New treatments for type 2 diabetes: current status of development

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1 New treatments for type 2 diabetes: current status of development Bruce H.R. Wolffenbuttel, internist endocrinologist University Medical Center Groningen Dept. of Endocrinology: Blog: Relevant relationships (last 5 years) Bv. Sponsorship or research support Bv. Honorarium or other (financial) compensation. Disclosure statement (Company) names Eur. Committee: KP7 EU grant (Meerdere) DiabetesFonds NL Juvenile Diabetes Research Foundation NWO Min VWS, AZ, Econ Affairs Provinces Groningen, Friesland, Drenthe Nierstichting (Kidney Foundation) Zon MW MENZIS EASD / EFSD AstraZeneca Becton Dickinson Eli Lilly Thermo Fisher Novo Nordisk Roche Sanofi Aventis Boehringer Ingelheim Bayer The complete presentation can be downloaded from 1

2 Treatment of type 2 diabetes: a stairway to heaven? Complex insulin Simple insulin Triple medication R/ Dual medication R/ Metformin Lifestyle Several drug choices: Sulphonylurea Thiazolidinediones DPP 4 inhibitors GLP1 receptor agonists SGLT2 inhibitors Do not forget, T2DM integrative approach includes: BP lowering Cholesterol lowering Weight reduction Secondary prevention NHG standaard Individualize!! Current treatment algorithms are of limited help in caring for INDIVIDUALS with T2DM 2

3 What patients don't like 1. Hypoglycaemia 2. Weight gain 3. Interference with normal life Injections Brussels sprouts 1 3

4 1. Current therapy is not perfect What if the UKPDS had stopped after 3 4 years Proportion of patients with events Conventional (411) Intensive (951) Metformin (342) Years from randomisation M v C P= M v I P= Remember: These data apply ONLY to recently diagnosed diabetes w. obesity! 4

5 Metformin in type 2 diabetes Editor of Plos ONE 5

6 Measurement of carotid intima media thickness (IMT) IMT='surrogate endpoint': * Is vascular disease * Predicts c.v. events The CIMT study: insulin+metformin vs. insulin+placebo 6

7 Meta analysis of hypoglycaemia with sulphonylurea Schopman et al, DMRR2014 Meta analysis of cardiovascular side effects of sulphonylurea 7

8 langer leven sneller dood Meta analysis of cardiovascular side effects of sulphonylurea In many studies no separate analysis of which SU was used (for instance gliclazide vs. others)! 8

9 Metformin and SU in T2DMSummary: Metformin is a cheap BG lowering without promoting weight gain, but also without (significant) effect on CVD SU lower BG, but stimulate appetite, increase body weight, may provoke nasty hypoglycaemia, and higher CVD incidence (RR 1.26) If you want to prescribe an SU, probably gliclazide is associated with lowest incidence of hypoglycaemia Boussageon et al, PlosONE 2012; Phung et al, Diab Med 2014; Schopman et al, DMRR2014 Insulin: the best there is?? Insulin treatment in type 2 diabetes is associated with: Better glycaemic control Small improvements in dyslipidaemia Increase in body weight Hypoglycaemia but also: Heart rhythm disturbances 1 Increase in BP 2,3 Inflammation of the vascular wall 4,5 Mitogenic effects 6,7 Inflammation of adipose tissue 8 related to hypoglycaemia sodium retention obesity & insulin resistance insulin growth factor influx macrophages 1. Chow E, et al. Diabetes 2014; 63: ; 2. Kanoun F, et al. Diabetes Metab. 2001; 27: Sarafidis PA, Am J Nephrol 2007; 27: 44 54; 4. Andersson CX, et al. Diabetes Metab Res Rev 2008; 24: Barrett EJ, Liu Z. Rev Endocr Metab Disord 2013; 14: 21 7; 6. Lundby A, et al. J Appl Toxicol doi: /jat Rostoker R, et al. Endocr Relat Cancer 2015; 22: ; 8. Jansen HJ, et al, Diabetologia 2013; 56:

10 Higher insulin dose is associated with more atherosclerosis Muis MJ et al. Atherosclerosis 2005; 181: Insulin use and dose is associated with increased risk of CVD and mortality 120 In T2DM, exogenous insulin may be associated with increased risk of diabetes related complications Event rate (per 1,000 person years) Low dose Mid dose High dose 0 Insulin + metformin Insulin only and insulin+metformin All cause mortality Insulin only Insulin + metformin Insulin only and insulin+metformin Combined endpoint Insulin only Currie CJ, et al. J Clin Endocrinol Metab 2013;98:

11 Insulin use and dose is associated with increased risk of CVD and mortality 120 In T2DM, exogenous insulin may be associated with increased risk of diabetes related complications Event rate (per 1,000 person years) Low dose Mid dose High dose 0 Insulin + metformin Insulin only and insulin+metformin All cause mortality Insulin only Insulin + metformin Insulin only and insulin+metformin Combined endpoint Insulin only Currie CJ, et al. J Clin Endocrinol Metab 2013;98: Pro and contra of insulin therapy in T2DM PRO Best reduction of HbA1c Individual adaptation of insulin dosage Long term experience for decades Long term UKPDS data suggest benefits and slightly better prognosis after 20 years CONTRA Most patients already obese before start insulin therapy Inadvertent weight increases of 5 15 kg are common, not exception High risk for hypoglycaemia, which is associated with more c.v. events No data showing superiority in preventing CVD vs other therapies Uncertainty between potential relation between insulin therapy and cancer risk 11

12 Food for thought ALS INSULINE ZO VEILIG IS WAAROM MOGEN PILOTEN DIE INSULINE SPUITEN NIET VLIEGEN? 2 12

13 2. New drugs for type 2 diabetes 13

14 Long acting insulins GLP1 RA/DPP4i SGLT2i GLP1 RA/DPP4i Biological activities of GLP 1 appetite Food preferences (in animals) GLP-1 made by L-cells in jejunum & ileum heartprotection heartfunction bloodpressure stomach emptying glucose production insulin sensitivity glucose uptake and storage insulin release glucagon release insulin synthesis β-cell proliferation β-cell apoptosis } animals Baggio & Drucker. Gastroenterol 2007;132;

15 Metabolism of GLP 1 Meal Intestinal GLP 1 release Active GLP 1 DPP 4 GLP 1 inactive Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. Metabolism of GLP 1 Meal Intestinal GLP 1 release GLP 1 agonist Exenatide, liraglutide, lixisenatide, dulaglutide (injections) Active GLP 1 DPP 4 Sitagliptine, vildagliptine, saxagliptine, linagliptine (tablets) DPP 4 inhibitor GLP 1 inactive Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. 15

16 A typical comparison of DPP4i (sitagliptin) vs. SU 50 hypoglycaemia Incidence (%) % P< % 0 Week 52 Glipizide + metformin Sitagliptin + metformin Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9:

17 DPP 4 inhibitors & cardiovascular risk: interim analysis Monami M, et al. Diab Obes Metabol 2012 (online) Saxagliptin: cv outcome DM2, 2 o prev/high risk, saxagliptin vs placebo, FU 2,1 y Primary End Point = cardiovascular death, myocardial infarction, or ischemic stroke SAVOR TMI 53 study. Scirica B, et al. New Engl J Med

18 Saxagliptin: cv outcome SAVOR TMI 53 study. Scirica B, et al. New Engl J Med 2013 Alogliptin: cv outcome study (EXAMINE) 5380 DM2, 2 o prev recent AMI/unstable angina, linagliptin vs placebo, FU 1,5 y Primary End Point = cardiovascular death, myocardial infarction, or ischemic stroke EXAMINE study. White B, et al. New Engl J Med

19 Primary composite cardiovascular outcome* ITT analysis for superiority * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina Green JB et al. NEJM 2015; DOI: /NEJMoa Confirmed acute pancreatitis & pancreatic cancer ITT HR 1.93 (0.96, 3.88), p=0.065 Patients Events Sitagliptin (n=7332) Placebo (n=7339) Sitagliptin Placebo Acute pancreatitis 23 (0.3%) 12 (0.2%) Severe Mild Unknown severity ITT HR 0.66 (0.28, 1.51), p=0.32 Sitagliptin n=7332 Placebo n=7339 Pancreatic cancer 9 (0.1%) 14 (0.2%) Green JB et al. NEJM 2015; DOI: /NEJMoa

20 Confirmed charter defined malignancy* Event ITT HR 0.91 (0.77, 1.08), p=0.27 Sitagliptin n=7332 Placebo n=7339 Total number of malignancies Number of patients with malignancy 268 (3.7%) 290 (4.0%) 5 most common types of malignancy Prostate Lung (bronchus) Colon (large intestine, cecum, appendix) Bladder Melanoma 41 (0.6%) 43 (0.6%) 21 (0.3%) 28 (0.4%) 15 (0.2%) 49 (0.7%) 35 (0.5%) 34 (0.5%) 25 (0.3%) 11 (0.1%) Pancreatic cancer 9 (0.1%) 14 (0.2%) *Newly diagnosed malignancy or 1st recurrence of previously diagnosed malignancy during the study period Green JB et al. NEJM 2015; DOI: /NEJMoa Demagogia no increased HF with alo & sita SAVOR TIMI: Saxagliptin, n=8280, placebo, n=8212 EXAMINE, alogliptin, pat's w. history of HF TECOS, sitagliptin, all pat's 20

21 Wanneer DPP4 remmer gebruiken? Patiënt op metformine die: geen hypoglycemie mag hebben (bv. piloot, taxichauffeur) niet wil aankomen in gewicht Nadeel: kosten Classification of GLP 1 receptor agonists acc. to chemical structure Gorgojo Martinez JJ. Hipertens Riesgo Vasc 2014;31:

22 GLP 1 therapy with insulin proof of concept: exenatide (5 10 µg 2x/d) or sitagliptin (100mg/d) in DM2 treated with insulin glargine and metformin glargine + MF glargine + MF + sitagliptin glargine + MF + exenatide Response to standardized breakfast at 4 wks of treatment Arnolds S, et al. Diabetes Care 2010;33:

23 Glargine + exenatide vs. basal bolus insulin regimen: 4B study Participants: T2DM HbA1c % op Glargine + metformin 108 clinics, 17 countries (EU, S.Korea, Mex, Arg, Russia) GLP1 receptor agonist 2dd10mcg Optimization of Insulin Glargine Glargine + MF continued Insulin analogue 3x daags Week 12 wk BIO Phase 30 wk Intervention phase Diamant M et al, Diabetes Care

24 Glargine + exenatide vs. basal bolus insulin regimen: 4B study INS better HRQOL EXE Diamant M et al, Diabetes Care 2014 Wanneer GLP 1 receptor agonist gebruiken? Patiënt met T2DM en: Falen van orale medicatie, in plaats van insuline Onvoldoende regulatie met basale insuline, in plaats van maaltijd gerelateerd insuline Nadeel: kosten Voordeel: combinatie preparaat van GLP1 en basale insuline in één pen is onderweg 24

25 Incretin based therapy: c.v. outcome studies No studies have been terminated for safety concerns Can GLP1 receptor agonists modify the natural course of T2DM? 25

26 Woman, 59 years, type 2 diabetes Type 2 diabetes, since 6 yrs Weight 90 kg BMI 30 kg/m 2 intolerant for metformin; R/ gliclazide + sitagliptin simvastatin normal bloodpressure Goal: glycaemic improvement but wants to loose weight Does not consider insulin to be an option stop sitagliptin; start GLP1 rec. agonist, is paying this HERSELF 100 Euro per month Weight 75 kg (BMI 25) No hypo s No side effects Obesity a risk factor for many chronic disorders Metabolic consequences Diabetes Cardiovascular disease Dynamic consequences Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux Cancer Various types of cancer 5 15 kg during GLP1 RA therapy = fewer long term sequelae?? Other Gall stones Alzheimer s disease Cognitive disturbances Outcome of car accidents Postoperative complications 26

27 Possible scenarios regarding body weight benefit of GLP1 agonists 105 Body weight (kg) Insulin therapy (weight ) Scenario 1 Scenario 2 (best one) Scenario Time (years) Possible benefits of long term reduction of excess body weight: 'Metabolic' / 'Dynamic' / 'Cancer' / 'Other'? Treatment with DPP4 inhibitor sitagliptin will postpone the transition to insulin therapy Metformin + SU vs. Metformin + sitagliptin but costs are high Blonde L, et al. Diabetes

28 Long term and real world data are needed to really really really judge the merit of GLP1 treatment 'Real World' experiences Thong KY, et al. Br J Diab Vasc Dis 2014;14:

29 Patients in the ABCD Nationwide Exenatide and Liraglutide Audit n=12,955 Total exenatide and liraglutide patients n=1,882 Exenatide n=6,717 n=2,487 n=1,023 Liraglutide n=6,238 n=1,221 Patients with week HbA1c and excluding exenatide switching to liragutide and liraglutide 1.8 mg Patients with week HbA1c and week weight n=1,427 n=848 Patients using exenatide or liraglutide as add on therapy Non insulin n=1,027 Insulin n=400 Non insulin n=495 Insulin n=353 BMI kg/m 2 n=559 BMI kg/m 2 n=478 Thong KY, et al. Br J Diab Vasc Dis 2014;14:52 59 HbA1c reduction with GLP1 agonists: also beneficial effect when BMI <35 kg/m (n=20) (n=123) (n=185) (n=157) (n=74) (n=31) (n=129) (n=146) (n=110) (n=62) Mean HbA1c change (%) Exenatide BMI (kg/m 2 ) Liraglutide Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and baseline HbA1c, age, gender, ethnicity as covariates. Exenatide; P=0.67 for effect of BMI group, liraglutide; P=0.024 for effect of BMI group Thong KY, et al. Br J Diab Vasc Dis 2014;14:

30 Body weight reduction with GLP1 Agonist: also beneficial effect when BMI <35 kg/m 2 0 (n=22) (n=117) (n=193) (n=157) (n=76) (n=31) (n=130) (n=146) (n=101) (n=62) Mean weight change (kg) Exenatide BMI (kg/m 2 ) Liraglutide Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and age, gender, ethnicity as covariates. Exenatide; P<0.001 for effect of BMI group, liraglutide; P=0.021 for effect of BMI group Thong KY, et al. Br J Diab Vasc Dis 2014;14:52 59 Retrospective analysis of U.S. health insurance claims data from the IHCIS IMPACT database, which contains medical and pharmacy claims, eligibility data, and laboratory results from 86.4 million covered patients. Of these, 63.7 million (74%) have pharmacy benefits and 12.6 million (15%) have laboratory results; the database includes all data for individuals in all U.S. census regions and represents 46 health plans. Dalal MR, et al. Endocr Pract

31 Dalal MR, et al. Endocr Pract 2015 Dalal MR, et al. Endocr Pract

32 Wanneer GLP 1 receptor agonist gebruiken? Patiënt met T2DM en: Falen van orale medicatie, in plaats van insuline Onvoldoende regulatie met basale insuline, in plaats van maaltijd gerelateerd insuline Nadeel: kosten Geen verhoogd c.v. risico (lixisenatide) Voordeel: combinatie preparaat van GLP1 en basale insuline in één pen is onderweg 3 32

33 SGLT2 inhibitors SGLT2 inhibitors Dapagliflozin (Farxiga R ) Empagliflozin (Jardiance R ) Canagliflozin (Invokana R ) 33

34 Dapagliflozin vs glipizide 814 DM2, metformin 1500 mg/d, HbA1c 7,7 ±0,9%, rct dapagliflozin vs glipizide Nauck M, et al. Diabetes Care 2011;34:2015 Dapagliflozin vs glipizide 814 DM2, metformin 1500 mg/d, HbA1c 7,7 ±0,9%, rct dapagliflozin vs glipizide Nauck M, et al. Diabetes Care 2011;34:2015 Nauck M, et al. Diabetes 2011;60(Suppl.1):Poster 40 LB 34

35 Dapagliflozin vs glipizide 814 DM2, metformin 1500 mg/d, HbA1c 7,7 ±0,9%, rct dapagliflozin vs glipizide Nauck M, et al. Diabetes Care 2011;34:2015 Dapagliflozin: effects on bloodpressure Heerspink H, et al. Diabetes, Obesity and Metabolism 2013;15:853 35

36 Dapagliflozin: genital and urinary tract infections GTI UTI Johnsson K, et al. J Diab Complic 2013 dx.doi.org/ /j.jdiacomp & dx.doi.org/ /j.jdiacomp Exciting news ahead?? 36

37 Results of the EMPA REG OUTCOME studie 7020 patients with type 2 diabetes at high risk for cardiovascular events 14 % reduction of primary outcome: combination of CV death, non fatal AMI, and non fatal stroke 38 % reduction of CV death 35 % reduction of hospitalization for heart failure 32 % reduction of overall mortality Zinman B, et al. NEJM 2015 Ketoacidosis in type 1 diabetes Ketoacidosis with slightly elevated BG values, as SGLT2 inhibitor causes glucosuria and therefore keeps BG low 37

38 SGLT2 inhibitors: summary of (side )effects bloodglucose, HbA1c limited hypoglycaemia bloodpressure (natriuresis, osmotic diuresis) weight (glucosuria, diuresis) genital infections (glucosuria) CARDIOVASCULAR BENEFIT WITH EMPAGLIFLOZIN Misra M. J Pharmacy Pharmacol 2013;65:317, Zinman B, NEJM 2015 SGLT2 remmers; verwachte effecten Daling van bloedglucose, HbA1c, bloeddruk, gewicht Weinig tot geen hypoglycemie Nadeel: meer genitale infecties (door glucosurie) Gebruik: Als 3e medicament als niet op insuline kunnen/durven/willen Mensen T2DM hoog risico HVZ (boven op bestaande behandeling) EVIDENCE! 38

39 4 39

40 New long acting insulins Insulin glargine 300 (Toujeo) 40

41 Toujeo compared to Lantus in T2DM Reduces proportion of patients who experience nocturnal hypoglycemia 10% higher dose Better compromise between HbA 1C and hypoglycemia: Lower risk of nocturnal hypoglycemia at all levels of HbA 1C Nocturnal documented ( 54 mg/dl [<3.0 mmol/l]) Pooled analysis in T2DM 1,2 Nocturnal confirmed ( 70 mg/dl [ 3.9 mmol/l]) or severe EDITION 2 in T2DM 3 Confirmed ( 70 mg/dl [ 3.9 mmol/l]) or severe Patients with 1event from baseline to Month 6, % Lantus 33% Toujeo Relative risk (95% CI) 0.67 ( ) Lantus Toujeo Relative risk (95% CI) 0.75 ( ) 25% 25 Estimated number of events per participant year from Week 9 to Month Toujeo Lantus p=0.159 p= HbA 1C at Month 6 (%) Any time (24 h) Nocturnal 1. Ritzel R et al. Diabetes Obes Metab Apr Data on file, Meta analysis T2DM_pack_ doc, pg 10; Adapted from Yki Järvinen H et al. Diabetes Care. 2014;37: Insulin degludec 41

42 5 Some final thoughts on costs of type 2 diabetes treatment 42

43 New drugs are more expensive than old drugs Price per month: SU: 3 4 Euro, Metformin: 3 4 DPP4 i & SGLT2 remmer: 40 Insulin: GLP1 RA: 100 Short term costs vs long term benefits Miele LG Obesity a risk factor for many chronic disorders Metabolic consequences Diabetes Cardiovascular disease Can a 5 15 kg reduction of body weight reduce weight related morbidities? Dynamic consequences Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux Cancer Various types of cancer Other Gall stones Alzheimer s disease Cognitive disturbances Outcome of car accidents Postoperative complications 43

44 Long term costs of diabetes treatment Quality adjusted life year (QALY): 1. measure of disease burden, including both the quality and the quantity of life lived 2. the number of years of life that would be added by an intervention Methodology Retrospective administrative claims including medical claims, pharmacy claims, laboratory data, from large, US health plan Probability of diabetes complications using the UKPDS outcomes model age, sex, ethnicity, smoking, BMI, HbA1c, SBP, lipids, PVD, atrial fibrillation, ischemic heart disease, and congestive heart failure; and blindness at diagnosis Probability of death from other cause estimated based on the US 2007 mortality tables Zhang Y, et al. Diabetes Care 2014;37:

45 QALY vs. Costs Expected QALYs prior to the first event A % Men 7% Expected medication cost per QALY (USD/QALY) Δ 6.5% B % Women 7% 6.5% met+sulf+insulin met+dpp IV+insulin met+glp 1+insulin met+insulin Expected medication cost per QALY (USD/QALY) QALYs vs. cost incurred by the four different treatment regimens as a function of glycemic control goal. Comparison of the expected QALYs vs. the expected medication cost per QALY incurred from diagnosis to first event (diabetes related complication or death) for men (A) and women (B). Each of the four treatments is compared as the glycemic control goal is varied from 6.5% (48 mmol/mol) to 8% (64 mmol/mol). Results are presented using HbA1c of 6.5% (48 mmol/mol) ( ), 7% (53 mmol/mol) ( ), and 8% (64 mmol/mol) ( ) as the glycemic control goal Zhang Y, et al. Diabetes Care 2014;37: Drawbacks of the UKPDS Model Only predicts 1st event of any diabetes related complications Does not allow series of events Does not incorporate morbidities, like neuropathy or foot ulceration Hypoglycaemia and hyperglycaemia also excluded No single allowance for other co morbid conditions, like COPD, osteo arthritis, depression. & those associated with obesity, which are predicted to be less with GLP1 RA therapy 45

46 saxa? Empa Things to consider when assessing LONG TERM effectivity and costs of new therapies Glycaemic effects BMI>35 kg/m 2 GLP1RA restriction not evidence based Health related quality of life incl. daily activities & work Patients prefer GLP1RA vs insulin Effects on diabetic complications Longer term studies needed Time to insulin dependence Will postpone insulin Side effects Risk of pancreatitis in real world weight increase & hypoglycaemia experience not substantiated pancreatic and other organ safety Long term costs of: Inclusive models needed to assess other med's, other co morbidities & benefit on obesity assoc. disorders their complications absent from work, unemployment, social support 46