Update sul danno macrovascolare: fisiopatologia e

indicazioni per la prevenzione

Marco Giorgio BaroniDepartment of ExperimentalMedicine Sapienza University of Rome, Italy

Il sottoscritto Marco Giorgio Baroni

dichiara di aver ricevuto negli ultimi due anni compensio finanziamenti dalle seguenti Aziende Farmaceutichee/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.).

Association of Cardiometabolic Multimorbidity With Mortality

The Emerging Risk Factors Collaboration JAMA. 2015;314:52-60.

2x

2x2x

2x

The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:829-841.

Diabetes and Survival, According to Sex and Diabetes Status.

.

0

7

6

5

4

3

2

1

040 50 60 70 80 90

Age (year)

Year

s of

life

lost

Men7

6

5

4

3

2

1

040 50 60 70 80 900

Age (year)

WomenNon-vascular deathsVascular deaths

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

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.

Ray KK et al Lancet 2009;373:1765–1772.

All Cause MortalityIntensive vs Standard Glucose Lowering

CI: confidence interval; HR: hazard ratio.

Major cardiovascular EventsIntensive vs Standard Glucose Lowering

Turnbull FM et al Diabetologia 2009; 52:2288–2298

Effect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM Patients

Study Year Glucose-loweringdrug 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

*CV mortality, non-fatal MI, non-fatal stroke

0.6 1 1,2Favors placeboFavors study drug

Age (yrs)

LDL-cholesterol mmol/l)Systolic BP (mmHg)

UKPS 23: Risk Factors for CHD

Turner RC et al BMJ 1999;316:823-828

HbA1c (%)

Estim

ated

HREs

timat

edHR

Estim

ated

HREs

timat

edHR

Chart1

120

130

140

150

160

Valore Y 1

1

1.6

1.85

Foglio1

Valori di XValore Y 1

1201

1301.6

140

150

1601.85

160Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

170

Chart1

6

7

8

9

Valore Y 1

1

1.5

1.55

Foglio1

Valori di XValore Y 1

61

71.5

8

91.55

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Chart1

45

50

55

60

65

Valore Y 1

1

1.8

1.9

2.4

Foglio1

Valori di XValore Y 1

451

50

551.8

601.9

652.4

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Chart1

3

3.5

4

4.5

Valore Y 1

1

1.5

2.3

Foglio1

Valori di XValore Y 1

31

3.51.5

4

4.52.3

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Effect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM Patients

Study Year Glucose-loweringdrug 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

0.6 1 1,2*CV mortality, non-fatal MI, non-fatal stroke Favors study drug

Favors placebo

SGLT2

SGLT1

SGLT2 inhibitors reduce glucose

reabsorption at the proximal tubule

causing glycosuria and osmotic

diuresis

Filtered glucose load > 180 g/die

Potential of SGLT2 Inhibition

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

00%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

00%

Patients with event/analysedEmpagliflozin 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)

EMPA-REG OutcomesIncident or Worsening Nephropathy

Wanner C et al N Engl J Med 2016;375:323-34

CANVAS - Primary MACE Outcome: CV Death, NonfatalMyocardial 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 Programand 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 ‘‘non-

assessable’’ 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.

CVD-REALData Sources: Health Records Across SixCountries

Kosiborod M. et al.: al Journal of the American College of Cardiology (2018)

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

Outcomes in patients with and without cardiovascular disease at baseline

Cavender, M.A. et al. J Am Coll Cardiol. 2018;71(22):2497–506

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:

Conclusions - CVD Real • In >300.000 patients with Type 2 diabetes, treatment with SGLT-2

inhibitors versus other oGLDs was associated with significantreductions 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 cardiovasculardisease• 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 thanpreviously considered

Kosiborod M. et al.: al Journal of the American College of Cardiology (2018)

EASEL Circulation 2018

primary composite outcome

(HR, 0.57; 95% CI, 0.50–0.65; P

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 long-standing 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

232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

Placebo

Empagliflozin 10 mgEmpagliflozin 25 mg

16 28 52 94 10880 12266 1360 150 164 178 192 20640

CANVAS Program - Effects on Systolic BP

Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Blood Pressure

Syst

olic

Blo

od P

ress

ure

Dia

stol

ic B

lood

Pre

ssur

e

Baker WL et al J Am Soc Hypertens 2014;8:262–275

Relationship between Changes in BP and Urinary Na+ and GlucoseExcretion after 2-week SGLT2 inhibitors

Kawasoe et al. BMC Pharmacol Toxicol 2017;18:23-33

Relationship between Changes in BP and Urinary Na+ and GlucoseExcretion 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-loweringdrug 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 glucosecontrol 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

SUSTAIN-6 - New or Worsening Nephropathy

LEADER - Time to first renal event

Placebo

Semaglutide

HR, 0.6495% CI (0.46−0.88)

p=0.005

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

0

Overall mean at baseline: 135.6 mmHg

104

ETD: –2.59*[–4.09;–1.08]

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 ElectrolyteOutput in Healthy Subjects

P=0.0009

P=0.0013 P=0.0004

P=0.2595

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 NovelTherapeutic 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 relativelystable patients

• Differences in HbA1c reduction between compunds

Magnitude of cardioprotection and HbA1c loweringwith 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?

Diapositiva numero 1Diapositiva numero 2Association of Cardiometabolic Multimorbidity With MortalityThe 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 GlucoseIperglicemia come moltiplicatore…..All Cause Mortality�Intensive vs Standard Glucose Lowering Major cardiovascular Events�Intensive vs Standard Glucose Lowering Effect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM PatientsUKPS 23: Risk Factors for CHDEffect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM PatientsPotential of SGLT2 InhibitionEMPA-REG CV OUTCOME – Main ResultsEMPA-REG Outcomes�Incident or Worsening NephropathyCANVAS - Primary MACE Outcome: CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke Key Outcomes in the CANVAS Program�and EMPA-REG OUTCOME SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS TrialsDiapositiva numero 18�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 DrugsOutcomes in patients with and without cardiovascular disease at baselineLower Cardiovascular Risk Associated with SGLT-2 inhibitorsConclusions - CVD Real Diapositiva numero 24Possible Mechanisms Accounting for EMPA-REG OUTCOME ResultsGlycated Hemoglobin LevelsPOTENTIAL MECHANISMS TO EXPLAIN CV BENEFIT��Glucose ControlPossible Mechanisms Accounting for EMPA-REG OUTCOME ResultsEMPA-REG CV OUTCOME – Effects on Systolic BPCANVAS Program - Effects on Systolic BP Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Blood PressureRelationship between Changes in BP and Urinary Na+ and Glucose Excretion after 2-week SGLT2 inhibitorsRelationship between Changes in BP and Urinary Na+ and Glucose Excretion after 6-month SGLT2 inhibitorsPossible Mechanisms Accounting for EMPA-REG OUTCOME ResultsConclusions – SGLT2 inhibitorsEffect of Glucose-Lowering Drugs on 3-Point MACE* in T2DM PatientsGLP-1 targets multiple organs to improve glucose control in T2DM�Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40Diapositiva numero 41Diapositiva numero 42LEADER & SUSTAIN 6 – Renal OutcomesSUSTAIN-6 - Systolic Blood PressureDiapositiva numero 45Effect of 3h GLP-1 infusion on Urine Fluid and Electrolyte Output in Healthy SubjectsPossible Mechanisms Regulating Antihypertensive Effect(s) of Incretin-based Diabetes TherapiesGlycated Hemoglobin and Body Weight in SUSTAIN 6Selective Targeting of GLP-1 Signalling as a Novel Therapeutic Approach for CVD in DiabetesGLP-1 RA e CVD: open questions…..Magnitude of cardioprotection and HbA1c lowering with GLP-1 receptor agonistsDiapositiva numero 52Network Plot for All StudiesForest Plots for All-Cause MortalityRanking Plos for All-Cause MortalityIn conclusione….Diapositiva numero 57