Il razionale delle associazioni terapeutiche sulla protezione cardiovascolare

Transcription

1 Il razionale delle associazioni terapeutiche sulla protezione cardiovascolare Alessandra Dei Cas UOC di Endocrinologia e Malattie del Metabolismo Dipartimento di Medicina e Chirurgia Università di Parma

2 La Dr.ssa Alessandra Dei Cas dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: - Boehringher - Elly Lilly Italia - Sanofi - Novonordisk - MSD - Doc Generici

3 Agenda Razionale fisiopatologico (compatibilità e complementarietà di meccanismo di azione) Razionale treat to target Razionale treat to benefit

4 The ominous octet

5 Site of action of glucose lowering agents

6 Absolute mortality rates in the Emerging Risk Factors Collaboration Study (n=689300, FU: 12.8 yrs; confirmed in the UK Biobank n=499808) Mortality Rate (per 1000 person-years) EMPAREG 30 DEVOTE ORIGIN ELIXA 20 CANVAS 10 0 None Diabetes Stroke MI Diabetes and MI Diabetes and Stroke Stroke and MI Diabetes, Stroke and MI The Emerging Risk Factors Collaboration, JAMA 2015

7 The RIACE Study: consecutive patients with diabetes from 19 Outpatient Diabetes Clinics in Italy, years Prevalence of any CVD in patients attending Outpatient Diabetes Clinics N= 15,773 In Any CVD 23% No CVD 77% Pugliese G et al.; Cardiovasc Diabetol 2014

8 ADA Standards of Medical Care in Diabetes 2018

9 Agenda Razionale fisiopatologico (compatibilità di meccanismo di azione) Razionale treat to target Razionale treat to benefit

10 Glucose-lowering therapy options

11 Guardiamo all efficacia Standard di cura SID-AMD 2016

12 Effetti collaterali dei farmaci anti-diabetici Standard di cura SID-AMD 2016

13 Actions and potential side effects of GLP-1RA and SGLT2i

14 Agenda Razionale fisiopatologico (compatibilità di meccanismo di azione) Razionale treat to target Razionale treat to benefit

15 ADA Standards of Medical Care in Diabetes 2018

16 CVOT trials and CV outcomes

17 Primary outcome reduction in the EMPAREGoutcome and CANVAS program Median FU= 3.1 yrs - 14% Median FU= 2.4 yrs - 14% NNT= 154/year NNT= 217/year

18 Weighted means of HRs in Denmark, Norway and Sweden for new users of dapagliflozin vs new DDP-4i (PS 1:3 matched for age, gender, fraility, comorbidity and treatment) Lancet Diabetes Endocrinol. 2017;5(9):

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20 Summary of design and outcomes of ELIXA, LEADER, SUSTAIN-6 and EXSCEL trials LEADER MACE NNT= 200/year SUSTAIN-6 MACE NNT=83/year

21 A classification of GLP-1 RAs Comparison of prandial vs. non-prandial GLP-1 receptor agonists Parameters Prandial GLP-1 Ras (short-acting, exendin-4 derived) Non-prandial GLP-1 Ras (long-acting, mostly GLP-1 derived*) Compounds Exenatide, Lixisenatide Exenatide-LAR, Liraglutide*, Albi*-, Dula-*, Taspo*-, Sema*-glutide Half-life 2-5h 12h-several days Effects Fasting blood glucose levels Modest reduction Strong reduction Post-prandial glucose levels Strong reduction Modest reduction Fasting insulin secretion Modest stimulation Strong stimulation Post-prandial insulin secretion Reduction Modest stimulation Glucagon secretion Reduction Reduction Gastric emptying rate Deceleration No effect Blood pressure Reduction Reduction Heart rate No effect or small increase (0-2 bpm) Moderate increase (2-5 bpm) Body weight reduction 1-5kg 2-5kg Induction of nausea 20-50%, attenuates slowly (weeksmany months) 20-40%, attenuates quickly (~4-8 weeks) Meier J et al.; Nat Rev Endocrinol 2012 (modified)

22 Severe Hypoglycemia and Glucose Control in the DEVOTE trial 00-6 am - 40% - 37% (NNT 40) N Engl J Med Aug 24;377(8):

23 Association between day-to-day fasting glycaemic variability and outcomes (DEVOTE-2) Severe hypoglycaemia Hazard ratio [95% CI] p-value Unadjusted 4.11 [3.15; 5.35] < Adjusted for HbA 1c 4.15 [3.17; 5.44] < Adjusted for HbA 1c and BC 3.37 [2.52; 4.50] < MACE Unadjusted 1.36 [1.12; 1.65] Adjusted for HbA 1c 1.30 [1.06; 1.58] Adjusted for HbA 1c and BC 1.21 [0.98; 1.49] All-cause mortality Unadjusted 1.58 [1.23; 2.03] Adjusted for HbA 1c 1.53 [1.19; 1.98] Adjusted for HbA 1c and BC 1.33 [1.01; 1.75] ,5 1,0 2,0 4,0 8,0 Hazard ratio [95% CI] Variability is reported on a continuous scale Adjusted for HbA 1c : most recent HbA 1c on a continuous scale. Adjusted for HbA 1c and BC: most recent HbA 1c on a continuous scale and BC (investigational product, sex, region, age at baseline, smoking status at baseline, diabetes duration at baseline, cardiovascular risk-group inclusion criteria, insulin-naïve at baseline and renal function [egfr] at baseline). BC, baseline characteristics Zinman et al. Diabetologia 2017

24 Prossime associazioni precostituite. SGLT2i+DPP4i saxagliptin and dapagliflozin 2.5/5 or 5/10 mg linagliptin 5 mg and empagliflozin 10 or 25 mg GLP-1 RA+insulin basale IDegLira (degludec 300U+Lira 10.8) iglarlixi (glargine 100 e lixisenatide rapporto 2:1 o 3:1) DPP4i+Pioglitazone pioglitazone and DPP-4 inhibitors

25 Conclusions The use of drug combinations is mandatory to target DM pathophysiological mechanisms Combining therapies offers opportunities to enhance efficacy (HbA1C, weight, blood pressure) and diminish side effects Cardiovascular safety of drug combination should refert to that of the single monocomponent

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27 Efficacy in HbA1C reduction in patients receiving empagliflozin and linagliptin or dapagliflozin and saxagliptin as add-on therapy * At 52 weeks Postgraduate Medicine 2017;129:

28 Body changs in patients receiving empagliflozinand linagliptin or dapagliflozin and saxagliptin as add-on therapy Postgraduate Medicine 2017;129:

29 IDegLira in subjects uncontrolled on basal insulin Summary of key clinical findings from DUAL II, V and VII End-of-treatment HbA 1c (%) Change in HbA 1c (%) DUAL II 8.7 DUAL V 8.4 DUAL VII 8.2 DUAL II DUAL V DUAL VII Basal insulin switch Basal insulin switch 1.5 Change in body weight (kg) Hypoglycaemia (events/subject-year) DUAL II DUAL V DUAL VII DUAL II DUAL V DUAL VII Basal insulin switch Basal insulin switch IDegLira, insulin degludec/liraglutide Buse et al. Diabetes Care 2014;37: ; Lingvay et al. JAMA 2016;315: ; Billings et al. ADA 2017;136-OR

30 Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial LS mean change (%) 0,0-0,2 Riduzione HbA1c , ,6-0,8-1, , % CI: 0.6, 0.4 p< iglarlixi iglar 0.7 iglarlixi iglar At week 30 Aroda VR, et al. Diabetes Care 2016

31 A treatment algorithm based on cardiac and renal comorbidities and CVOTs.

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