2020 Symposia Series 2 2020 Symposia Series 2
Improving Glycemic and Cardiorenal Outcomes in T2DM: The Expanding Role of SGLT2 Inhibitors
Learning Objectives • Describe evidence supporting use of SGLT2 inhibitors in the setting of existing cardiovascular disease (CVD), heart failure (HF), or renal disease • Integrate SGLT2 inhibitors into the treatment plans of patients with type 2 diabetes (T2DM) according to evidence-based guidelines and patient- specific factors • Implement patient-centered management for patients with T2DM within the context of current guidelines 3 SGLT2 = sodium-glucose cotransporter 2.
CVD and T2DM • CVD is the leading cause of death among patients with diabetes ‒ Risk highest for individuals with prior history of CVD and with increasingly poorer glycemic control • ~1/3 of patients with T2DM have comorbid CVD ‒ 68.4% of patients with T2DM are hypertensive ‒ 43.5% have high LDL-C • Mitigating CVD risk is important to improving long-term outcomes for patients with T2DM • Updated guidance from the ADA recommends using treatments that convey both glycemic and CVD benefits LDL-C = low-density lipoprotein cholesterol. Centers for Disease Control and Prevention. www.cdc.gov/diabetes/library/features/diabetes-stat-report.html. Accessed June 1, 2020; 4 Einarson TR, et al. Cardiovasc Diabetol . 2018;17:83; Raghavan S, et al. J Am Heart Assoc. 2019;8:e011295.
Case Study: Diane, a 57-Year-Old With 6-Year History of T2DM • New patient presenting for annual physical • Stent placement 2 years ago after hospitalization for ACS • Physical exam ‒ Height 5 ft 6 in ‒ Weight: 165 lb ‒ BMI: 26.6 kg/m 2 ‒ BP: 144/92 mm Hg on ACE inhibitor ‒ No overt retinopathy or neuropathy 5 ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome.
Case Study (cont’d): Diane’s History and Laboratory Values • • Lab Results Current Medications ‒ ‒ FPG: 136 mg/dL Metformin 1500 mg/day ‒ ‒ PPG: 196 mg/dL Ramipril 10 mg/day ‒ ‒ A1C: 7.8% Atorvastatin 80 mg/day ‒ ‒ LDL-C: 81 mg/dL on statin Aspirin 81 mg/day ‒ Mild renal impairment • Family/Social History • eGFR: 59 mL/min/1.73 2 ‒ Full-time office manager ‒ Albuminuria present ‒ Engages in group exercise • A/C ratio = 360 mcg/mg on 3 days per week spot test ‒ Enjoys traveling, visiting grandchildren A1C = glycated hemoglobin; A/C = albumin/creatinine; eGFR = estimated glomerular filtration rate; FPG = fasting plasma glucose; 6 PPG = postprandial glucose.
ADA 2020: Use Agents That Address Patient-Specific Comorbidities For all patients: lifestyle modification For most patients: metformin Indicators of high-risk or established ASCVD, HF, or CKD HF or CKD predominates ASCVD predominates PREFERABLY : PREFERABLY: SGLT2i with evidence of reducing HF and/or SGLT2i with GLP-1 RA with CKD progression in CVOTs if eGFR is adequate proven CVD EITHER/OR proven CVD OR benefit if eGFR benefit If SGLT2i not tolerated or contraindicated or inadequate eGFR, is adequate add GLP-1 RA with proven CVD benefit If A1C above target If A1C above target If further intensification required or patient unable to tolerate Choose agent with CV safety; Avoid TZD in setting of HF GLP-1 RA and/or SGLT2i, choose agents with CV safety CKD = chronic kidney disease; CVOT = cardiovascular outcome trial. 7 Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.
Baseline Characteristics of SGLT2 Inhibitor CVOTs CANVAS & EMPA-REG CANVAS-R CREDENCE DECLARE-TIMI 58 DAPA-HF* VERTIS-CV Characteristics Empagliflozin Canagliflozin Canagliflozin Dapagliflozin Dapagliflozin Ertugliflozin N 7020 10,142 4401 17,160 4744 8246 Established — 100 72 50 41 100 ASCVD, % 100 Renal 11 18 7 40.6 22 Albuminuric impairment, % Nephropathy Nephropathy eGFR <60 eGFR <60 eGFR <60 CKD Baseline eGFR, 74 77 56 85 66 76 mL/min/1.73 2 Baseline HF, % 11 14 15 10 100 24 *DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline. Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 8 2017;377:644-657; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128.
Outcomes of SGLT2 Inhibitor CVOTs CANVAS & EMPA-REG CANVAS-R CREDENCE DECLARE-TIMI 58 DAPA-HF* VERTIS-CV Characteristics Empagliflozin Canagliflozin Canagliflozin Dapagliflozin Dapagliflozin Ertugliflozin MACE + MACE + CV Primary outcome MACE MACE Renal composite HHF or CV death composite death or HHF — Est. ASCVD, % 100 72 50 41 100 — MACE 0.86 (0.74-0.99) 0.86 (0.75-0.97) 0.80 (0.67-0.95) 0.93 (0.84-1.03) 0.97 (0.85-1.11) CV death 0.62 (0.49-0.77) 0.87 (0.72-1.06) 0.78 (0.61-1.00) 0.98 (0.82-1.17) 0.82 (0.69-0.98) 0.92 (0.77-1.11) HHF 0.65 (0.50-0.85) 0.67 (0.52-0.87) 0.61 (0.47-0.80) 0.73 (0.61-0.88) 0.70 (0.59-0.83) 0.70 (0.54-0.90) CV death or HHF 0.66 (0.55-0.79) 0.78 (0.67-0.91) 0.69 (0.57-0.83) 0.83 (0.73-0.95) 0.75 (0.65-0.85) 0.88 (0.75-1.03) Fatal/non-fatal — 1.18 (0.89-1.56) 0.87 (0.69-1.09) NR 1.01 (0.84-1.21) 1.0 (0.76-1.32) stroke *DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline. HHF = hospitalization for heart failure; MACE = major adverse cardiovascular event (composite of CV death, myocardial infarction [MI], or stroke). Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644- 657; Percovic V, et al. Lancet Diabetes Endocrinol. 2018;6:691-704; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Radholm K, et al. Circulation. 2018;138:458-468; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128; Zoler ML. 9 9 www.medscape.com/viewarticle/929647. Accessed June 1, 2020; Cannon CP, et al. ADA 2020. The VERTIS-CV Trial. Presentation. June 16, 2020.
Outcomes in Observational Studies Are Consistent With CV Benefit of Treatment With SGLT2 Inhibitors Characteristics CVD-REAL Patorno et al EASEL CVD REAL 2 CVD REAL Nordic N 309,056 224,999 25,258 >400,00 91,930 Established 13 16-18 100 27 25 ASCVD, % All-cause death, 0.67 0.51 — — 0.78 (0.69-0.87) MI, stroke (0.60-0.75) (0.37-0.70) 0.49 0.66 0.57 0.51 All-cause death 0.51 (0.45-0.58) (0.41-0.57) (0.25-1.74) (0.49-0.66) (0.37-0.70) 0.61 0.70 0.57 0.64 HHF 0.70 (0.61-0.81) (0.51-0.73) (0.54-0.92) (0.45-0.73) (0.50-0.82) Due to the timing of data collection, the majority of patients in these studies received either dapagliflozin or canagliflozin; smaller percentages received empagliflozin. EASEL also included a small percentage treated with SGLT2 inhibitors not currently approved in the US (ipragliflozin, tofogliflozin, luseogliflozin). Birkeland KI, et al. Lancet Diabetes Endocrinol. 2017;5:709-717; Kosiborod M, et al. Circulation. 2017;136:249-259; Kosiborod M, et al. J Am Coll 10 Cardiol. 2018;71:2628-2639; Patorno E, et al. BMJ. 2018;360:k119; Udell JA, et al. Circulation. 2018;137:1450-1459.
Improvements in Renal Outcomes With SGLT2 Inhibitors • CREDENCE evaluated effect of canagliflozin on progression of renal disease in patients with T2DM and CKD; outcomes showed reduced risk on: ‒ Primary endpoint (sustained creatinine doubling, ESRD, or CV or renal death): 0.70 (0.59-0.82) ‒ Other endpoints • Sustained creatinine doubling, ESRD, or renal death: 0.66 (0.53-0.81) • ESRD: 0.68 (0.54-0.86) • Dialysis, transplant, or renal death: 0.72 (0.54-0.97) ‒ Patients with baseline eGFR <45 had renal, but not glycemic, benefit with canagliflozin All data presented as hazard ratio (95% confidence interval). ESRD = end-stage renal disease. Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al. 11 N Engl J Med. 2019;380:347-357.
Improvements in Renal Outcomes With SGLT2 Inhibitors (cont’d) • Data from EMPA-REG, DECLARE-TIMI 58, and DAPA-HF suggest renal benefit with empagliflozin and dapagliflozin in CVOTs • Renal-specific trials ongoing ‒ EMPA-Kidney (NCT03594110) ‒ Dapa-CKD (NCT03036150) Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med. 2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al. N 12 Engl J Med. 2019;380:347-357.
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