How To Get Better Health Care

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1 Kardiovaskulär säkerhet vid behandling av typ 2-diabetes Vad säger senaste data? Michael Alvarsson Kliniken för Endokrinologi, Metabolism och Diabetes Karolinska Universitetssjukhuset Solna

2 Near-normal glucose seems to be good for your heart

3 but is it good for you?

4 Near-normal glucose seems to be good for your heart

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7 Vad har vi för verktyg i verktygslådan?

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9 Hur säkra är de nya verktygen?

10 Baseline Risk of Patient Populations Enrolled in CV Outcome Trials of DPP-4 Inhibitors Risk Factors Stable CAD-CVD-PAD Post ACS patients Alogliptin EXAMINE (N=5,380) 1 ACS within days Presented Sept 2013 Saxagliptin SAVOR-TIMI (N=16,492) 2 Pre-existing CVD or multiple risk factors for CVD Presented Sept 2013 Sitagliptin TECOS (N=~14,000) 3 Pre-existing CVD End Dec 2014 Linagliptin CARMELINA (N=8,300) 4 Pre-existing CVD + albuminuria or impaired renal function End Jan 2018 Vildagliptin does not have an ongoing CV outcomes trial CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS = acute coronary syndrome; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. 1. White W et al. N Engl J Med. 2013;369: Scirica BM et al. N Engl J Med. 2013;369: Green JB et al. Am Heart J 2013;166: e7. 4. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. NCT Accessed September 12,

11 EXAMINE, SAVOR-TIMI, and TECOS HbA 1c Range, % Duration of Treatment (as part of usual care) Primary End point EXAMINE R Alogliptin Placebo CV death, Nonfatal MI, or Nonfatal stroke SAVOR- TIMI R Saxagliptin Placebo CV death, Nonfatal MI, or Nonfatal stroke TECOS R Sitagliptin Placebo CV death, Nonfatal MI, Nonfatal stroke, or UA req. hospitalization Randomization Year 1 Year 2 Year 3 Median Duration of Follow-up a a Approximate median duration of follow-up for TECOS, based on the expected event rate at study initiation. EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin. CV = cardiovascular; MI = myocardial infarction; UA = unstable angina. 1. White WB et al. N Engl J Med. 2013;369: Scirica BM et al. N Engl J Med 2013;369: Green JB et al. Am Heart J. 2013;166: e7. 12

12 SAVOR-TIMI 53, EXAMINE, and TECOS: Major Adverse Cardiovascular Events Test for heterogeneity for 3 trials: p=0.877, I 2 =0% 1. Scirica BM et al. N Engl J Med 2013; 369: White WB et al. N Engl J Med 2013; 369: Green JB et al. NEJM 2015; DOI: /NEJMoa *Lower Confidence Limit not given for EXAMINE trial

13 SAVOR-TIMI 53, EXAMINE, and TECOS: Hospitalization for Heart Failure Test for heterogeneity for 3 trials: p=0.178, I 2 =42% 1. Scirica BM et al. N Engl J Med 2013; 369: White WB et al. N Engl J Med 2013; 369: Green JB et al. NEJM 2015; DOI: /NEJMoa

14 Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA) N=6068 Randomized, Double-blind, Placebo-controlled ACS HbA1c % Primary outcome: MACE+ Follow-up 2 years

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17 Ongoing CV safety trials GLP-1 receptor agonists LEADER (liraglutide (Victoza ), Novo Nordisk) SUSTAIN 6 (semaglutide, Novo Nordisk) EXSCEL (exenatide weekly (Bydureon ), AstraZeneca) REWIND (dulaglutide (Trulicity ), Lilly) DPP-4 inhibitors CARMELINA (linagliptin (Trajenta ), Boehringer Ingelheim) CAROLINA (linagliptin vs glimepiride, Boehringer Ingelheim) SGLT2-inhibitors CANVAS (canagliflozin (Invokana ), Janssen) DECLARE (dapagliflozin (Forxiga ), AstraZeneca)

18 EMPA-REG OUTCOME

19 EMPA-REG OUTCOME

20 Summering Metformin sitter i orubbat bo! (UKPDS) SU ifrågasatt (ADVANCE) Insulin -? (ORIGIN) Glitazoner PROactive + MACE, - HF GLP-1 RA ELIXA neutral effekt DPP-4 hämmare 3 RCT neutral effekt (HF?) SGLT2-hämmare EMPA-REG trendbrott?

21 Slutsats Metformin tryggt att använda vid hög CV risk SU känns otryggt Basalinsulin bättre än måltidsinsulin (hypo-risk) Pioglitazon i nödfall GLP-1 RA sannolikt säkert DPP-4 hämmare känns säkert SGLT2-hämmare lovande (inte bara säkert utan bra?) Gäller detta även för pat utan hög CV risk?

22 Tack för uppmärksamheten!