Update sul danno macrovascolare: fisiopatologia e indicazioni per la prevenzione Marco Giorgio Baroni Department of Experimental Medicine Sapienza University of Rome, Italy
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.).
The Emerging Risk Factors Collaboration JAMA. 2015;314:52-60. Association of Cardiometabolic Multimorbidity With Mortality 2x 2x 2x 2x
Diabetes and Survival, According to Sex and Diabetes Status. 7 Men Non-vascular deaths 7 Women 6 Vascular deaths 6 Years of life lost 5 4 3 2 1 5 4 3 2 1. 0 0 40 50 60 70 80 90 Age (year) 0 0 40 50 60 70 80 90 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;364:829-841.
Hazard Ratios for Major Causes of Death, according to Baseline Levels of Fasting Glucose The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:829-841
Iperglicemia come moltiplicatore.. Svensson et al. Diab Vasc Dis Res 2013;10:520 9. Das et al. Am Heart J 2006;151:1087 93.
All Cause Mortality Intensive vs Standard Glucose Lowering CI: confidence interval; HR: hazard ratio. Ray KK et al Lancet 2009;373:1765 1772.
Major cardiovascular Events Intensive vs Standard Glucose Lowering Turnbull FM et al Diabetologia 2009; 52:2288 2298
*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 0.84 0.72-0.98 0.02 ORIGIN 2012 Insulin glargine 1.02 0.94-1.11 NS DEVOTE 2017 Insulin degludec 0.91 0.78-1.06 NS SAVOR 2013 Saxagliptin 1.00 0.89-1.12 NS EXAMINE 2013 Alogliptin 0.96 0.80-1.15 NS TECOS 2015 Sitagliptin 0.98 0.89-1.08 NS ELIXA 2015 Lixisenatide 1.02 0.89-1.17 NS EMPA-REG 2015 Empagliflozin 0.86 0.74-0.99 0.038 LEADER 2016 Liraglutide 0.87 0.78-0.97 Favors study drug Favors placebo 0.01 SUSTAIN-6 2016 Semaglutide 0.74 0.58-0.95 0.02 CANVAS 2017 Canagliflozin 0.86 0.75-0.97 0.6 1 1,2
Turner RC et al BMJ 1999;316:823-828 UKPS 23: Risk Factors for CHD HbA1c (%) Age (yrs) Estimated HR Systolic BP (mmhg) LDL-cholesterol mmol/l) Estimated HR Estimated HR Estimated HR
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 0.84 0.72-0.98 0.02 ORIGIN 2012 Insulin glargine 1.02 0.94-1.11 NS DEVOTE 2017 Insulin degludec 0.91 0.78-1.06 NS SAVOR 2013 Saxagliptin 1.00 0.89-1.12 NS EXAMINE 2013 Alogliptin 0.96 0.80-1.15 NS TECOS 2015 Sitagliptin 0.98 0.89-1.08 NS ELIXA 2015 Lixisenatide 1.02 0.89-1.17 NS EMPA-REG 2015 Empagliflozin 0.86 0.74-0.99 0.038 *CV mortality, non-fatalmi, non-fatalstroke 0.6 1 1,2 Favors placebo Favors study drug
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
EMPA-REG CV OUTCOME Main Results Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Favours empagliflozin Favours placebo Zinman B et al N Engl J Med 2015;373:2117-28
EMPA-REG Outcomes Incident or Worsening Nephropathy Wanner C et al N Engl J Med 2016;375:323-34
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
Key Outcomes in the CANVAS Program and EMPA-REG OUTCOME Zinman Bet al. N Engl J Med. 2015;373:2117-2128; Wanner K et al. N Engl J Med. 2016;375:323-334; Neal B et al N Engl J Med. 2017 DOI: 10.1056/NEJMoa1611925
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 0.72 0.95) compared to only 2% in those without prior CV events (HR 0.98, 95% CI0.74 1.30). 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 0.77 1.06)
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.
Kosiborod M. et al.: al Journal of the American College of Cardiology (2018) CVD-REAL Data Sources: Health Records Across Six Countries
Event Rates in Patients With and Without Cardiovascular Disease Stratified by Treatment With SGLT2 Inhibitors or Other Glucose- Lowering Drugs
Cavender, M.A. et al. J Am Coll Cardiol. 2018;71(22):2497 506 Outcomes in patients with and without cardiovascular disease at baseline
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
Conclusions - CVD Real In >300.000 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)
primary composite outcome (HR, 0.57; 95% CI, 0.50 0.65; P <0.0001 EASEL Circulation 2018
Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:717 725
Glycated Hemoglobin Levels -0.3% EMPA-Reg NEJM 2015
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
Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:717 725
EMPA-REG CV OUTCOME Effects on Systolic BP Placebo Empagliflozin 25 mg Empagliflozin 10 mg 0 16 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Placebo 2322 Empagliflozin 10 mg 2322 Empagliflozin 25 mg 2323 2235 2250 2247 2203 2161 2235 2193 2221 2197 2133 2174 2169 2073 2125 2129 2024 2095 2102 1974 2072 2066 1771 1853 1878 1492 1556 1571 1274 1327 1351 1126 1189 1212 981 1034 1070 735 790 842 450 518 528 171 199 216
CANVAS Program - Effects on Systolic BP
Baker WL et al J Am Soc Hypertens 2014;8:262 275 Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Blood Pressure Diastolic Blood Pressure Systolic Blood Pressure
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
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
Possible Mechanisms Accounting for EMPA-REG OUTCOME Results Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA et al Diabetes Care 2016;39:717 725
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
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 0.84 0.72-0.98 0.02 ORIGIN 2012 Insulin glargine 1.02 0.94-1.11 NS DEVOTE 2017 Insulin degludec 0.91 0.78-1.06 NS SAVOR 2013 Saxagliptin 1.00 0.89-1.12 NS EXAMINE 2013 Alogliptin 0.96 0.80-1.15 NS TECOS 2015 Sitagliptin 0.98 0.89-1.08 NS ELIXA 2015 Lixisenatide 1.02 0.89-1.17 NS EMPA-REG 2015 Empagliflozin 0.86 0.74-0.99 0.038 LEADER 2016 Liraglutide 0.87 0.78-0.97 0.01 SUSTAIN-6 2016 Semaglutide 0.74 0.58-0.95 0.02 CANVAS 2017 Canagliflozin 0.86 0.75-0.97 0.6 1 1,2 *CV mortality, non-fatal MI, non-fatal stroke Favors study drug Favors placebo
GLP-1 targets multiple organs to improve glucose control in T2DM
Anti-Atherosclerotic potential of GLP-1 action
GLP-1R Dependent Intracellular Signal Pathways in the Cardiomyocyte
Effect of GLP-1 RAs on CVD outcome Bethel MA et al Lancet 2018
Effect of GLP-1 RAs on CVD outcome Bethel MA et al Lancet 2018
LEADER & SUSTAIN 6 Renal Outcomes LEADER - Time to first renal event SUSTAIN-6 - New or Worsening Nephropathy Placebo HR, 0.64 95% CI (0.46 0.88) 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;375:1834-1844.
SUSTAIN-6 - Systolic Blood Pressure Overall mean at baseline: 135.6 mmhg ETD: 2.59* [ 4.09; 1.08] 0 104 ETD: 1.27 [ 2.77;0.23] Marso SP et al N Engl J Med. 2016;375:1834-1844.
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: 10.1136/bmj.d7771
Effect of 3h GLP-1 infusion on Urine Fluid and Electrolyte Output in Healthy Subjects P=0.0009 P=0.2595 P=0.0013 P=0.0004 Gutzwiller J-P et al J Clin Endocrinol Metab 2004;89:3055 3061
Possible Mechanisms Regulating Antihypertensive Effect(s) of Incretin-based Diabetes Therapies Lovshin JA, Zinman B Can J Diabetes 38;2014:364e371
Glycated Hemoglobin and Body Weight in SUSTAIN 6 Marso SP et al. N Engl J Med 2016.
Selective Targeting of GLP-1 Signalling as a Novel Therapeutic Approach for CVD in Diabetes Tate M et al British Journal of Pharmacology 2015;172 721 736 721
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
Magnitude of cardioprotection and HbA1c lowering with GLP-1 receptor agonists Taylor SI. GLP-1 receptor agonists: differentiation within the class. Lancet 2018
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 176 310 participants The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events,myocardial infarction (MI), unstable angina, and stroke
Network Plot for All Studies Zheng SL et al. JAMA April 17, 2018
Forest Plots for All-Cause Mortality Zheng SL et al. JAMA April 17, 2018
Ranking Plos for All-Cause Mortality Zheng SL et al. JAMA April 17, 2018
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?