01/09/2017. Outline. SGLT 2 inhibitor? Diabetes Patients: Complex and Heterogeneous. Association between diabetes and cardiovascular events

Transcription

1 MICROVASCULAR COMPLICATIONS Incidence of outcome g 1 Cardioprotective Effects of SGLT2s Relevant for Which T2 Diabetes Patient? SGLT 2 inhibitor? 58 year old, waist circumference 5 cm, PMH: IHD On statin, ACE inhibitor, aspirin, Metformin 1g bd HbA1c 7.9% 82 year old female Type 2 diabetes, 2 years Cataracts Waist circumference 88 cm Metformin 1g/day HbA1c 7.9% Roger Chen MB BS (Hons), FRACP, PhD Concord Repatriation General Hospital Clinical Associate Professor of Medicine, University of Sydney Boden Institute, Charles Perkins Centre Diabetes Patients: Complex and Heterogeneous Diabetes and CVD Outline UKPDS, Accord, Advance and VADT CV safety What about the new agents SGLT 2 inhibitors : In whom, when to use and in whom and when not to use Diabetes is a lifelong condition associated with serious complications retinopathy Leading cause of blindness in adults 1,2 nephropathy Leading cause of Stroke Two- to four-fold increase in CV mortality and stroke 5 Cardiovascular disease (CVD) Eight out of ten individuals with diabetes die from endstage renal CV events 6 disease 3,4 Peripheral arterial disease (PAD) A major risk factor for Leading cause of non-traumatic lower-extremity amputation, lower extremity amputations 7,8 and is associated with 1. UKPDS Group. Diabetes Res 1990;13: Fong DS, et al. Diabetes Care 03;26(Suppl 1):S99-S2. increased 3. Hypertension CVD events 8 in Diabetes Study. J Hypertens 1993;11: Molitch ME, et al. Diabetes Care 03;26(Suppl 1):S94-S Kannel WB, et al. Am Heart J 1990;1(3): Gray RP, et al. In Textbook of Diabetes 2nd Edition, King s Fund. London: British Association, Mayfield JA, et al. Diabetes Care 03;26(Suppl 1):S78-S American Diabetes Association (ADA). Diabetes Care 03;26: neuropathy MACROVASCULAR COMPLICATIONS 2-year follow-up (%) Association between diabetes and cardiovascular events No CVD + no diabetes (n=2796) No CVD + diabetes (n=569) 0 Composite Mortality CVD death New MI Stroke New CHF P <0.01, P <0.001 versus patients without diabetes OASIS registry: prospectively collected from patients hospitalized with unstable angina or non-q-wave MI CHF, congestive heart failure; MI, myocardial infarction Malmberg K et al. Circulation 00;2:14 19

2 Primary composite endpoint (%) 2 Decreased cardiovascular mortality with intensive control Hazard ratio = 0.47 (95% CI, ; p = 0.008) Conventional therapy Intensive therapy Months of follow-up Composite endpoint of death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation or surgery for PAD Gæde P, et al. N Engl J Med. 03; 348: Mechanism of action of agents SU Impaired GLP1 insulin agonist secretion DPP4 inhibitor Islet β-cell (e.g. alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) Islet α-cell GLP1 agonist GLP1 glucagon (e.g. exenatide, liraglutide) agonist secretion SGLT2 inhibitor (e.g. canagliflozin, hepatic dapagliflozin) Metformin glucose DPP4: Dipeptidyl peptidase-4 production GLP1: glucagon-like peptide 1 SGLT2: sodium glucose co-transporter-2 Insulin GLP1 Metformin agonist Decreased incretin effect lipolysis glucose SGLT2i reabsorptio n Metformin Decreased Neurotransmitter glucose dysfunction uptake Insulin GLP1 agonist 1. Inzucchi SE et al. Diabetes Care 12; 35: DeFronzo RA. Diabetes 09; 58: Bailey CJ. The Role of the Kidney in Glucose Control. Available from: Accessed 7 April 14. Figure 1 Effects of SGLT2 inhibitors Permission obtained from Nature Publishing Group Chao, E. C. & Henry, R. R. SGLT2 inhibition a novel strategy for diabetes treatment. Nat. Rev. Drug Discov. 9, () Køber, L. (16) Better results from prevention than from additional treatment Nat. Rev. Cardiol. doi:.38/nrcardio.15.5

3 3 Potential effects of SGLT 2 inhibition 13 Finally : a move away from only glycaemic control Lowers blood glucose levels Lowers blood pressure via osmotic diuresis Increases urinary caloric loss with reductions in body weight Reduces albuminuria possibly due to alterations in tubuloglomerular feedback Decreases uric acid Osmotic diuresis- risk of dehydration, hypotension Mycotic infections UTIs Euglycaemic DKA Efficacy for blood glucose lowering depends on renal function Lipids Blood pressure Weight Other markers Direct cardiac effects Renal effects Australia Canaglifozin (not available) Dapagliflozin Empagliflozin Ertugliflozin (? Soon to arrive) Clinical Outcomes with Empagliflozin CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99) CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina Favours empagliflozin Favours placebo CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 15;373:

4 Proportion of exposure time (%) 4 CANVAS adverse events 23 CVD REAL:Contribution of SGLT2 inhibitor: All countries combined Canagliflozin Dapagliflozin Empagliflozin % 6.7% 5.6% 41.8% 52.7% 51.0% 49.1% 42.3% 45.3% HHF All-cause death HHF + all-cause death

5 5 Hospitalization for heart failure or all-cause death primary analysis Which patient Clinical Trial Data: Solid History of cardiovascular disease (TGA indication for Empagliflozin) Renal: Indicated if egfr is > 45 Mean age 60 years More than years of diabetes Class effect? Likely with some potential differences Await results if Declare TIMI (large cohort of primary prevention) No established data in youth, Type 1 diabetes, elderly Need results of NIH studies- what is the best second line treatment GUIDE study Data are on treatment, unadjusted. P-value for SGLT2i vs other glucose-lowering drug: <0.001 Heterogeneity p-value: SENSITIVITY ANALYSES When not to use? Take home messages Recurrent UTIs, mycotic infections Type 1 diabetes, insulin deficiency Pregnancy, paediatric population, frail elderly Prone to dehydration, postural hypotension Urinary incontinence egfr < 45 (future studies) Care with diuretics? Peripheral vascular disease/peripheral neuropathy SGLT 2 inhibitors have the potential for a significant role in cardioprotection (Empagliflozin indication) Focus is also on non glycaemic effects of medications SGLT 2 inhibitor prescription requires careful thought and consideration Potent medications with a variety of effects (cardio/ reno protective, heart failure) Need to ensure patient has no contraindications Need to ensure patient is advised re potential side effects Suspend if unwell- UTI, hospitalisation Review and review