The Flozins Quest for Clarity?

Transcription

1 The Flozins Quest for Clarity? Choosing Wisely with Academic Detailing 2018 ARE THEY THE REAL DEAL

2 Disclosure statements The Academic Detailing Service is operated by Dalhousie Continuing Professional Development, Faculty of Medicine and funded by the DHW. Dalhousie University Office of Continuing Professional Development has full control over content. 2

3 Disclosure statements Isobel Fleming has no actual or potential conflict of interest in relation to this topic or presentation Dr. Brian Moses has presented CME presentations sponsored by Boehringer Ingelheim, Janssen and Astra Zeneca. 3

4 Learning Objectives To review the evidence evaluating sodium glucose co-transporter 2 inhibitors (SGLT2) in type 2 diabetes To discuss a patient case To promote clinical sharing and discussion about the appropriate place in therapy of the SGLT2 inhibitors 4

5 Sodium glucose co-transporter 2 inhibitors Canagliflozin (Invokana) Dapagliflozin (Forxiga) Empagliflozin (Jardiance) 5

6 Evidence from Canagliflozin (Invokana) CANVAS Trial N Engl J Med 2017;377: Empagliflozin (Jardiance) EMPA-REG OUTCOME Trial N Engl J Med 2015;373: Liraglutide (Victoza) LEADER trial N Engl J Med 2016;375:

7 Annabel 70 year old active senior Past history Hypertension 15 years T2DM 12 years Lab work BP 132/78 egfr 58 A1C 8.0 LDL 2.0 7

8 Annabel Medications Irbesartan/HCTZ 150/12.5 daily Atorvastatin 40 mg daily Metformin 1000mg BID Gliclazide 160 mg daily 8

9 Annabel Would you add an SGLT2 inhibitor? Would you make any other changes? 9

10 What is T2DM? Age Environment Body fat Insulin resistance Genes T2DM inefficient Insulin secretion

11 Complications ACUTE Hypoglycemia HHNS CHRONIC Microvascular Retinopathy Nephropathy Neuropathy Macrovascular Accelerated atherosclerosis MI Stroke 80% Lower extremity gangrene CHF

12 Well designed RCTs wanted 2 TYPES Target trials Drug trials Will a A1C vascular events? Compare A1C levels Compare A1C lowering therapies

13 Study Microvascular CVD Mortality UKPDS ACCORD ADVANCE VADT Initial trial Long term F/U

14 Microvascular outcomes early indicators Retinopathy Nephropathy Macrovascular outcomes.???? Did you know agents can be approved without direct evidence that they risk of morbidity & mortality

15 Well designed RCTs wanted 2 TYPES Target trials Compare A1C levels Drug trials Compare A1C lowering therapies How do the therapy options compare? Exposes effects of mechanisms outside of AIC?

16 SUs Glucose lowering agent Retinopathy, nephropathy, neuropathy Outcomes CVD death, MI, stroke Mortality?????? Repaglinide?????? TZDs Pioglitazone MACE? risk HF???? Rosiglitazone risk HF & MI??? DPP-4 Inhibitors Sita-, saxa- & alogliptin No benefit vs Pl No benefit vs Pl linagliptin?????? GLP agonists Dulaglutide, Albiglutide?????? Exenatide No benefit vs Pl No benefit vs Pl Liraglutide MACE vs Pl risk vs Pl SGLT-2 Inhibitors Dapagliflozin?????? Canagliflozin MACE??? Empagliflozin MACE vs Pl risk vs Pl Insulin??????

17 SGLT2 GLP-1 Outcomes EMPA REG CANVAS LEADER Empagliflozin 10mg or 25mg Canagliflozin 100mg - 300mg (71% 300mg) Liraglutide 1.8 mg Median f/u yrs CV death, MI, stroke % vs 12.1% 0.86 ( ) ARR 1.6% NNT % vs 7.6% 0.86 ( ) ARR 1.1% NNT 90 13% vs 14.9% 0.87 ( ) ARR 1.9% NNT 53 CV death 3.7 vs ( ) ARR 2.2 NNT 45 NS (RR 0.87) 4.7% vs 6% 0.78 ( ) ARR 1.3% NNT 77 Non-fatal MI NS (RR 0.87) NS (RR 0.85) NS (RR 0.88) Stroke NS (RR 1.18) NS (RR 0.90) NS (RR 0.86)

18 Who do these results apply to? Trial population Time since Diagnosis % egfr MACE /yr CV death/yr EMPA REG n=7, yrs f/u 99.5% CVD 10% HF 5yr (18%) >5-10 (25%) >10 (57.4%) 26% 4% 1.8% CANVAS n=10, yrs f/u 65.6% CVD 14.4% HF LEADER n=9, yrs f/u 81% CVD 18% HF 13.5 yrs 12.8 yrs Included but % not reported 3.2% 1.3% 21% 4% 1.6%

19 Vascular Outcome Studies % patients on background medications Met Ins ASA/ AP Statin B block ACE/ ARB Diuretics SGLT2 EMPA-REG empagliflozin SGLT2 CANVAS canagliflozin GLP-1 LEADER Liraglutide

20 What caused the results? Not A1C Change in A1C EMPA REG CANVAS LEADER vs vs vs 8.2 Pattern of CV benefit Different for empagliflozin and canagliflozin than with liraglutide

21 SGLT2 GLP-1 Outcomes HR (95% CI) EMPA REG Empagliflozin CANVAS Canagliflozin LEADER Liraglutide Hosp for Heart Failure 0.65 ( ) 0.67 ( ) NS

22 Other benefits Both empagliflozin and canagliflozin

23 Best guess of underlying cause for SGLT 2 inhibitors Also: Early hemodynamic changes, whole body Na+ content BP and weight cardiac O 2 demand Changes in cardiac energy metabolism

24 Adverse effects Genital & UT infections Genital infections NNH 22 empagliflozin Genital infections NNH 6 (females), 12 (males) canagliflozin UTIs NNH 24 (females with empagliflozin) Volume depletion (dry mouth/polydipsia to orthostatic hypotension/syncope) NNH 14 to 38 (canagliflozin) Amputations Fractures NNH 96 (canagliflozin) NNH 286 (canagliflozin) Increase potassium, hemoglobin and hematocrit

25 Adverse effects Diabetic ketoacidosis Post marketing Health Canada warnings: Acute kidney injury (canagliflozin and dapagliflozin) 2015 Fractures and amputations with canagliflozin Sept 2017

26 Unanswered questions Are CV benefits a class effect? What about effects in people without established CVD new onset T2DM people without T2DM Will a combination of these agents show additive CV benefit?

27 Drug Metformin Glucophage Glumetza Secretagogues Diabeta & Diamicron Amaryl GlucoNorm (repaglinide) ~ $ per day < < Pioglitazone DPP-4 inhibitors 2.85 SGLT-2 inhibitors 2.85 GLP-1 agonists

28 Annabel 70 year old active senior Past history Hypertension 15 years T2DM 12 years Lab work BP 132/78 egfr 58 A1C 8.0 LDL

29 Annabel Medications Irbesartan/HCTZ 150/12.5 daily Atorvastatin 40 mg daily Metformin 1000mg BID Gliclazide 160 mg daily 29

30 Annabel Would you add an SGLT2 inhibitor? Would you make any other changes? 30

31 Annabel If Annabel had experienced a recent TIA and was started on low dose ASA, Would this influence your decision?

32 Canadian Diabetes Association 2018 Guidelines For patients not at target after metformin, consider adding empagliflozin, canagliflozin or liraglutide In Patients with clinical CVD

33 Canadian Diabetes Association 2018 Guidelines For patients not at target after metformin, consider adding An agent best suited to the individual By Prioritizing patient characteristics

34 Are SGLT2s the REAL DEAL for Annabel