T2DM Treatment Intensification after Basal Insulin: GLP-1 RA or Rapid-Acting Insulin?

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1 T2DM Treatment Intensification after Basal Insulin: GLP-1 RA or Rapid-Acting Insulin? Francesco Giorgino Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases

2 Dualities of interest GRANT SUPPORT: Eli Lilly and Company, NovoNordisk, AstraZeneca, Bristol Myers Squibb, Sanofi CONSULTANT: Sanofi, Roche Diagnostics, Merck Sharp & Dohme, Novartis, Lifescan, AstraZeneca, Bristol Myers Squibb, NovoNordisk, Takeda 2

Phenotype Features Which May Influence Response to Anti-Hyperglycemic Therapy in Type 2 Diabetes GENERAL CLINICAL FEATURES Diabetes duration Age/Life expectancy Frailty Risk from hypoglycemia

3 Phenotype Features Which May Influence Response to Anti-Hyperglycemic Therapy in Type 2 Diabetes GENERAL CLINICAL FEATURES Diabetes duration Age/Life expectancy Frailty Risk from hypoglycemia Overweight/Obesity Metabolic Syndrome PATTERNS OF GLUCOSE ABNORMALITY Baseline HbA 1c Fasting hyperglycemia Postprandial hyperglycemia Rate of hyperglycemia progression Rate of hypoglycemia SPECIFIC DISEASE MECHANISMS Beta-cell autoimmunity (e.g. LADA) Monogenic diabetes (e.g. MODY) SPECIFIC COMORBITIES CHD/CVD Heart failure Liver dysfunction, NAFLD/NASH CKD Cognitive dysfunction LADA: Latent autoimmune diabetes of adulthood; MODY: maturity onset diabetes of the young; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; CKD: Chronic kidney disease 3

4 Efficacy of Diabetes Therapies of Fasting and Post-prandial Hyperglycemia (adapted from AACE 2009) Metformin Basal Insulin Fasting Post-prandial + + Acarbose Glinide DPP-4 Inhibitor GLP-1 RA (prandial) Prandial Insulin Fasting - -/ Post-prandial Sulphonylurea Pioglitazone SGLT-2 Inhibitor GLP-1 RA (non-prandial) Fasting +/ /++ ++ Post-prandial ++ +/ Adapted from Rodbard et al. Endocrine Practice :

Clinical Recommendations for Intensifying Therapy by PPG Control Intensify (prandial control) Add GLP-1 receptor agonist or DPP-4 inhibitor Glycemic control not at goal Add prandial insulin Total

5 Clinical Recommendations for Intensifying Therapy by PPG Control Intensify (prandial control) Add GLP-1 receptor agonist or DPP-4 inhibitor Glycemic control not at goal Add prandial insulin Total daily dose: U/kg 50% basal analog 50% prandial analog Less desirable: NPH and regular insulin or premixed insulin Insulin titration every 2-3 days to reach glycemic goal Inzucchi SE, et al. Diabetes Care 2012;35: Garber AJ, et al. Endocrine Pract 2013; 19(Suppl.2):1-48 5

6 Outline Mechanistic rationale and clinical evidence for addition of GLP-1 RAs to basal insulin When to administer short-acting GLP-1 RAs and rapid-acting insulin in relation to meals Comparison of short-acting GLP-1 RAs/basal insulin vs. rapid-acting insulin/basal insulin regimens

7 Drug Mechanism of action and Effects Phenotypes Basal Insulin GLP-1 RA (prandial, short-acting) GLP-1 RA (non-prandial, long-acting) Hepatic glucose output Reduction of FPG Body weight gain ß-cell protection (?) Insulin secretion (glucose-dependent) Glucagon secretion (post-prandial) Gastric emptying Reduction of PPG > FPG Satiety and body weight reduction ß-cell lipotoxicity and inflammation Insulin secretion (glucose-dependent) Glucagon secretion (fasting) Reduction of FPG > PPG Satiety and body weight reduction ß-cell lipotoxicity and inflammation Elevated FPG Prevalent insulin secretory defect Rapid progression of ß-cell failure (e.g., LADA) Elevated PPG Overweight/Obesity Metabolic syndrome Elevated FPG (and PPG) Overweight/Obesity Metabolic syndrome Adapted from Inzucchi SE, et al. Diabetes Care 2012;35: , Meier JJ. Nat Rev Endocrinol :

Apoptosis (% basal) Apoptosis (% basal) Exendin-4 Inhibits Palmitate-induced Apoptosis

of basal) Human Islets Human Islets 400 300 200 150 100 50 GPR40 GAPDH 100 0 Palm Ex-4

8 Apoptosis (% basal) Apoptosis (% basal) Exendin-4 Inhibits Palmitate-induced Apoptosis in β-cells by Inhibiting GPR40 Expression and Preventing JNK Activation GPR40/GAPDH (% of basal) Human Islets Human Islets GPR40 GAPDH Palm Ex Mouse Islets Time (h) INS-1E p-54 p-46 p I.Blot: JNK-P Basal Palm Exendin Ex-4 + Palmitate 0 Palm Ex Palmitate P-JNK Topro Natalicchio A et al, Diabetologia 56: , 2013

9 Exenatide Added to Insulin Therapy: A Retrospective Review of Clinical Practice 188 patients, retrospective review of medical records Baseline data: BMI 40.4, HbA 1c 8.05 ± 1.47%, total daily insulin dose 99.9±90.0 U Mean duration of treatment, 350 [208] days Results: 0.54% reduction in HbA 1c (at months) Body weight reduction of 5.5 ± 10.8 kg (at months) Reduction of mean insulin total daily dose of 14.8 ± 35.3 U (at 6 12 months) 26.1% discontinued exenatide because of GI effects Yoon NM, et al. Clin Ther 2009;31:

10 Glucose level (mmol/l) Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial John B. Buse, MD, PhD; Richard M. Bergenstal, MD; Leonard C. Glass, MD; Cory R. Heilmann, PhD; Michelle S. Lewis, PhD; Anita Y.M. Kwan, MS; Byron J. Hoogwerf, MD; and Julio Rosenstock, MD Ann Intern Med ;154: Change in HbA 1c Level % Insulin glargine + placebo Insulin glargine + exenatide Week Insulin glargine + exenatide, baseline Insulin glargine + placebo, baseline Insulin glargine + exenatide, 30 wk Insulin glargine + placebo, 30 wk Data are LS mean CI; p < 0.001; p < 0.01 for between-group comparison 10

11 Change in body weight (kg) Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial John B. Buse, MD, PhD; Richard M. Bergenstal, MD; Leonard C. Glass, MD; Cory R. Heilmann, PhD; Michelle S. Lewis, PhD; Anita Y.M. Kwan, MS; Byron J. Hoogwerf, MD; and Julio Rosenstock, MD Ann Intern Med ;154: Changes in body weight and glucose levels over 30 weeks Week Insulin glargine + placebo Insulin glargine + exenatide Number of Participants Reporting Adverse Events Variable Exenatide Group (n = 137), n (%) Placebo Group (n = 122), n (%) Patients with SAE 8 (6) 11 (9) Death 0 (0) 1 (1) Withdrew from the study because of an adverse event 13 (9) 1 (1) Patients with TEAE 109 (79) 86 (70) TEAEs in >5% of participants Nausea 56 (41) 10 (8) Diarrhea 25 (18) 10 (8) Vomiting 25 (18) 5 (4) Headache 19 (14) 5 (4) Constipation 14 (10) 2 (2) Upper respiratory tract infection 11 (8) 9 (7) Back pain 9 (7) 2 (2) Nasopharyngitis 8 (6) 6 (5) Cough 7 (5) 7 (6) Asthenia 7 (5) 1 (1) Hypoglycemia Minor 34 (25) 35 (29) Minor nocturnal 23 (17) 32 (26) Major 0 (0) 1 (1) SAE: serious adverse event; TEAE: treatment-emergent adverse event 11

12 Insulin glargine + MET ± TZDs + LIXISENATIDE vs Insulin glargine + MET ± TZDs + PLACEBO Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1) Riddle MC, Forst T, Aronson R, Sauque-Reyna L, Souhami E, Silvestre L, Ping L, Rosenstock J. Diabetes Care. 2013;36: Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L) Riddle MC, Aronson R, Home P, Marre M, Niemoeller E, Miossec P, Ping L, Ye J, Rosenstock J Diabetes Care. 2013;36: Basal insulin ± MET + LIXISENATIDE vs Basal insulin ± MET + PLACEBO Basal insulin ± SUs + LIXISENATIDE vs Basal insulin ± Sus + PLACEBO Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia) Seino Y, Min KW, Niemoeller E, Takami A; EFC10887 GETGOAL-L Asia Study Investigators Diabetes Obes Metab Oct;14(10):

GetGoal-Duo 1: Addition of Lixisenatide to Titrated Glargine plus OADs in Insulin-Naïve Patients - Study Design Insulin glargine (morning) + metformin (± TZDs) + lixisenatide Screening Criteria

0% and 10% Insulin glargine (morning) + metformin (± TZDs) R (n = 446) 20 μg 15 μg 10 μg if n=223 7% HbA 1c 9% + Mean fasting SMPG 140 mg/dl n=223 Insulin glargine (morning) + metformin (± TZDs)

13 GetGoal-Duo 1: Addition of Lixisenatide to Titrated Glargine plus OADs in Insulin-Naïve Patients - Study Design Insulin glargine (morning) + metformin (± TZDs) + lixisenatide Screening Criteria T2DM for 1 year MET 1.5 g/d ±TZD ± SU or Glinide HbA 1C : 7.0% and 10% Insulin glargine (morning) + metformin (± TZDs) R (n = 446) 20 μg 15 μg 10 μg if n=223 7% HbA 1c 9% + Mean fasting SMPG 140 mg/dl n=223 Insulin glargine (morning) + metformin (± TZDs) + placebo Insulin glargine weekly titration Insulin glargine dose adjusted to maintain fasting SMPG target Target fasting SMPG between 80 and 100 mg/dl (both inclusive) 12-week run-in phase 24-week double-blind period Glinide stopped at enrollment; SMPG=Self-monitored plasma glucose Riddle MC et al. Diabetes Care 2013; 36:

GetGoal-L: Addition of Lixisenatide in Patients Inadaquately Controlled on a Stable Dose of Basal Insulin Lixisenatide in combination with: GetGoal-L: Basal insulin ± metformin GetGoal-L Asia: Basal

14 GetGoal-L: Addition of Lixisenatide in Patients Inadaquately Controlled on a Stable Dose of Basal Insulin Lixisenatide in combination with: GetGoal-L: Basal insulin ± metformin GetGoal-L Asia: Basal insulin ± sulfonylurea 24 weeks + variable extension 52 weeks + 3 days F/U 24 weeks + 3 days F/U 1 wk 20 µg Lixisenatide QD (SC) 1 wk 15 µg Key Inclusion Criteria T2DM (+Asian for -L Asia) HbA 1c 7.0% 10.0% Stratified by HbA 1c (<8.0%/ 8.0%) & Met (-L) or SU (-L Asia) use (yes/no) Basal insulin 30 U/day (-L); 10 U/day (-L Asia) 1 wk 10 µg R 10 µg 15 µg All patients: background treatment at a stable dose Diet & lifestyle counselling every 3 months from D1 1 wk 20 µg Placebo Single-blind Screening run-in Main double-blind treatment period W-3 W-1 W0 W4 W12 W24 Primary endpoint Variable extension period // End of treatment 3 d F/U F/U Visit Change in HbA 1C Riddle MC et al. Diabetes Care 2013; 36:

15 Lixisenatide Effects in Patients on Basal Insulin: Change in HbA 1c at 24 weeks: Primary Endpoint HbA 1c change from baseline (%) Lixisenatide 20μg QD Placebo Baseline HbA 1c (%) Background therapy Study duration (wk) GetGoal-Duo Titrated glargine + MET ± TZD 24 GetGoal-L 1 GetGoal-L Asia Basal insulin ± MET Basal insulin ± SU 24 p< vs placebo; p<0.001 vs placebo; following 12 week run-in period; MET, metformin; SU, sulfonylurea; TZD, thiazolidinedione; QD, once daily 1. Riddle MC et al. Diabetes Care 2013;36: ; 2. Seino Y et al. Diabetes Obes Metab 2012;14: Riddle MC et al. Diabetes Care 2013;36:

16 Lixisenatide Effects in Patients on Basal Insulin: Change in 2-hr PPG at 24 weeks: Secondary Endpoint PPG change from baseline (mmol/l) Lixisenatide 20μg QD Placebo Baseline PPG (mmol/l) Background therapy Study duration (wk) GetGoal-Duo p< vs placebo; MET, metformin; SU, sulfonylurea; TZD, thiazolidinedione; QD, once daily 0.08 ~13.0 Titrated glargine + MET ± TZD 24 GetGoal-L 1 GetGoal-L Asia ~16.0 Basal insulin ± MET Basal insulin ± SU Riddle MC et al. Diabetes Care 2013;36: ; 2. Seino Y et al. Diabetes Obes Metab 2012;14: Riddle MC et al. Diabetes Care 2013;36:

17 Lixisenatide Effects in Patients on Basal Insulin: Change in Body Weight at 24 weeks: Secondary Endpoint Mean change in body weight from baseline (kg) Lixisenatide 20μg QD Placebo GetGoal-Duo GetGoal-L 1 GetGoal-L Asia NS Background therapy Study duration (wk) Titrated glargine + MET ± TZD 24 Basal insulin ± MET 24 p< versus placebo; p<0.001 versus placebo; p < 0.01; NS = not significant; MET, metformin; SU, sulfonylurea; TZD, thiazolidinedione; QD, once daily Basal insulin ± SU Riddle MC et al. Diabetes Care 2013;36: ; 2. Seino Y et al. Diabetes Obes Metab 2012;14: Riddle MC et al. Diabetes Care 2013;36:

GetGoal-L Subanalysis: Effects of Lixisenatide on HbA 1c Change at Week 24 by FPG at Baseline LS mean change ± SE in HbA 1c from baseline to Week 24 (%) Basal insulin + Lixisenatide Basal insulin +

18 GetGoal-L Subanalysis: Effects of Lixisenatide on HbA 1c Change at Week 24 by FPG at Baseline LS mean change ± SE in HbA 1c from baseline to Week 24 (%) Basal insulin + Lixisenatide Basal insulin + Placebo FPG 6.7 mmol/l (Baseline HbA 1c 8.1%) FPG >6.7 to 8.9 mmol/l (Baseline HbA 1c 8.4%) FPG >8.9 mmol/l (Baseline HbA 1c 8.7%) n = 102 n = 56 n = 99 n = 55 n = 103 n = LS mean difference 0.57; p < LS mean difference 0.30; p = LS mean difference 0.29; p = mitt population with LOCF. HbA1c: glycated hemoglobin; FPG: fasting plasma glucose; LS: least squares; SE: standard error; mitt: modified intent-to-treat; LOCF: last observation carried forward Vidal J, et al. Diabetologia 2013;56(Suppl.1):S9 18

19 GetGoal-L Subanalysis: Effects of Lixisenatide on Body Weight by FPG at Baseline LS mean change ± SE in body weight from baseline to Week 24 (kg) FPG 6.7 mmol/l FPG >6.7 to 8.9 mmol/l FPG >8.9 mmol/l Basal insulin + Lixisenatide Basal insulin + Placebo n = 103 n = 56 n = 103 n = 56 n = 105 n = LS mean difference 1.75; p < LS mean difference 1.09; p = LS mean difference 1.00; p = mitt population with LOCF. FPG: fasting plasma glucose; LS: least squares; SE: standard error; mitt: modified intent-to-treat; LOCF: last observation carried forward Vidal J, et al. Diabetologia 2013;56(Suppl.1):S9 19

Addition of Liraglutide to Metformin Followed by Basal Insulin Detemir over 1 Year: Change in HbA 1c Screening Run-in period 12 weeks R Randomized period 26 weeks Extension period 26 weeks

20 Addition of Liraglutide to Metformin Followed by Basal Insulin Detemir over 1 Year: Change in HbA 1c Screening Run-in period 12 weeks R Randomized period 26 weeks Extension period 26 weeks Observational group Metformin + liraglutide 1.8 mg HbA 1c <7% Week 26 Week 38 Randomized treatment group Metformin + sulfonylurea Metformin + liraglutide 1.8 mg R Metformin + liraglutide 1.8 mg + IDet HbA 1c >7% Randomized control group Metformin + liraglutide 1.8 mg Time (weeks) 52 Rosenstock J, et al. J Diab Compl 2013;27:

21 Addition of Liraglutide to Metformin Followed by Basal Insulin Detemir Over 1 Year: Change in HbA 1c HbA 1c (%) MET + LIRA 1.8 mg MET + LIRA 1.8 mg + IDet Observational MET + LIRA 1.8 mg Time (weeks) Run-in period Randomized period Improvements in glycemic control (p < ) and weight reductions (p = 0.04) were sustained over 1 year, with low rates of hypoglycemia Rosenstock J, et al. J Diab Compl 2013;27:

22 Outline Mechanistic rationale and clinical evidence for addition of GLP-1 RAs to basal insulin When to administer short-acting GLP-1 RAs and rapid-acting insulin in relation to meals Comparison of short-acting GLP-1 RAs/basal insulin vs. rapid-acting insulin/basal insulin regimens

23 Does Timing of Injection of GLP-1 RA Matter? The Lixisenatide Main Meal Study Randomization stratified on: Main meal of the day Screening values of HbA 1c (<8%, 8%) Main meal determination Inclusion criteria: T2DM >1 yr HbA 1c % FPG 13.9 mmol/l (250 mg/dl) Pretreatment >3 months metformin 1.5g/d Breakfast n = 37 Lunch n = 239 Dinner n = 175 Breakfast group (n = 226) Main meal group (n = 225) 202 completed (89.4%) 189 completed (84%) Screening = 3 weeks Treatment = 24 weeks The main meal was determined by asking patients: "On most days, at which meal do you eat the largest amount of food? A dietary consultation was also performed to confirm the patient s assessment FPG, fasting plasma glucose Presented at IDF 2013 by B Ahrén; op09. ; Ahrén B et al. IDF 2013;Abstract OP-0454.

24 Main Meal of the Day: Determination Main meal of the day as determined by the patient, n (%) Breakfast Lunch Dinner Main meal of the day as determined by the dietician, n (%) Breakfast Lunch Dinner Main meal (n = 225) 19 (8.4) 119 (52.9) 87 (38.7) 28 (12.5) 118 (52.7) 78 (34.8) Breakfast (n = 226) 18 (8.0) 120 (53.1) 88 (38.9) 18 (8.0) 122 (54.2) 85 (37.8) Main meal assessment consistent between patient and dietician 193 (86.2) 185 (81.9) Main meal assessment NOT consistent between patient and dietician 30 (13.4) 40 (17.7) No dietician assessment 1 1 Randomized population Patients were recruited from 77 centers across 10 countries (Canada, Czech Republic, France, Germany, Poland, Romania, Russian Federation, Spain, Ukraine, and the USA) Presented at IDF 2013 by B Ahrén; op09. Ahrén B et al. IDF 2013;Abstract OP-0454.

25 Mean HbA 1c ± SE Primary Endpoint: HbA 1c Change over Time Breakfast Main meal (n = 224) Breakfast (n = 226) Baseline HbA 1c, % HbA 1c, % (Week 24 LOCF) LS mean change, % LS mean difference, % (95% CI) 0.09 (-0.067, 0.242) Screening Baseline 8 Main meal Study period (weeks) LOCF Statistical superiority not demonstrated (p = ) Flexibility of timing of administration and of use according to patients needs mitt population with LOCF Presented at IDF 2013 by B Ahrén; op09. Ahrén B et al. IDF 2013;Abstract OP-0454.

26 Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs. Lankisch MR, Ferlinz KC, Leahy JL, Scherbaum WA; Orals Plus Apidra and LANTUS (OPAL) study group Diabetes Obes Metab. 2008;10: HbA 1c (%) Patients with HbA 1c > % at screening (n) Patients who achieved HbA 1c <6.5% at end-point, n(%) Patients with HbA 1c >7.0% at baseline (n) Total Breakfast injection Main mealtime injection (30.7) 45 (27.8) 52 (33.8) Overall Breakfast group Main meal group Patients with HbA 1c >7.0% at baseline achieving HbA 1c <7.0% at end-point, n (%) 83 (44.1) 35 (36.5) 48 (52.2) HbA 1c, haemoglobin A 1c p = for differences between the two treatment groups 26

27 Outline Mechanistic rationale and clinical evidence for addition of GLP-1 RAs to basal insulin When to administer short-acting GLP-1 RAs and rapid-acting insulin in relation to meals Comparison of short-acting GLP-1 RAs/basal insulin vs. rapid-acting insulin/basal insulin regimens

28 Addition of Exenatide BID vs Insulin Lispro TID to Basal Insulin Glargine: Change in HbA 1c HbA 1c (%) Time (wk) ExBID + IG 7.19% (n=247) LisTID+ IG 7.16% (n=263) Patients (%) % 49.0% HbA 1c 7% ExBID + IG (n=244) LisTID+ IG Values are LS Mean ± SE calculated using MM8M Reduction in HbA 1c with exenatide BID was non-inferior to insulin lispro Diamant M, et al. Diabetes 2013;62(Suppl.1):Abstract 70OR 28

29 Addition of Exenatide BID vs Insulin Lispro TID to Basal Insulin Glargine: Body Weight and Composite Endpoint Change in body weight (kg) Time (wk) ExBID + IG (n = 247); Baseline 91±17 LisTID + IG (n = 263); Baseline 89± kg -4.6 kg (-5.2, -3.9) -2.5 kg Patients achieving target (%) % P< ExBID + IG (n = 242) LisTID+ IG (n = 262) 22.9% HbA 1c 7% and weight gain 1kg LS Mean ± SE calculated using MMRM, P< P value calculated using logistic regression analysis Diamant M, et al. Diabetes 2013;62(Suppl.1):Abstract 70OR 29

Addition of Exenatide BID vs Insulin Lispro TID to Basal Insulin Glargine: Incidence of Hypoglycemia Incidence (%) 100 90 80 70 60 50 40 30 20 10 0 p = 0.004 29.5 40.7 p = 0.106 0.6 2.2 p < 0.001 15.

30 Addition of Exenatide BID vs Insulin Lispro TID to Basal Insulin Glargine: Incidence of Hypoglycemia Incidence (%) p = p = p < Overall rate per patient-year (Minor and Major): 2.1 (ExBID + IG) vs (LisTID + IG) As treated population; Fisher s exact test ExBID + IG (n = 315) LisTID+ IG (n = 312) p = Minor Major Non-Nocturnal Nocturnal Diamant M, et al. Diabetes 2013;62(Suppl.1):Abstract 70OR 30

31 A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON) Mathieu C, Rodbard HW, Cariou B, Handelsman Y, Philis-Tsimikas A, Ocampo Francisco AM, Rana A, Zinman B; on behalf of the BEGIN: VICTOZA ADD-ON (NN ) study group Diabetes Obes Metab Jan 20 [Epub ahead of print] IDeg+Lira reduced HbA 1c more than IDeg+IAsp ( 0.74% vs. 0.39%, p = ) IDeg+Lira vs. versus IDeg+IAsp subjects had less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss ( 2.8 kg vs kg) More IDeg+Lira (49.4%) than IDeg+IAsp (7.2%) subjects achieved HbA 1c <7.0% without confirmed or severe hypoglycaemia and without weight gain Mathieu C, et al. Diabetes Obes Metab 2014;Published online 11 Feb

32 HARMONY 6: Type 2 DM Uncontrolled on Glargine Plus Oral Agents Randomized to Once-Weekly GLP-1 RA Albiglutide vs TID Prandial Insulin (Lispro) Added to Titrated Glargine Mean ( SE) A 1C, % Albiglutide (n=282) Lispro (n=281) 7.8% 7.65% Albiglutide met non-inferiority criteria vs Lispro at week 26 (p < ) Albiglutide did not meet superiority criteria vs Lispro (p = 0.053) Neutral effect on body weight Week ITT population with LOCF Change From Baseline in Weight, kg kg 92.4 kg 92.5 kg 91.8 kg Mean FPG ( SE), mg/dl mg/dl mg/dl Week Week Model-adjusted change from baseline for the ITT population, LOCF Rosenstock J, et al. Diabetes Care, in press 32

33 Once-daily prandial lixisenatide versus oncedaily rapid-acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: analysis of data from five randomized, controlled trials Raccah D, Lin J, Wang E, Germé M, Perfetti R, Bonadonna RC, de Pablos- Velasco P, Roussel R, Rosenstock J J Diabetes Complications. 2014;28:

34 Addition of Lixisenatide QD vs RAI to Basal Insulin: Pooled Analysis Patients (%) acheiving composite endpoint Composite endpoint: HbA 1c <7%, no weight gain, and no documented symptomatic hypoglycemia p = Matched population: n = 288 Basal + LIXI 15.3 Basal + RAI Raccah D, et al. J Diabetes Complications 2014;28:

35 GetGoal DUO-2: Lixisenatide Added to Insulin Glargine vs Basal-Plus and Basal-Bolus Insulin Therapies Screening T2DM patients Basal insulin ± OADs HbA 1c 7.5% & 10% Run-in R HbA 1c between 7-9% Mean fasting SMBG (140mg/dL) 26-week open-label treatment period n=285 Basal Bolus = 3 RAI injections per day Discontinue DPPIV and SU Insulin glargine introduced and/or optimized 12 weeks R n=285 Basal Plus = 1 RAI injection per day Lixisenatide n= µg 20 µg Insulin glargine adjusted in all groups (fasting SMPG mg/dl) NCT

36 Conclusions A substantial proportion of patients on basal insulin (i.e., ~40 50%), with or without oral anti-diabetes agents, do not reach their HbA 1c goal, due to uncontrolled PPG, and require additional therapies Rapid-acting insulins and short-acting GLP-1 RAs offer treatment options for targeting PPG Basal insulin/glp-1 RAs combination therapy may provide complementary targeting of FPG and PPG, further HbA 1c decrease, body weight control, reductions in insulin dose, favorable effects on extra-glycemic endpoints T2DM treatment recommendations (e.g., ADA/EASD, AACE) endorse the addition of GLP-1 RAs to basal insulin The short-acting GLP-1 RAs lixisenatide QD and exenatide BID have been best validated as add-on therapies to basal insulin (glargine) Addition of short-acting GLP-1 RAs that preferentially target PPG is a good alternative to rapid-acting prandial insulins due to: similar efficacy on HbA 1c reduction; additional benefits on body weight; low risk of hypoglycemia 36

37 Treatment Intensification after Basal Insulin by GLP-1 RA vs. Rapid-acting Insulin: Open Questions Different efficacy in specific T2DM subtypes: LADA, long duration T2DM, obese/metabolic syndrome Safety issues in T2DM subgroups: High hypoglycemia risk, elderly/frail, GI disturbances Tailoring of therapies according to specific glycemic phenotypes Prevalent fasting or postprandial hyperglycemia use of short-acting vs. long-acting GLP-1RAs Long-term impact on occurrence and/or progression of microvascular and macrovascular complications 37

38 38

Francesca Porcellati

XX Congresso Nazionale AMD Razionali e Benefici dell Aggiunta del GLP-1 RA Short-Acting all Insulina Basale Francesca Porcellati Dipartimento di Medicina Interna, Sezione di Medicina Interna, Endocrinologia