Update sul danno macrovascolare: fisiopatologia e indicazioni per la prevenzione

Transcription

1 Update sul danno macrovascolare: fisiopatologia e indicazioni per la prevenzione Marco Giorgio Baroni Department of Experimental Medicine Sapienza University of Rome, Italy

2 Il sottoscritto Marco Giorgio Baroni dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: - Sanofi - Novo Nordisk - Abbott - Takeda Dichiara altresì il proprio impegno ad astenersi, nell ambito dell evento, dal nominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.).

3 The Emerging Risk Factors Collaboration JAMA. 2015;314: Association of Cardiometabolic Multimorbidity With Mortality 2x 2x 2x 2x

4 Diabetes and Survival, According to Sex and Diabetes Status. 7 Men Non-vascular deaths 7 Women 6 Vascular deaths 6 Years of life lost Age (year) Age (year) On average, a 50-year old with diabetes but no history of vascular disease is ~6 years younger at time of death than a counterpart without diabetes The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:

5 Hazard Ratios for Major Causes of Death, according to Baseline Levels of Fasting Glucose The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:

6 Iperglicemia come moltiplicatore.. Svensson et al. Diab Vasc Dis Res 2013;10: Das et al. Am Heart J 2006;151:

7 All Cause Mortality Intensive vs Standard Glucose Lowering CI: confidence interval; HR: hazard ratio. Ray KK et al Lancet 2009;373:

8 Major cardiovascular Events Intensive vs Standard Glucose Lowering Turnbull FM et al Diabetologia 2009; 52:

9 *CV mortality, non-fatal MI, non-fatal stroke Effect of Glucose-Lowering Drugs on 3-Point MACE* Study Year Glucose-lowering drug in T2DM Patients HR 95% CI P-value PROACTIVE 2005 Pioglitazone ORIGIN 2012 Insulin glargine NS DEVOTE 2017 Insulin degludec NS SAVOR 2013 Saxagliptin NS EXAMINE 2013 Alogliptin NS TECOS 2015 Sitagliptin NS ELIXA 2015 Lixisenatide NS EMPA-REG 2015 Empagliflozin LEADER 2016 Liraglutide Favors study drug Favors placebo 0.01 SUSTAIN Semaglutide CANVAS 2017 Canagliflozin ,2

10 Turner RC et al BMJ 1999;316: UKPS 23: Risk Factors for CHD HbA1c (%) Age (yrs) Estimated HR Systolic BP (mmhg) LDL-cholesterol mmol/l) Estimated HR Estimated HR Estimated HR

11 Effect of Glucose-Lowering Drugs on 3-Point MACE* Study Year Glucose-lowering drug in T2DM Patients HR 95% CI P-value PROACTIVE 2005 Pioglitazone ORIGIN 2012 Insulin glargine NS DEVOTE 2017 Insulin degludec NS SAVOR 2013 Saxagliptin NS EXAMINE 2013 Alogliptin NS TECOS 2015 Sitagliptin NS ELIXA 2015 Lixisenatide NS EMPA-REG 2015 Empagliflozin *CV mortality, non-fatalmi, non-fatalstroke ,2 Favors placebo Favors study drug

12 Potential of SGLT2 Inhibition Filtered glucose load > 180 g/die 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% SGLT2 SGLT1 SGLT2 inhibitors reduce glucose reabsorption at the proximal tubule causing glycosuria and osmotic diuresis

13 EMPA-REG CV OUTCOME Main Results Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Favours empagliflozin Favours placebo Zinman B et al N Engl J Med 2015;373:

14 EMPA-REG Outcomes Incident or Worsening Nephropathy Wanner C et al N Engl J Med 2016;375:323-34

15 CANVAS - Primary MACE Outcome: CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke Neal B et al N Engl J Med 2017 Neal B, et al. N Engl J Med. 2017

16 Key Outcomes in the CANVAS Program and EMPA-REG OUTCOME Zinman Bet al. N Engl J Med. 2015;373: ; Wanner K et al. N Engl J Med. 2016;375: ; Neal B et al N Engl J Med DOI: /NEJMoa

17 SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS Trials 1/3 in primary prevention in Canvas Subjects with prior CV events in the CANVAS trial had 18% reduction in CV death (HR 0.82, 95% CI ) compared to only 2% in those without prior CV events (HR 0.98, 95% CI ). 40% of deaths in the EMPA-REG trial were due to undefined causes, which were assessed as CV deaths. After elimination of these nonassessable deaths from the analysis, the superiority of empagliflozin was abrogated (HR 0.90, 95% CI )

18 The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes were identified. Patients newly prescribed an SGLT-2i or other glucose-lowering drugs (GLDs) were matched based on a propensity score 153,078 patients were included in each group (total 306,156). At baseline, 13% had established CVD. In the SGLT-2i group, 53.2% of patients received canagliflozin, 41.4% received dapagliflozin, and 5.4% empagliflozin.

19 Kosiborod M. et al.: al Journal of the American College of Cardiology (2018) CVD-REAL Data Sources: Health Records Across Six Countries

20 Event Rates in Patients With and Without Cardiovascular Disease Stratified by Treatment With SGLT2 Inhibitors or Other Glucose- Lowering Drugs

21 Cavender, M.A. et al. J Am Coll Cardiol. 2018;71(22): Outcomes in patients with and without cardiovascular disease at baseline

22 Lower Cardiovascular Risk Associated with SGLT-2 inhibitors Kosiborod M. et al.: al Journal of the American College of Cardiology (2018) P-value for SGLT2i vs ogld: <.001

23 Conclusions - CVD Real In > patients with Type 2 diabetes, treatment with SGLT-2 inhibitors versus other oglds was associated with significant reductions in: All-cause death Hospitalization for heart failure Myocardial infarction and stroke Broad population of patients with Type 2 diabetes in general practice, the overwhelming majority (87%) did not have known cardiovascular disease Benefits may extend to those at the lower end of the risk spectrum HHF and death analyses similar to those seen in EMPA-REG OUTCOME The cardiovascular benefits of SGLT-2i may not be specific to a single compound, and may extend to a broader population of patients with T2D than previously considered Kosiborod M. et al.: al Journal of the American College of Cardiology (2018)

24 primary composite outcome (HR, 0.57; 95% CI, ; P < EASEL Circulation 2018

25 Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:

26 Glycated Hemoglobin Levels -0.3% EMPA-Reg NEJM 2015

27 POTENTIAL MECHANISMS TO EXPLAIN CV BENEFIT Glucose Control Hyperglycemia is a weak risk factor for CV disease. Intensive glycemic control failed to decrease CV events in ACCORD, ADVANCE and VADT studies in T2D patients with longstanding diabetes duration. HbA1c reductions of >1% in ACCORD and ADVANCE had no benefit on MACE In UKPDS and VADT it took 10 years to demonstrate a small (- 10%), significant, reduction in CV events

28 Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:

29 EMPA-REG CV OUTCOME Effects on Systolic BP Placebo Empagliflozin 25 mg Empagliflozin 10 mg Placebo 2322 Empagliflozin 10 mg 2322 Empagliflozin 25 mg

30 CANVAS Program - Effects on Systolic BP

31 Baker WL et al J Am Soc Hypertens 2014;8: Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Blood Pressure Diastolic Blood Pressure Systolic Blood Pressure

32 Relationship between Changes in BP and Urinary Na + and Glucose Excretion after 2-week SGLT2 inhibitors Kawasoe et al. BMC Pharmacol Toxicol 2017;18:23-33

33 Relationship between Changes in BP and Urinary Na + and Glucose Excretion after 6-month SGLT2 inhibitors Kawasoe et al. BMC Pharmacol Toxicol 2017;18:23-33

34 Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:

35 Conclusions SGLT2 inhibitors In patients with Type 2 diabetes, treatment with SGLT-2 inhibitors is associated with significant reductions in: All-cause death Hospitalization for heart failure Myocardial infarction and stroke Mechanisms may involve, sodium excretion, lowering of blood pressure,. Efficacy in secondary prevention, but possibly also in primary prevention The cardiovascular benefits of SGLT-2i may not be specific to a single compound, and may extend to a broader population of patients with T2D than previously considered

36 Effect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM Patients Study Year Glucose-lowering drug HR 95% CI P-value PROACTIVE 2005 Pioglitazone ORIGIN 2012 Insulin glargine NS DEVOTE 2017 Insulin degludec NS SAVOR 2013 Saxagliptin NS EXAMINE 2013 Alogliptin NS TECOS 2015 Sitagliptin NS ELIXA 2015 Lixisenatide NS EMPA-REG 2015 Empagliflozin LEADER 2016 Liraglutide SUSTAIN Semaglutide CANVAS 2017 Canagliflozin ,2 *CV mortality, non-fatal MI, non-fatal stroke Favors study drug Favors placebo

37 GLP-1 targets multiple organs to improve glucose control in T2DM

38 Anti-Atherosclerotic potential of GLP-1 action

39 GLP-1R Dependent Intracellular Signal Pathways in the Cardiomyocyte

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41 Effect of GLP-1 RAs on CVD outcome Bethel MA et al Lancet 2018

42 Effect of GLP-1 RAs on CVD outcome Bethel MA et al Lancet 2018

43 LEADER & SUSTAIN 6 Renal Outcomes LEADER - Time to first renal event SUSTAIN-6 - New or Worsening Nephropathy Placebo HR, % CI ( ) p=0.005 Semaglutide Marso SP et al N Engl J Med. 2016;375:311-22; Marso SP et al N Engl J Med. 2016;375:

44 SUSTAIN-6 - Systolic Blood Pressure Overall mean at baseline: mmhg ETD: 2.59* [ 4.09; 1.08] ETD: 1.27 [ 2.77;0.23] Marso SP et al N Engl J Med. 2016;375:

45 Meta-analysis of Change in Systolic (top) and Diastolic Blood Pressure (mmhg) in T2DM Patients Treated with GLP1-Ra Visboll T et al BMJ 2012;344:d7771 doi: /bmj.d7771

46 Effect of 3h GLP-1 infusion on Urine Fluid and Electrolyte Output in Healthy Subjects P= P= P= P= Gutzwiller J-P et al J Clin Endocrinol Metab 2004;89:

47 Possible Mechanisms Regulating Antihypertensive Effect(s) of Incretin-based Diabetes Therapies Lovshin JA, Zinman B Can J Diabetes 38;2014:364e371

48 Glycated Hemoglobin and Body Weight in SUSTAIN 6 Marso SP et al. N Engl J Med 2016.

49 Selective Targeting of GLP-1 Signalling as a Novel Therapeutic Approach for CVD in Diabetes Tate M et al British Journal of Pharmacology 2015;

50 GLP-1 RA e CVD: open questions.. Only the LEADER trial of liraglutide and the SUSTAIN 6 trial of semaglutide met their prespecified criteria for statistical significance. The results of the ELIXA trial of lixisenatide did not show any trend toward cardioprotection, EXSCEL trial of extended-release exenatide represented an apparent near miss with respect to statistical significance Differences in the study design might have contributed to the absence of cardioprotection with lixisenatide. ELIXA was done in the setting of acute coronary syndrome, LEADER, SUSTAIN 6, and EXSCEL were done in chronic settings in relatively stable patients Differences in HbA1c reduction between compunds

51 Magnitude of cardioprotection and HbA1c lowering with GLP-1 receptor agonists Taylor SI. GLP-1 receptor agonists: differentiation within the class. Lancet 2018

52 OBJECTIVE To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis 236 trials randomizing participants The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events,myocardial infarction (MI), unstable angina, and stroke

53 Network Plot for All Studies Zheng SL et al. JAMA April 17, 2018

54 Forest Plots for All-Cause Mortality Zheng SL et al. JAMA April 17, 2018

55 Ranking Plos for All-Cause Mortality Zheng SL et al. JAMA April 17, 2018

56 In conclusione. in prevenzione secondaria SGLT2 inhibitors e GLP-1 analoghi si sono dimostrati efficaci nel ridurre gli eventi CV e la mortalità, e devono essere presi in considerazione nella terapia del diabete. I meccanismi coinvolti sembrano essere sia glicemici che extra-glicemici I risultati dei trials sono quasi tutti in in prevenzione secondaria, ma quelli di real-world sono derivati da pazienti in prevenzione primaria. Risultati estrapolabili su tutti?

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