 50 40 p=0.0015 p<0.0001 p=0.0120 p<0.0001 Exenatide OW Sitagliptin Pioglitazone 30 20 10 0 <7.0% 6.5% ADA/EASD 1 AACE/ACE 2 Significantly more patients achieve HbA 1c targets with exenatide OW compared with sitagliptin or pioglitazone HbA 1c 1. Nathan et al. Diabetes Care 2009;32:193 203; 2. Rodbard et al. Endocr Pract 2009;15:540 59 Bergenstal et al. Lancet 2010;376:431 9

Change in body weight (kg) Change in weight over 26 weeks 4 3 2 1 Exenatide OW (n=160) Sitagliptin (n=166) Pioglitazone (n=165) 0 1 2 3 * 4 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) Significantly greater reductions in weight with exenatide OW by Week 1 vs. pioglitazone and Week 4 vs. sitagliptin Change in HbA 1c over 26 weeks; *p<0.05 for exenatide vs. pioglitazone; p<0.0001 for exenatide vs. pioglitazone; p<0.05 for exenatide vs. sitagliptin; p<0.0001 for exenatide vs. sitagliptin; p<0.001 for exenatide vs. pioglitazone Bergenstal et al. Lancet 2010;376:431 9

Adverse events (%) Safety and tolerability 40 35 30 25 20 15 10 5 0 Nausea Diarrhoea Vomiting Headache Fatigue Constipation Injection site pruritis URTI Sinusitis Peripheral oedema Exenatide OW (100 mg) Sitagliptin (100 mg) Pioglitazone (45 mg) Incidence of minor hypoglycaemia was low and similar between groups (1 3%) Nausea was predominantly mild Bergenstal et al. Lancet 2010;376;431 9; Bydureon. EMA: Summary of Product Characteristics. 2011; Available from: http://www.medicines.org.uk/emc/medicine/24665/spc/ (accessed 2 November 2011)

DPP-4 inhibitors vs GLP-1 receptor agonists DPP-4 inhibitors (GLP-1 in physiological range, limited by endogenous secretion) Moderate efficacy No weight change Well tolerated Oral GLP-1 receptor agonists (Pharmacological levels of GLP-1, not limited by endogenous secretion) Greater efficacy Weight loss Gastrointestinal side effects Injection Antibody formation

GLP-1 Receptor Agonists in Clinical Practice Advantages Efficacy in HbA 1c reduction Body weight reduction Very low risk of hypoglycemia (except when combined with SU) Favorable effects on cardiovascular risk factors and biomarkers. Adverse Effects Gastrointestinal (nausea, vomiting). Pancreatitis? Disadvantages Injectable Expensive Unknown long term safety

Liraglutide vs. exenatide twice daily (LEAD-6) Randomised, open-label, parallel-group, international multicentre study Primary endpoint: change in HbA 1c Screening 26 weeks 1 Extension: 14 weeks 2 Liraglutide (n=233) 0.6 mg OD 1 week 1.2 mg OD 1 week 1.8 mg OD 24 weeks Liraglutide (n=202) 1.8 mg OD 14 weeks Adults 18 80 years with T2D HbA 1c : 7.0 11.0% BMI 45 kg/m 2 Metformin and/or SU continued at pre-study dose Liraglutide (n=187) 1.8 mg OD 12 weeks 1.2 mg OD 1 week Exenatide (n=231) 5 g BID 4 weeks 10 g BID 22 weeks 0.6 mg OD 1 week 1. Buse et al. Lancet 2009;374:39 47; 2. Buse et al. Diabetes Care 2010;33:1300 3

Mea HbA 1c change by week Exenatide Liraglutide HbA 1c target 7.21% 6.95% p<0.0001 0 Time (weeks) Mean (2SE); data for weeks 0 26 are only for patients who participated in the LEAD-6 extension phase. Buse et al. Lancet 2009;374:39 47; Buse et al. Diabetes Care 2010;33:1300 3

Buse et al. Lancet 2009;374:39 47 Post-prandial glucose control

Post-prandial glucose control: exenatide BID vs OW (DURATION-1) Drucker et al., Lancet 2008; 372:1240

Body weight (kg) Body weight change over 40 weeks (LEAD 6) Exenatide group switched to liraglutide (Week 26) 98 Exenatide Liraglutide Exenatide liraglutide 94 90 860 0 4 8 12 16 20 24 28 32 36 40 Time (weeks) Mean (2SE); data for weeks 0 26 are only for patients that participated in the LEAD-6 extension phase Buse et al. Diabetes Care 2010;33:1300 3

Reduction in SBP in liraglutide-treated patients across the LEAD trials Change in Systolic Blood Pressure (mmhg) All subjects. ***p 0.0001, **p<0.001, *p<0.05 vs. comparator Marre et al. Diabetic Medicine 2009;26;268 78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373:473 81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224 30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046 55 (LEAD-5); Buse et al. Lancet 2009; 374:39 47 (LEAD-6)

Proportion of subjects experiencing nausea (%) Safety and tolerability 20 18 16 Exenatide 10 μg BID 14 Liraglutide 1.8 mg OD 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) p<0.0001 Nausea was less persistent with liraglutide than exenatide Minor hypoglycaemia rates after 40 weeks: Exenatide liraglutide: 1.30 episodes/patient-year, down from 2.60 at Week 26* Liraglutide liraglutide: 0.74 episodes/patient-year, down from 1.93 at Week 26 One major hypoglycaemic episode in liraglutide arm *p=0.0131 compared with liraglutide arm; p<0.0001 for treatment differences (estimated treatment rate ratio for liraglutide vs. exenatide, 0.448). Data are number (%) of patients exposed to treatment (safety population) Buse et al. Lancet 2009;374:39 47; Buse et al. Diabetes Care 2010;33:1300 3

Antibody binding capacity (%B/T) Antibodies against liraglutide and exenatide 70 60 Liraglutide antibodies n=113 Exenatide antibodies n=90 n=25 50 40 30 20 10 n=4 n=4 0 Treatment Time Continued liraglutide Exenatide liraglutide Exenatide Exenatide liraglutide Exenatide liraglutide Week 79 ( 5 days off drug) Week 26 Week 40* Week 78* *Patients switched from exenatide to liraglutide treatment at Week 26. Buse et al. J Clin Endocrinol Metab 2011;96:1695 702

Liraglutide vs. exenatide once weekly (DURATION-6: Trial design) Randomized, open-label 26-week, international multicenter, noninferiority, head-to-head clinical trial Primary endpoint: change in HbA 1c from baseline Secondary endpoints: proportion with HbA 1c,<7.0% FPG, change in body weight Exenatide OW 2 mg (n=461) Failure of DE plus: - metformin - SU - metformin + SU, or - metformin + pioglitazone Liraglutide 1.8 mg (n=450) Weeks: 0 26 DE, diet and exercise Buse et al. Diabetologia 2011;54(Suppl. 1):S38(Abstract 75)

HbA 1c change from baseline at Week 26 Exenatide OW 2 mg Liraglutide 1.8 mg (n=461) (n=450) 0,0-0,2-0,4-0,6 Change in HbA 1c -0,8-1,0-1,2-1,4-1,6-1,3-1,5 Estimated treatment difference: 0.21% (95% CI: 0.08, 0.34) (p< 0.05) CI, confidence interval Buse et al. Diabetologia 2011;54(Suppl. 1):S38(Abstract 75)

Mean weight change (kg) Weight change from baseline at Week 26 Exenatide OW 2 mg Liraglutide 1.8 mg 0.0 (n=461) (n=450) 0.8 1.8 2.7 2.68 3.6 3.58 Estimated treatment difference: 0.90 kg (95% CI: 0.4, 1.41) (p< 0.05) Buse et al. Diabetologia 2011;54(Suppl. 1):S38(Abstract 75)

Adverse events (%) Safety and tolerability 40 35 30 25 20 15 10 5 Injection site nodule Nausea Diarrhoea Vomiting 0 Exenatide OW (100 mg) Liraglutide (1.8 mg) No episodes of major hypoglycaemia were reported Minor hypoglycaemia was 10.8% with exenatide OW and 8.9% with liraglutide Buse et al. Diabetologia 2011;54(Suppl. 1):S38(Abstract 75); DURATION-6 top-line study results available at: https://investor.lilly.com/releasedetail2.cfm?releaseid=554248.

GLP-1 receptor agonists. Head to Head RCT Compared with exenatide, liraglutide is associated with: Greater HbA 1c reduction than both exenatide BID and OW Similar weight loss to exenatide BID Greater weight loss vs. exenatide OW Lower incidence of GI events vs. exenatide BID Increased incidence of GI events vs. exenatide OW GI, gastrointestinal

Patients reaching target (%) GLP-1RA vs other antihyperglycemic agents. 45 40 35 30 25 40% Composite outcome of HbA1c<7.0%, no weight gain, and no hypoglycemia 32% ** 25% ** 20 15 10 5 11% *** * 15% * 8% * 6% *** * *** 8% * *** 0 Liraglutide Liraglutide Exenatide Sitagliptin Glargine SU TZD Placebo 1.8 mg 1.2 mg 10 BID (n=1513) (n=1077) (n=186) (n=210) (n=225) (n=447) (n=226) (n=505) *p<0.01 vs. liraglutide 1.8 mg; **p<0.001 vs liraglutide 1.8 mg; ***p<0.0001 vs liraglutide 1.2 mg Zinman B, et al. Diabetes Obes Metab. 2012;14:77-82

Difficulties when treating patients with A1c <8.0% A lower baseline A1c value is associated with a smaller reduction in absolute A1c for T2D therapies The effect of baseline A1c on treatment efficacy varies for the different classes of T2D therapies Hypoglycemia risk also increases as a patient s A1c decreases for example, with an SU, hypoglycemia rate increases fivefold as A1c decreases from 8.0% to 6.0%

LIRA-EXE (LEAD 6) and LIRA DPP-4 studies Post hoc analysis of 26-week data from the LEAD-6 and LIRA DPP-4 studies: - only patients treated as add-on to metformin with a baseline A1c <8.0% were included - for liraglutide, only patients receiving the 1.8 mg dose were included LEAD-6 1 Screening Adults 18 80 years with T2D A1c 7.0 11.0% BMI 45 kg/m 2 Main study: 26 weeks Liraglutide 1.8 mg OD (n=233) Exenatide BID (n=231) Metformin and/or SU continued at pre-study dose LIRA DPP-4 2 Adults 18 80 years with T2D A1c 7.5 10.5% BMI 45 kg/m 2 BID, twice daily; BMI, body mass index; OD, once daily Liraglutide 1.8 mg (n=221) Liraglutide 1.2 mg (n=225) Sitagliptin 100 mg (n=219) Metformin 1500 mg/day King A, Montanya E, Pratley R et al. AACE Meeting, May2012 1. Buse et al. Lancet 2009;374:39 47 (LEAD-6); 2. Pratley et al. Lancet 2010;375:1447 56

Baseline demographics LEAD-6 LIRA DPP-4 Liraglutide 1.8 mg OD n=44 Exenatide 10 µg BID n=41 Liraglutide 1.8 mg OD n=72 Sitagliptin 100 mg OD n=61 Age (years) 54.3 (9.3) 55.2 (10.7) 58.5 (8.2) 56.8 (8.9) Diabetes duration (years) 6.9 (5.2) 3.9 (3.2) 5.7 (6.1) 6.1 (5.2) A1c (%) 7.4 (0.3) 7.3 (0.3) 7.6 (0.3) 7.6 (0.3) FPG (mmol/l) 8.5 (2.1) 8.2 (1.6) 8.8 (1.74) 8.9 (1.3) BMI (kg/m 2 ) 34.0 (5.2) 34.2 (5.8) 31.9 (4.7) 32.0 (4.8) Body weight (kg) 94.8 (18.7) 96.5 (19.6) 91.4 (18.1) 90.6 (18.2) Data are mean (SD) from ITT analysis set King A, et al AACE Meeting, May2012

Change in A1c (%) Change in HbA1c LEAD-6 LIRA DPP-4 Liraglutide 1.8 mg Exenatide 10 µg Liraglutide 1.8 mg Sitagliptin 100 mg Baseline A1c: 7.4% 7.3% 7.6% 7.6% ETD: -0.27% (95% CI: -0.55 to 0.00) ETD: -0.53% (95% CI: -0.76 to -0.30)* Data are LS mean (2SE). Estimated treatment differences (ETD) were calculated by ANCOVA on ITT, LOCF p=0.05, *p<0.0001 King A, et al AACE Meeting, May2012

Patients reaching target (%) Proportion of patients achieving glycemic targets A1c <7.0% A1c 6.5% OR=3.3 [95% CI: 1.2 to 9.5] * OR=6.0 [95% CI: 2.7 to 13.1] *** OR=3.4 [95% CI: 1.3 to 8.6] * OR=4.8 [95% CI: 2.1 to 10.9] ** LEAD-6 LIRA DPP-4 LEAD-6 LIRA DPP-4 Liraglutide 1.8 mg Exenatide 10 µg Sitagliptin 100 mg Data are mean. Treatment comparisons were performed by logistic regression for the ITT population, LOCF ***p<0.0001, **p<0.005, *p<0.05 CI, confidence interval; OR, odds ratio King A, et al AACE Meeting, May2012

Change in body weight (kg) Change in body weight LEAD-6 LIRA DPP-4 Baseline Liraglutide 1.8 mg Exenatide 10 µg Liraglutide 1.8 mg Sitagliptin 100 mg weight: 94.8 kg 96.5 kg 91.4 kg 90.6 kg ETD: -1.06 kg (95% CI: -2.54 to 0.42) Data are mean (2SE). ETD were calculated by ANCOVA on ITT, LOCF *p<0.0001 ETD: -2.96 kg (95% CI: -4.19 to -1.73)* King A, et al AACE Meeting, May2012

GLP-1RA and DPP4 inhibitors in patients on metformin and baseline A1c <8% In patients on treatment with metformin, and with baseline HbA1c <8.0%, the addition of an incretin-based therapy results in: - superior reductions in A1c (~1%) with liraglutide than with exenetide (0.60%) or sitagliptin (0.48%). - ~80% of patients treated with liraglutide achieve an A1c <7.0%. - superior reductions in body weight (~3.5 kg) with liraglutide than with exenetide (2.62 kg) or sitagliptin (0.5 kg).

Conclusions Metformin is the recommended initial pharmacological agent in type 2 diabetic patients. In most patients it is maintained throughout the progression of the disease When monotherapy with metformin fails to control hyperglycemia, and a second agent is added, incretin based therapies: - achieve better body weight control than SU and TZDs - have a very low risk of hypoglycemia, similar to placebo and much lower than SU

Conclusions Compared with DPP-4 inhibitors, GLP-1 receptor agonists are associated with: - Greated HbA 1c reduction - Greater weight loss - Increased incidence of gastrointestinal events - Similar very low rate of hypoglycemia - Higher increment in treatment satisfaction

Conclusions Among GLP-1RA: liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA 1c reduction and weight loss exenatide BID may offer an advantage where postprandial glucose control is a primary concern exenatide OW generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens In patients with baseline HbA1c below 8.0% on metformin alone, the addition of the GLP-1RA liraglutide achieves superior reductions in HbA 1c and body weight than exenatide BID and sitagliptin