Nuove opportunità terapeutiche nel Diabete Mellito

Transcription

1 Nuove opportunità terapeutiche nel Diabete Mellito Raffaele Napoli UOSD Medicina Interna ad indirizzo Diabetologico Dipartimento di Scienze Mediche Traslazionali, Università Federico II di Napoli 1

2 Potenziali conflitti d interessi Il prof. Raffaele Napoli dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti aziende: Astra Zeneca Boehringer Ingelheim Eli Lilly MSD Novo Nordisk Sanofi Alpha Sigma Takeda 2

3 Diabetes-related deaths in the Swedish NDR, Rawshani A, et al. N Engl J Med 2017;376:

4 Cardiometabolic Risk 4

5 Impact of Intensive Therapy for Diabetes Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT * in T1DM Initial Trial Long Term Follow-up UKPDS Lancet 1998; Holman RR et al. NEJM 2008; DCCT Research Group. NEJM 1993; Gerstein HC et al. NEJM 2008; Patel A et al. NEJM 2008; Duckworth W et al. NEJM

6 Severe Hypoglycemic Events Frier BM et al. Diabetes Care

7 Standards of Medical Care in Diabetes-ADA American Diabetes Association Standards of Medical Care in Diabetes, 2017

8 Standards of Medical Care in Diabetes-ADA STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January 2018

9 Drug-specific and patient factors to consider in treatment of T2D adults STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care January 2018

10 Gliflozins Block SGLT2 and Reduces Glucose and Na + Reabsorbtion Reduced glucose and sodium reabsorption SGLT2 SGLT2 Glucose Sodium Dapagliflozin Glucose filtration Proximal tubule Remaining glucose is reabsorbed by SGLT1 (10%) a Increases urinary volume by only ~1 additional void/day (~375 ml/day) in a 12-week study of healthy patients and patients with Type 2 diabetes 1 HbA 1c, glycated hemoglobin; SBP, systolic blood pressure; SGLT, sodium glucose co-transporter Increased urinary excretion of excess glucose ~70 g/day corresponding to 280 kcal/day a Decrease in intracellular sodium concentration Based on this MOA, the following occur 3 : Diuresis Natriuresis HbA 1c reduction Weight loss SBP reduction 10

11 EMPA-REG Outcome Trial Zinman B et al., N Engl J Med 2015;373:

12 EMPA-REG Outcome Trial Zinman B et al., N Engl J Med 2015;373:

13 CANVAS Trial Neal B et al., N Engl J Med

14 Pleiotropic effects of Glp-1 or Glp-1R agonists Meier JJ Nat Rev Endocrinol

15 LEADER Trial Marso SP, et al. N Engl J Med. 2016; 375:

16 Standards of Medical Care in Diabetes-ADA STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January

17 Eligibility for EMPA-REG OUTCOME Diabetes Collaborative Registry: Slide kindly provided by Peter Fenici In a large US-based outpatient registry, ~1 in 6 patients with T2DM met the main eligibility criteria for EMPA- REG OUTCOME Royal College of General Practitioners (RCGP) Research and Surveillance Centre database 16% of T2D patients from the UK-eMR database met the inclusion criteria Arnold S, et al. Presented at: 52 nd EASD Annual Meeting; September 12-16, 2016; Munich, Germany.;McGovern A, et al Diabetes Therapy

18 CVD-REAL Slide kindly provided by Peter Fenici CardioVascular events in Diabetes- Reduction of Events According to real Life data Comparative Effectiveness study comparing the risk of all-cause death, hospitalization for HF, myocardial infarction and stroke in patients with Type 2 diabetes newly initiated on SGLT2 inhibitors vs other glucose-lowering drugs Kosiborod M et al.,circulation 2017; Kosiborod M, et al. J Am Coll Cardiol 2018

19 What we know today: Side-by-side plot of the CVOTs and RWEs results These studies differ in design, patient population, comparator and follow-up period. The graph does not represent a direct H2H comparison between studies. *On-treatment population. ACD, all-cause death; HR, hazard ratio; HHF, hospitalization for heart failure 1. Zinman B, et al. N Engl J Med 2015;373(22): Neal B, et al. N Engl J Med 2017;376: Kosiborod M, et al. Circulation. 2017;136(3): Birkeland KI, et al. Lancet Diabetes Endocrinol. 2017; 5(9): Persson F, et al. Diabetes Obes Metab. 2017; Udell JA, et al. Circulation. 2017; Nov 13 [Epub ahead of print] 7. Kosiborod M, et al.. J Am Coll Cardiol (in press). DOI: /j.jacc

20 Cardiometabolic Risk

21 Multifactorial Intervention and CDV in T2D Gaede P et al., NEJM 2008

22 SGLT2i & GLP1RA Effects and Potential CV Impact Reductions in blood pressure Small increases in HDL-cholesterol and reduced TG Improved endothelial function to reduce arterial stiffness Potential effects on CV risk factors Reductions in uric acid Weight loss and reduced visceral fat Reductions in urinary albumin excretion Modified from Inzucchi SE, et al. Diab Vasc Dis Res 2015;12:90 100

23 Empagliflozin modulates several factors related to CV risk Other Weight Visceral adiposity Uric acid LDL-C HDL-C Triglycerides Glucose Insulin Albuminuria BP Arterial stiffness Sympathetic nervous system activity Oxidative stress Adapted from Inzucchi SE, Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100

24 Incident or worsening nephropathy* Cumulative probability of event (%) Placebo Empagliflozin HR 0.61 (95% CI 0.53, 0.70) p<0.001 * (1.) Progression to macroalbuminuria (urinary albumintocreatinine ratio, >300 mg of albumin per gram of creatinine); (2.) a doubling of the serum creatinine level, accompanied by an egfr of 45 ml per minute per 1.73 m2, as calculated by themdrd formula; (3.) the initiation of renal-replacement therapy; or (4.) death from renal disease Months Christoph Wanner et al. published online June 14, 2016, at NEJM.org 24

25 Doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease 8 Placebo Empagliflozin 7 HR 0.54 (95% CI 0.40, 0.75) p<0.001 Cumulative probability of event (%) Months Christoph Wanner et al. published online June 14, 2016, at NEJM.org 25

26 egfr (CKD-EPI) over 192 weeks Christoph Wanner et al. published online June 14, 2016, at NEJM.org 26

27 Composite renal outcome Patients with an event (%) Subjects with event (%) Macroalbuminuria, doubling of serum creatinine,* ESRD, renal death (N=605) Liraglutide Placebo HR: % CI (0.67 ; 0.92) p=0.003 No. at risk Liraglutide Placebo Time Time since since randomisation (months) *And egfr 45 ml/min/1.73 m 2 per MDRD. The cumulative incidences were estimated with the use of the Kaplan Meier method and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; egfr, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; MDRD, modification of diet in renal disease Mann JFE et al. N Engl J Med 2017;377: doi: /nejmoa

28 New onset of persistent macroalbuminuria Patients with an an event (%) Liraglutide Placebo HR: % CI (0.60 ; 0.91) p= Time since randomisation (months) No. at risk Liraglutide Placebo Full analysis set. EAC-confirmed index events from randomisation to follow-up. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months. Macroalbuminuria was defined as urine albumin >300 mg/g creatinine. CI, confidence interval; EAC, event adjudication committee; HR, hazard ratio Mann JFE et al. N Engl J Med 2017;377: doi: /nejmoa

29 egfr during the trial, according to egfr at baseline egfr (ml/min/1.73 m 2 ) No. of patients Liraglutide Placebo egfr (ml/min/1.73 m 2 ) No. of patients Liraglutide Placebo egfr >90 ml/min/1.73 m 2 at baseline Liraglutide Placebo Time from randomisation (months) egfr ml/min/1.73 m 2 at baseline Liraglutide Placebo Time from randomisation (months) egfr (ml/min/1.73 m 2 ) No. of patients Liraglutide Placebo No. of patients Liraglutide Placebo egfr (ml/min/1.73 m 2 ) egfr ml/min/1.73 m 2 at baseline Liraglutide 67.5 Placebo Time from randomisation (months) egfr <30 ml/min/1.73 m 2 at baseline Liraglutide 18 Placebo Time from randomisation (months) Mann JFE et al. N Engl J Med 2017;377: doi: /nejmoa

30 Drug-specific and patient factors to consider in treatment of T2D adults STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January 2018

31 The Algorithm of Therapy 81.1% 27% 36.3% 2.4% ADA 2007

32 Osservatorio ARNO Diabete Il profilo assistenziale della popolazione con diabete Rapporto 2017, Volume XXX, Collana Rapporti Arno

33 New Perspectives in T2D Treatment Hieronymus Bosh, The Garden of Earthly Delights, 1490

34 Combination injectable therapy for type 2 diabetes If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day) and A1C remains above target, consider advancing to combination injectable therapy STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January 2018

35 Combination injectable therapy for type 2 diabetes STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January 2018

36 Complementary actions of basal insulin and a GLP-1 RA target the underlying pathophysiology of type 2 diabetes BRAIN GLP-1 RA Decreased energy intake Increased satiety LIVER Inhibition of hepatic glucose production Basal insulin PANCREAS Inhibition of hepatic glucose production GLP-1 RA GLP-1 RA Glucose-dependent insulin and glucagon secretion Insulin synthesis ADIPOSE TISSUE Insulin receptor activation Basal insulin SKELETAL MUSCLE GI TRACT Increased glucose disposal Basal insulin GLP-1 RA Inhibits gastric emptying 1. Baggio & Drucker. Gastroenterol 2007;132: ; 2. Niswender. Postgrad Med 2011;123:27 37

37 Advantages when combining a GLP-1 RA and a basal insulin Efficacy Side effects HbA 1c FPG PPG WEIGHT HYPOGLYCAEMIA NAUSEA GLP-1 RA monotherapy Basal insulin GLP-1 RA/insulin combined

38 Meta-analysis comparing basal insulin/glp-1 RA and basal insulins HbA1c Eng C et al. Lancet 2014

39 Hypoglycemia Body weight Eng C et al. Lancet 2014

40 Insulin products in the U.S. calculated and costs as AWP and NADAC per 1,000 units of specified dosage form/product STANDARDS OF MEDICAL CARE IN DIABETES 2018, Diabetes Care, January 2018

41 Safety CV ORIGIN ELIXA DEVOTE LEADER IGlarLixi IDegLira

42 Daily treatment with Insulin-GLP1RA fixed combination and Basal-Bolus IDegLira Basal - Bolus 1 pen1 1 Injection 1 1 SMPG test 2 Daily Regimen M T W T F S S * pens * Injections 3 SMPG test 2 EVENING DINNER LUNCH BREAKFAST Daily Regimen M T W T F S S 1. Buse JB et al. Diabetes Care 2014; 2. Owens D et al. Diabetes and Primary Care 2004; 3. NICE. Technology Appraisal number

43 IDegLira titration IDegLira is dosed in accordance with patients needs based on pre-breakfast (fasting) blood glucose Below target At At individualised target individualised target Above target -2 dose steps Maintain dose +2 dose steps ADA guidelines recommend a fasting and pre-meal glucose goal of 4.4 to <7.2 mmol/l ADA, American Diabetes Association; IDegLira, insulin degludec/liraglutide Xultophy Summary of Product Characteristics (SmPC), 2017; American Diabetes Association. Diabetes Care 2017;40(Suppl.1):S64 S74

44 iglarlixi

45 DUAL VII Billings et al. Diabetes Care 2018

46 Lixisenatide - Get Goal Duo 2 Rosenstock J et al. Diabetes Care 2016

47 La Parabola dei ciechi (1568), Pieter Bruegel il Vecchio, Museo Nazionale di Capodimonte, Napoli