DECLARE One Year On John Wilding Obesity & Endocrinology Clinical Research University of Liverpool & Aintree University Hospital Liverpool, UK
Outline • SGLT2 inhibitors for diabetes treatment • Cardiovascular & heart failure risk in diabetes • DECLARE TIMI-58 – reminder of key results • DECLARE – outcomes in patients with prior MI and prior heart failure • DECLARE – renal outcomes • DECLARE – efficacy and safety in older patients • DAPA-HF – CV outcomes in heart failure with and without diabetes
Expected clinical effects of SGLT2 inhibition based on the mode of action HbA 1c reduction Reduced glycaemia Increased glucose excretion Loss of energy Weight loss (calories) Increased sodium Blood pressure Reduced sodium excretion reduction load HbA 1c , glycated haemoglobin; SGLT2, sodium – glucose co-transporter 2 Adapted from: Abdul-Ghani MA, et al. Endocr Rev. 2011;32:515 – 31.
Is Isch chaemic heart dis isease is is th the le leading cause of f ith T2D 1 mortality in in patients with Ischaemic heart Non-cardiovascular 40% 35% disease causes 10% 15% Other heart disease Stroke (predominantly congestive) 1. Low Wang CC et al. Circulation 2016;133:2459 – 502
T2 T2D in increases th the ris risk of f developing heart failu ilure Survival outcomes in 2 – 3 fold increased risk patients with diabetes and of heart failure vs patients HF are worse than those for without T2D 1 patients with heart failure and no diabetes 4,5 68% of patients with T2D had Over half of all patients with evidence of left ventricle heart failure may have ~29% of all patients with dysfunction 5 years moderate to severe chronic heart failure also have T2D 5 after diagnosis 2 kidney disease 3 1. Nichols GA et al. Diabetes Care 2004;27:1879 – 84; 2. Faden G et al. Diabetes Res Clin Pract 2013;101:309 – 16; 3. Ahmed A et al. Heart fail clin 2008;4:387-399; 4. Cubbon RM et al. Diab Vasc Dis Res 2013;10:330; 5. MacDonald MR et al. Eur Heart J 2008;29:1377
SGLT2i outcome trials in T2DM Trial Name (SGLT-2 Inhibitor) Target Enrollment Timing EMPA-REG N=7000 OUTCOME Began 2010; reported Sept 2015 All prior CVD (empagliflozin) CANVAS N=5700 (canagliflozin) Began 2009; reported June 2017 Began 2013; reported June 2017 CANVAS-R N=4330 (canagliflozin) 66% prior CVD DECLARE N=17,160 Began 2013; reported Nov 2018 (dapagliflozin) 41% prior CVD CREDENCE N=3700 (canagliflozin) Began 2014; Reported April 2019 VERTIS N=8000 Began 2013- ending 2019 (ertugliflozin)
DECLARE-TIMI 58 Study Design Study design 17,160 patients T2DM double-blind 6.5%≤ HbA 1c <12%, Dapagliflozin 10 mg daily 1:1 CrCl ≥60 ml/min, ≥55 yrs (m) or ≥60 yrs (f) Placebo daily with ≥1 CV risk factor All other glucose-lowering agents per treating OR ≥40 yrs with eASCVD physician Event- driven duration: ≥1390 MACE S Single-blind PBO run-in R (1 – 2 months) Median follow-up: 4.2 years Primary safety endpoint Secondary endpoints • Composite of CV death, nonfatal MI, or • Cardiorenal composite nonfatal ischemic stroke (MACE) endpoint Dual Primary efficacy • MACE endpoints • All-cause mortality • Composite of hospitalization for heart failure or CV death Raz I, et al. Diabetes Obes Metab 2018;20:1102 – 1110;. Wiviott SD, et al. Am Heart J 2018;200:83 – 89; 3. Wiviott SD, et al. N Engl J Med 2018 [Epub ahead of print]
Patients with prior cardiac ischaemic event are more likely to have adverse CV outcomes MACE in REACH registry (n = 19,699) across the spectrum of atherothrombotic risk 25 Adj K-M (%) 20 Diabetes + ASCVD with prior ischemic CV death, MI or stroke event 15 Diabetes + ASCVD without prior ischemic event 10 Diabetes + only risk factors 5 0 0 5 10 15 20 25 30 35 40 Months Cavender et al. Circulation 2015;132:923
CV outcomes with dapagliflozin MACE – CV death, MI or ischemic stroke Prior MI – Placebo (N = 1,807) Patients with prior MI Prior MI – Dapagliflozin (N = 1,777) % with events: 17.8 % vs. 15.2 % No Prior MI – Placebo (N = 6,771) No Prior MI – Dapagliflozin (N = 6,805) 20% HR = 0.84 (95 % CI 0.72 to 0.99) ARR = 2.6 % Patients without prior MI % with events: 7.1 % vs. 7.1 % 15% Cumulative incidence HR = 1.00 (95 % CI 0.88 to 1.13) P-int ARR = 0.048 10% P-int HR = 0.11 ARR = 0.0 % 5% 0% 360 24 36 48 12 Months
HF outcomes with dapagliflozin by prior MI CVD or HF hospitalization Prior MI – Placebo (N = 1,807) Prior MI – Dapagliflozin (N = 1,777) No Prior MI – Placebo (N = 6,771) Patients with prior MI No Prior MI – Dapagliflozin (N = 6,805) % with events: 10.5 % vs. 8.6 % 12.5% HR = 0.81 (95 % CI 0.65 to 1.00) 10% Patients without prior MI ARR = 1.9 % Cumulative incidence % with events: 4.5 % vs. 3.9 % HR = 0.85 (95 % CI 0.72 to 1.00) 7.5% P-int ARR = 0.01 5% P-int HR = 0.69 ARR = 0.6 % 2.5% 0% 12 24 36 48 Months
Hospitalisation for HF 2.5% vs 3.3% HR 0.73 (0.61-0.88) P<0.001 14
Heart Failure: Ejection Fraction analysis - Methods DECLARE-TIMI-58 *EF available in 5202 pts N=17,160* HFrEF Not HFrEF EF <45% N=671 N=16,489 History of No history HF of HF HF without No HF known rEF N=15,173 EF≥45% n=808 EF unknown n=508 N=1,316 15
HHF and CV Death by HFrEF vs not HFrEF subgroups HHF CV death 19.0% 20 20 HFrEF: P for interaction: 0.449 P for interaction: 0.012 HR 0.64 Cumulative incident rate (%) [0.43, 0.95] 15 15 13.5% 12.4% HFrEF: HR 0.55 10 10 [0.34, 0.90] 7.2% 5 5 Not HFrEF: Not HFrEF: 2.5% HR 0.76 HR 1.08 2.7% [0.62, 0.92] [0.89, 1.31] 2.3% 2.1% 0 0 yrs 0 1 2 3 4 yrs 0 1 2 3 4 Not HFrEF defined as pts with HF without known Dapagliflozin HFrEF: Not HFrEF: Dapagliflozin reduced EF and pts without hx of HF Placebo Placebo (N=671) (N=16,489 16 )
Distribution of eGFR Categories Amongst the DECLARE-TIMI 58 Population eGFR <60 Total # of Patients: 7% (n=1265) eGFR ≥90 48% (n=8162) eGFR 60 to <90 45% (n=7732) Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
Mean eGFR change with Dapagliflozin vs. Placebo in the Total Population Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
The Renal Composite Outcomes and their Components in the DECLARE-TIMI 58 Trial Renal composite 40% reduction in eGFR to < 60 ml/min/1.73 m2 end-stage renal disease renal dealh Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
The Renal-Specific Outcome Predefined Sub-Group Analyses (1) Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
The Renal-Specific Outcome Predefined Sub-Group Analyses (2) Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
The Renal-Specific Outcome Predefined Sub-Group Analyses (3) Lancet Diabetes Endocrinol. 2019 Jun 10. pii: S2213-8587(19)30180-9
Explo loratory ry renal outcomes in in SGLT2i CV outcomes tria trials Renal composite: 1 CANVAS Program (canagliflozin) 1 • 40% reduction in eGFR Renal composite HR 0.60; 95% CI: 0.47 – 0.77 b • requirement for RRT • renal death Progression of albuminuria HR 0.73; 95% CI: 0.67 – 0.79 b Renal composite: 2 EMPA-REG (empagliflozin) 2 • doubling of serum creatinine c Renal composite HR 0.54; 95% CI: 0.40 – 0.75; p < 0.001 • requirement for RRT Incident or worsening HR 0.61; 95% CI: 0.53 – 0.70; p < 0.001 • renal death nephropathy a Renal composite: 3 DECLARE-TIMI 58 (dapagliflozin) 3 • 40% reduction in eGFR to Renal composite HR 0.53; 95% CI: 0.67 – 0.79 b < 60 ml/min/1.73 m 2 • end-stage renal disease • 0.2 0.7 1.2 renal deal Favours SGLT2i Favours placebo a Progression to macroalbuminuria, doubling of serum creatinine and eGFR ≤ 45 mL/min/1.73 m 2 , initiation of RRT or renal death; b p value not assessed due to statistical hierarchy; c plus eGFR ≤ 45 mL/min/1.73 m 2 . CI, confidence interval; CV, cardiovascular; eGFR, estimates glomerular filtration rate; HR, hazard ratio; RRT, renal replacement therapy; SGLT2i, sodium – glucose co-transporter 2 inhibitor. 1. Neal B, et al. N Engl J Med . 2017;377:644 – 57; 2. Wanner C, et al. N Engl J Med . 2016;375:323 – 34; 3. Wiviott SD et al. N Engl J Med 2019;380:347 – 57 2 3
Primary Outcome: ESKD, Doubling of Serum Creatinine, or Renal or CV Death 25 Participants with an event Hazard ratio, 0.70 (95% CI, 0.59 – 0.82) 340 Participants with an P = 0.00001 participants 20 245 event (%) 15 participants (%) 10 5 Placebo Canagliflozin 0 6 12 18 24 30 36 42 0 26 52 78 104 130 156 182 Months since randomization No. at risk Placebo 2199 2178 2132 2047 1725 1129 621 170 Canagliflozin 2202 2181 2145 2081 1786 1211 646 196
Background • Type 2 Diabetes Mellitus (T2DM) is a prevalent disorder in the elderly with approximately one quarter of people age >65 with T2DM. • Limited therapeutic experience and insufficient long-term safety data in very elderly patients, age ≥75 years, led some authorities not to recommend initiation of SGLT2i therapy at this age. • The DECLARE- TIMI 58 study included 7907 elderly patients (age ≥ 65) of whom 1096 were very elderly (≥75 years). • We studied the efficacy and safety of dapagliflozin in elderly and very elderly patients with T2DM.
Recommend
More recommend
