SGLT-2 inhibitie: cardiovasculaire risicointerventie. Cees J. Tack, internist

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1 SGLT-2 inhibitie: cardiovasculaire risicointerventie bij T2DM? Cees J. Tack, internist

2 Conflict of interest (potentiële) belangenverstrengeling zie hieronder Voor bijeenkomst mogelijk relevante relaties met bedrijven Onderzoeksondersteuning (grants): AstraZeneca Voordrachten / deelname adviesraad: MSD NovoNordisk

3 Doelen Twee nieuwe klassen: hier - SGLT-2 inhibitors Nieuwste studieresultaten Effect op CV risico Implicaties voor de interne geneeskunde / richtlijnen

4 Rol van de nieren in het glucosemetabolisme 180 g glucose dagelijks gefiltreerd Vrijwel alle glucose wordt in de proximale tubulus gereabsorbeerd door SGLT2 (~90%) en SGLT1 (~10%) Nierdrempel ~10 mmol/l (DM2: hoger)

5 Glucose Reabsorption in a Nondiabetic Person (Plasma Glucose <10 mmol/l ) Glomerulus Proximal Convoluted Tubule Early Distal Urine Glucose reabsorption into tissue Glucose SGLT2 SGLT1 Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose linked co-transporter. Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

6 Glucose Transport in Tubular Epithelial Cells Lumen Blood G SGLT2 High Capacity Low Affinity GLUT2 ATPase K Na + S1 Proximal Tubule G Na + K Glucose Sodium Potassium Lumen G 2Na + SGLT1 Low Capacity High Affinity S3 Proximal Tubule GLUT1 ATPase Blood 2K Adapted from Bakris GL et al. Kidney Int 2009;75: Marsenic O. Am J Kidney Dis. 2009;53:875-83

7 SGLT-2i lower glucose Cefalu WT ea. Lancet 2013; 382:

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9 How do we modify CV risk in T2DM? Glycaemic control Lifestyle modification Multifactorial Approach Platelet inhibition Management of dyslipidaemia Blood pressure control

10 Meta-analysis: Modest reduction in major cardiovascular events with glycaemia *Difference between more intensive and less intensive groups CI, confidence interval; HbA1c, glycosylated haemoglobin Trials Annual event rate, % More intensive Less intensive ΔHbA 1c (%) Turnbull FM et al. Diabetologia 2009;52: Favours more intensive Favours less intensive Major cardiac events 1 ACCORD ADVANCE UKPDS VADT Overall number of events, n Hazard ratio (95% CI) CI, confidence interval; HbA 1c, glycosylated haemoglobin Turnbull et al. Diabetologia 2009;52:

11 Een nieuwe trend: cardiovasculaire veiligheid

12 Cardiovascular outcomes trials Efficacy vs safety; superiority vs non-inferiority Efficacy trials Aim: Demonstrate CV benefit Initiation of treatment vs comparator Safety trials Aim: Demonstrate CV safety Initiation of treatment vs placebo No treatment adjustment Maintain similar HbA 1c in treatment arms Treatment adjustment (standard of care) Difference between treatment arms e.g. biomarkers such as HbA 1c or lipids Small/no difference in biomarkers e.g. HbA 1c observed between treatment arms Significant reduction in CV outcomes vs active comparator Lower CV risk vs placebo/active comparator Non-inferiority vs placebo No unacceptable increase in CV risk vs placebo as part of standard care

13 Recent and ongoing CVOTs SAVOR-TIMI 53 (saxagliptin) Class of drug of interest being evaluated: EXAMINE (Alogliptin) ELIXA (Lixisenatide) TECOS (Sitagliptin) EMPA-REG OUTCOME (Empagliflozin) LEADER (Liraglutide) FREEDOM CVO (ITCA Q 6 months) DPP-4i GLP-1RA SGLT-2i Basal insulin SUSTAIN 6 (Semaglutide) CANVAS-R (Canagliflozin) CARMELINA (Linagliptin) EXSCEL (Exenatide QW) CANVAS (Canagliflozin) CAROLINA (Linagliptin) DEVOTE (Degludec) REWIND (Dulaglutide QW) DECLARE-TIMI 58 (Dapagliflozin) CREDENCE (Canagliflozin) VERTIS CV (Ertugliflozin) HARMONY outcomes (Albiglutide QW)

14 Patients with event (%) EMPA-REG OUTCOME Study design and inclusion criteria EMPA 25 mg once daily Placebo EMPA 10 mg once daily Placebo once daily Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke HR: % CI: p=0.04 for superiority Screening Placebo run-in Randomisation (1:1:1) Treatment period Median duration: 2.6 years Median observation time: 3.1 years End of treatment Followup +30 days 10 N=7028 T2DM with established CV disease Age: 18 years; 20 years in Japan; 65 years in India Drug-naïve and HbA 1c 7.0 to 9.0% or stable background antidiabetes therapy* and HbA 1c 7.0 to 10.0% BMI 45.0 kg/m 2 and egfr 30 ml/min/1.73m Empagliflozin Placebo Primary endpoint Three-point MACE time to first occurrence of: CV death, non-fatal MI, or non-fatal stroke Patients at risk Month Empagliflo Placebo

15 CV death HR 0.62 (95% CI 0.49, 0.77) p<0.0001

16 Patients with an event (%) CANVAS Program: Primary outcome Death from CV causes, non-fatal MI or non-fatal stroke No. of patients HR: % CI: ( ) p<0.001 for noninferiority T2DM; p=0.02 HbA for 1c superiority %; 30 years + CVD*; 55 (men) or 50 years + high risk of CVD (n=4,330) Canagliflozin (100 or 300 mg/day) + standard of care Placebo + standard of care Placebo Canagliflozi n Weeks since randomisation Placebo Canagliflozin HR and 95% CI were estimated with the use of Cox regression models with stratification according to trial and history of CV disease for all canagliflozin groups combined versus placebo. Analyses are based upon the full integrated data set comprising all participants who underwent randomisation CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; T2DM, type 2 diabetes mellitus Neal B et al. N Engl J Med 2017;377:

17 Patients with event (%) Patients with event (%) SGLT-2i CVOTs Time to first occurrence of CV death, non-fatal MI*, or non-fatal stroke EMPA-REG OUTCOME 1 CANVAS Program HR: 0.86 (95.02% CI: 0.74 ; 0.99) p=0.04 for superiority HR: 0.86 (95% CI: 0.75 ; 0.97) p<0.001 for non-inferiority p=0.02 for superiority Empagliflozin Placebo 6 4 Canagliflozin Placebo Months since randomisation Weeks since randomisation No. at risk Empa Cana PBO PBO

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19 SGLT-2 inhibitors: Decrease in glomerular hyperfiltration Heerspink H et al. Circulation 2016;134:

20 SGLT-2 inhibitors: Decrease in glomerular hyperfiltration Heerspink H et al. Circulation 2016;134:

21 Doelen Twee nieuwe klassen: hier - SGLT-2 inhibitors Nieuwste studieresultaten Effect op CV risico Implicaties voor de interne geneeskunde / richtlijnen

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25 Klinische implicaties SGLT-2 remmers (m.n. empagliflozin), glucoseverlagers met CV-bonus Bijwerkingen: (uro)genitale infectie, keto-acidose, distale amputaties, skelet?, theor: dehydratie Internationale richtlijnen: voorkeur bij patiënten met cardiovasculaire ziekte (renaal?) Patiënten zonder diabetes? NHG standaard wordt herzien (zeer) beperkte plaats nadruk op veiligheid Leidraad voor internisten combinatie met insuline te overwegen

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