cardiovasculaire risico- interventie bij T2DM? Cees J. Tack, - PowerPoint PPT Presentation

SGLT-2 inhibitie: cardiovasculaire risico- interventie bij T2DM? Cees J. Tack, internist

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

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

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)

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

Glucose Transport in Tubular Epithelial Cells Lumen Blood K GLUT2 SGLT2 High Capacity Low Affinity G ATPase Na + S1 Proximal Tubule Lumen Blood Glucose G 2K GLUT1 SGLT1 Low Sodium Na + Capacity High Affinity G ATPase Potassium K 2Na S3 Proximal Tubule + Adapted from Bakris GL et al. Kidney Int 2009;75:1272-7 Marsenic O. Am J Kidney Dis. 2009;53:875-83

SGLT-2i lower glucose Cefalu WT ea. Lancet 2013; 382:941-50.

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

Meta-analysis: Modest reduction in major cardiovascular events with  glycaemia • *Difference between more intensive and less intensive groups Annual event rate, % • Δ HbA 1c CI, confidence interval; HbA1c, glycosylated haemoglobin Trials (%) Favours More Less • Turnbull FM et al. Diabetologia 2009;52:2288 – 2298 Favours more less intensive intensive intensive intensive Major cardiac events 1 ACCORD 1 2.11 2.29 – 1.01 ADVANCE 2 2.15 2.28 – 0.72 UKPDS 3 1.30 1.60 – 0.66 VADT 4 2.68 2.98 – 1.16 Overall number 1194 1176 – 0.88 of events, n 0.5 1.0 2.0 Hazard ratio (95% CI) CI, confidence interval; HbA 1c , glycosylated haemoglobin Turnbull et al. Diabetologia 2009;52:2288 – 2298

Een nieuwe trend: cardiovasculaire veiligheid

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

Recent and ongoing CVOTs 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Class of drug of interest being evaluated: SAVOR-TIMI 53 (saxagliptin) EXAMINE (Alogliptin) ELIXA (Lixisenatide) DPP-4i TECOS (Sitagliptin) GLP-1RA EMPA-REG OUTCOME (Empagliflozin) SGLT-2i LEADER (Liraglutide) Basal insulin FREEDOM CVO (ITCA Q 6 months) 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)

EMPA-REG OUTCOME Time to first occurrence of CV death, non-fatal MI † , or non-fatal stroke Study design and inclusion criteria 20 EMPA 25 mg once daily HR: 0.86 95.02% CI: 0.74 – 0.99 Placebo EMPA 10 mg once daily Patients with event (%) p =0.04 for superiority 15 Placebo once daily Follow- +30 Screening Placebo Treatment period up run-in Median duration: 2.6 years days 10 Median observation time: End of Randomisation 3.1 years treatment (1:1:1) N=7028 Empagliflozin • T2DM with established CV disease 5 • Age: ≥ 18 years; ≥ 20 years in Japan; ≤ 65 years in India Placebo • 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 2 0 0 6 12 18 24 30 36 42 48 Month Primary endpoint Patients at risk • Three-point MACE – time to first occurrence of: • CV death, non-fatal MI † , or non-fatal stroke Empagliflo 4687 4580 4455 4328 3851 2821 2359 1534 370 Placebo 2333 2256 2194 2112 1875 1380 1161 741 166

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

CANVAS Program: Primary outcome Death from CV causes, non-fatal MI or non-fatal stroke 20 100 HR: 0.86 18 95% CI: (0.75 – 0.97) 90 16 Canagliflozin (100 or p <0.001 for non- Patients with an event (%) 14 inferiority 300 mg/day) + 80 T2DM; HbA 1c 7.0 – 10.5%; p =0.02 for superiority standard of care 12 ≥ 30 years + CVD*; ≥ 55 70 10 (men) or ≥ 50 years + 8 high risk of CVD † Placebo 60 Canagliflozin (n=4,330) Placebo + standard of 6 50 care 4 2 40 0 30 26 78 0 52 130 182 234 286 338 156 260 312 104 208 20 10 0 0 26 52 78 104 130 156 182 208 234 260 286 312 338 Weeks since randomisation No. of patients Placebo 4347 4239 4153 4061 2942 1626 1240 1217 1187 1156 1120 1095 789 216 Canagliflozi 5795 5672 5566 5447 4343 2984 2555 2513 2460 2419 2363 2311 1661 448 n 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; 37 7 :644 – 657

SGLT-2i CVOTs Time to first occurrence of CV death, non-fatal MI*, or non-fatal stroke EMPA-REG OUTCOME 1 CANVAS Program 2 20 20 HR: 0.86 HR: 0.86 18 (95% CI: 0.75 ; 0.97) (95.02% CI: 0.74 ; 0.99) p <0.001 for non-inferiority p =0.04 for superiority Patients with event (%) 16 p =0.02 for superiority 15 Patients with event (%) 14 12 10 10 8 Empagliflozin 6 Canagliflozin 5 4 Placebo Placebo 2 0 0 0 6 12 18 24 30 36 42 48 0 130 156 26 52 78 104 182 208 234 260 286 312 338 Months since randomisation Weeks since randomisation No. at risk Cana 5795 5672 5566 5447 4343 2984 2555 2513 2460 2419 2363 2311 1661 448 Empa 4687 4580 4455 4328 3851 2821 2359 1534 370 PBO PBO 2333 2256 2194 2112 1875 1380 1161 741 166 4347 4239 4153 4061 2942 1626 1240 1217 1187 1156 1120 1095 789 216

SGLT-2 inhibitors: Decrease in glomerular hyperfiltration Heerspink H et al. Circulation 2016;134:752 – 772

SGLT-2 inhibitors: Decrease in glomerular hyperfiltration Heerspink H et al. Circulation 2016;134:752 – 772

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

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