Dr Brandon Orr-Walker Endocrinologist Clinical Head of Endocrinology and Diabetes Middlemore Auckland 17:45-18:10 What Can New Agents Offer Us?
Diabetes Management What do the new agents offer us? Brandon Orr-Walker August 2018
Outline Basic Premises and Assumptions Identifying the Opportunities Current state New treatment options, what new treatment options?
Basic Premises and Assumptions Only worth making the diagnosis if we are going to change the progression of disease Strong evidence base to reduce harm: Glycaemia BP Renal protection CVD risk Multifactorial management Early good control pays long term dividends We have people with diabetes at high risk of complications, and disparities exist Since 2003 majority of care for people with T2DM is to be in primary care Expertise in management is required to manage therapeutic challenge
Adapted from Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2000; 321:405 412.
Cumulative Incidence Hemoglobin A 1C Figure 5:DCCT-EDIC: Longterm Risk of Macrovascular Conventional Intensive Complications 0.12 12% 10% 8% 6% P < 0.001 P < 0.001 P = 0.61 0.10 0.08 0.06 0.04 0.02 Any Cardiovascular Outcome 42% risk reduction P = 0.02 Conventional Intensive DCCT End of Randomized Treatment EDIC Year 1 EDIC Year 7 0.00 0 2 4 6 8 1 1 1 1 0 2 4 6 Years Since Entry* 1 8 2 0 *Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years. DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Copyright 2002 American Medical Association. All rights reserved. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Copyright 2005 Massachusetts Medical Society. All rights reserved.
Pathophysiologic Approach to Treatment of T2DM Metformin Thiazolidinediones _ Impaired Insulin Secretion Hyperglycemia TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylureas Thiazolidinediones Metformin Increased Hepatic Glucose Production Decreased Glucose Uptake DeFronzo RA. Diabetes. 2009;58:773-795.
Clinical Inertia: Failure to advance therapy when recommended Brown JB et al. Diabetes Care 2004; 27(7): 1535 40.
CCM: Big Effort, Big Variation
Treatment Inertia= clinical inertia Two components: Clinician inertia Patient inertia Lack of access Health literacy Non-adherence Competing interests Refusal of treatment Uninformed/misinformed Well informed Lack of acceptable treatment options Many of the patient inertia factors can be clinician modified, and as healthcare professionals it is our role to do so to the best of our ability.
Treatment options in clinical inertia Two components: Clinician inertia Patient inertia Lack of access Health literacy Non-adherence Competing interests Refusal of treatment Uninformed/misinformed Well informed Lack of acceptable treatment options Many of the patient inertia factors can be clinician modified, and as healthcare professionals it is our role to do so to the best of our ability.
Acceptability of Treatment Options Patient (acceptability) Side effects Misconceptions Belief Experience of success ( especially for uptitration) Response of health care team Healthcare team Resource Competency Belief Promotion Treatment options per se Funding Advantages beyond targeted indication (external gains) Cost
Management of glycaemic control (NZ) Lifestyle modificatio n If above target First line drug therapy If above target >3 months Second line drug therapy If above target >3 months If above target (HbA 1c 50-55 mmol/mol [6.7 7.2%] or as individually agreed) Third line drug therapy Food, physical activity and behavioural strategies Metformin Gastrointestinal tolerance may be improved by If metformin gradual introduction Stop if not tolerated egfr <30 ml/min/1.73m 2 or Review medication adherence and contraindicate dose optimisation d Sulphonylurea Review medication adherence and dose optimisation Insulin 4 Review medication adherence and dose optimisation If measured HbA 1c does not meet or closely approach agreed target within 3 months, or if patient is symptomatic, drug therapy should be considered Sulphonylurea Educate the person on the possibility of hypoglycaemia Acarbose therapy 1 Thiazolidinedione (pioglitazone) 2, 3 If no congestive heart failure If at significant risk of hypoglycaemia Consider increased risk of fracture in women Guidance on the Management of Type 2 Diabetes 2011; available online at www.nzgg.org.nz
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Nice May 2017 Presentation title Date 18
ADA 2018 Standards of Care Presentation title Date 19
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Individualising HbA 1c goals Psycho- Bio- Patientcentred care -social Inzucchi et al. Diabetes Care 2012;35:1364 79
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No new DKD-specific treatment in the last 15 years RAAS blockade 23 High blood pressure identified as DKD risk IDNT 4, IRMA 2 5 Irbesartan No new DKD-specific treatment in the last 15 years Captopril 3 T1D factor T2D 1980 1990 2000 2010 2015 ß-blockers 1 Hydralazine 2 RENAAL 6 Losartan T2D
Cumulative % of patients with event RENAAL Patients Reaching the Primary Composite Endpoint* 50 40 30 Risk reduction=16% P=0.02 Placebo 20 10 Losartan 0 Placebo (n) 762 Losartan (n) 751 0 12 24 36 48 Months 689 692 In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker, *doubling of serum creatinine, end stage renal disease, Brenner and/or BM, centrally et al. acting N Engl agent J Med. death www.hypertensiononline 2001;345(12):861-869..org 2001 Massachusetts Medical Society. All rights reserved. 554 583 295 329 36 52
RENAAL
% of patients with event RENAAL First Hospitalization for Heart Failure 20 15 32% Risk reduction P=0.005 10 5 Placebo * (n) 0 0 12 24 36 48 Months 762 685 616 375 53 Losartan * (n) 751 701 637 388 74 * In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker, www.hypertensiononline Brenner and/or BM, centrally et al. acting N Engl agent J Med. 2001;345(12):861-869..org 2001 Massachusetts Medical Society. All rights reserved.
Presentation title Date 27 Newer agents Incretin Pathway SGLT2 inhibitors
Gila Monster Salivary product is GLP-1 agonist
Incretins Physiologically Regulate Insulin and Glucagon in a Glucose-dependent Manner GI tract Pancreas Ingestion of Food Release of Incretin Gut Hormones Active GLP-1 & GIP β-cells α-cells Glucose Dependent Insulin from β-cells (GLP-1 and GIP) Glucagon from α-cells (GLP-1) Glucose Dependent Glucose uptake and storage by muscles and other tissues Glucose output from the liver Physiologic glucose control Adapted from Kieffer TJ, Habener JF. Endocrine Reviews. 1999;20:876 913.; Ahrén B. Curr Diabetes Report. 2003;2:365-372. ; Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.; Drucker DJ. Expert Opin Investig Drugs. 2003;12:87-100.; Ahrén B et al. Horm Metab Res. 2004;36:867-876.
GLP-1 Actions in Peripheral Tissue Heart Brain Neuroprotection Appetite Gastric emptying Stomach Stomach Cardioprotection Cardiac output GI Tract GLP-1 Liver _ Insulin secretion β-cell neogenesis Glucose production Drucker DJ. Cell Metab. 2006;3:153-165. Muscle + Glucose Uptake β-cell apoptosis Glucagon secretion
Levels of Active Incretins GLP-1 and GIP Are Increased by DPP-4 Inhibition Meal Intestinal GIP and GLP-1 release DPP-4 Enzyme DPP-4 Inhibitor GIP-(1-42*) GLP-1(7-36)* Active XRapid Inactivation GIP-(3-42)* GLP-1(9-36)* Inactive GIP and GLP-1 Actions *Refers to amino acid number. Deacon CF et al. Diabetes. 1995;44:1126 1131.
Side Effects: GLP-1 Receptor Agonists and DPP-4 Inhibitors GLP-1 Receptor Agonists DPP-4 Inhibitors Side effects Gastrointestinal Well tolerated Weight Administration Other cardiac risk factors > 85% patients lose weight Twice-daily injection Triglycerides HDL Blood pressure Weight neutral Oral, once daily Unknown Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.
Presentation title Date 33 DPP4 inhibitors Januvia (Sitagliptin) Galvus (Vildagliptin) Onglyza (Saxagliptin) Tradjenta (Linagliptin) (NZ Approved) (NZ Approved) (NZ Approved)
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GLP-1 Receptor Agonists First-in-class (exenatide) approved in 2005 Augment insulin secretion Inhibit glucagon secretion Lower fasting glucose and improve postprandial glucose profile Schnabel CA, et al. Vasc Health Risk Manag. 2006;2:69-77.
Presentation title Date Slide no 36 GLP 1 agonists exenatide (Byetta/Bydureon), approved in 2005/2012 (NZ Approved) liraglutide (Victoza, Saxenda), approved 2010 lixisenatide (Lyxumia), approved in 2016 (NZ not available) albiglutide (Tanzeum), approved in 2014 dulaglutide (Trulicity), approved in 2014 semaglutide (Ozempic), approved in 2017.
Change in A1c (%) Exenatide Sustained A1c Reductions Over 82 Weeks 82-Week Completer 82-Week ITT Mean Baseline A1c 8.3% 8.4% 0.0 Placebo-controlled -0.5 Open-label extension (All patients 10 mg BID) -0.8% ± 0.1% -1.0-1.1% ± 0.1% -1.5 0 10 20 30 40 50 60 70 80 90 Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447. Time (week) Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447. 82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE.
Durability of Exenatide: Weight Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
A1c Level (%) Change in Body Weight (kg) Exenatide vs Insulin Glargine as Add-on Therapy in T2DM Exenatide group (n = 275) Insulin glargine group (n = 260) Heine RJ, et al. Ann Intern Med. 2005;143:559-569. * * * * 0 2 4 8 12 18 2 6 * *
Patients with an event (%) LEADER trial: Primary Outcome First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis in patients with type 2 diabetes and high CV risk. 20 15 Hazard ratio, 0.87 (95% CI, 0.78 0.97) P<0.001 for noninferiority P=0.01 for superiority 10 5 Placebo Liraglutide 0 0 6 12 18 24 30 36 42 48 54 Months since randomisation Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial Adapted from: Marso SP et al., NEJM 2016
LEADER trial: Death from Cardiovascular Causes Patients with an event (%) 20 Hazard ratio, 0.78 (95% CI, 0.66 0.93) P=0.007 15 10 Placebo Liraglutide 5 0 0 6 12 18 24 30 36 42 48 54 Months since randomisation Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial Adapted from: Marso SP et al., NEJM 2016
Presentation title Date 42 SGLT-2 inhibitors canagliflozin (Invokana) first for FDA approval (2013) dapagliflozin (Forxiga/Farxiga) (NZ approved) empagliflozin (Jardiance)
SGLT, sodium glucose cotransporter. Gerich JE. Diabet Med 2010;27:136 Renal glucose reabsorption in patients with hyperglycaemia 43 Filtered glucose load >180 g/day SGLT 2 When blood glucose increases above the SGLT 1 renal threshold (>~10 mmol/l or >180 mg/dl), the capacity of SGLTs is exceeded, resulting in urinary glucose
SGLT, sodium glucose cotransporter. *Loss of ~ 80 g of glucose per day = 240 cal/day. Bakris GL et al. Kidney Int 2009;75;1272 Empagliflozin increases urinary glucose excretion via SGLT2 inhibition 44 Filtered glucose load >180 g/day SGLT 2 SGLT2 inhibit ~90% or SGLT 1 compensate SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis ~ 80 g
GFR, glomerular filtration rate Cherney D et al. Circulation 2014;129:587 45 Renal anatomy and physiology Afferent arteriole Vasoconstriction decreases GFR Efferent arteriole Vasoconstriction increases GFR Bowman s capsule Key Flow of blood Flow of filtrate Proximal convoluted tubule
NO, nitric oxide; RAAS, renin angiotensin-aldosterone system Burke M et al. Current Vascular Pharmacology 2014;12:845 The kidney auto-regulates glomerular filtration by moderating afferent and efferent arteriole tone Afferent arteriole Prostaglandin s NO Efferent arteriole RAAS 46 Flow of filtrate Increased filtration
SGLT, sodium glucose cotransporter; GFR, glomerular filtration rate. Adapted from: Cherney D et al. Circulation 2014;129:587 Skrtic M et al. Diabetologia 2014;57:2599 Empagliflozin exerts a hemodynamic effect within the kidney 47 By restoring the Tubulo-Glomerular Feedback (TGF), empagliflozin increases the afferent arteriole tone, thereby lowering glomerular hypertension Action: narrowing Clinical implications: SGLT2 inhibition Afferent arteriole narrowing Glomerular pressure decreases Early clinical marker: Initial dip in GFR Reduction of albuminuria
Mean GFR (ml/min/1.73 m 2 ) Note: Data from two different studies. ACEi, angiotensin-converting enzyme inhibitor; GFR, glomerular filtration rate. 1. Sochett E et al. J Am Soc Nephrol 2006;17:1703; 2. Cherney D et al. Circulation 2014;129:587 Empagliflozin effect on glomerular hyperfiltration shows similar magnitude as ACE inhibitor Baseline ACEi Empagliflozin 48 200 180 160 140 120 100 80 60 40 20 0 177.7-35 ml/min 172.0-33 ml/min 142.8 139.0 ACEi Empagliflozin
Patients received JARDIANCE or placebo on top of standard of care for CV and T2D management 1 Standard of care + Placebo (n=2333) Randomised Standard of care + JARDIANCE and treated 10 mg (n=2345) (n=7020) Pooled Standard of care + JARDIANCE 25 mg (n=2342) Adults with T2D Established CV disease (CAD, PAD, MI or stroke) HbA 1c 7-10% egfr >30 ml/min/1.73m 2# Glucose-lowering therapy was to remain unchanged for the first 12 weeks The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering therapies. 1 Data from both doses of JARDIANCE were pooled for statistical analysis versus placebo # JARDIANCE can be used be used down to an egfr of 45 Slide ml/min/1.73m 3 of 20 2
CV risk factor profile at study entry 1 Patient characteristics 63 Age (years) 57% Pt with T2D duration >10 years 30.6 BMI (kg/m 2 ) 105 Waist circumference (cm) Previous CV events 76% Coronary artery disease 47% History of MI 23% History of stroke 10% Heart failure 21% Peripheral artery disease Data are mean or %. BMI, body mass index. 1. Zinman B et al. N Engl J Med 2015;373:2117 28. Slide 4 of 20
Patients treated appropriately for their CV risk 1 Glycaemic management Blood pressure management Lipid management Anti-platelet and anti-coagulant therapies Mean HbA 1c 8.1% Metformin use 74% Insulin use 48% SBP/DBP, mmhg 136/77 Any BP-lowering drug 95% ACEi/ARB 81% Any lipid lowering drug 81% Statins 77% Any anti-platelet / anticoagulant drug 89% Acetylsalicylic acid 83% In 7020 patients treated with 1 dose of study drug. SBP, systolic blood pressure; DBP, diastolic blood pressure. 1. Zinman B et al. N Engl J Med 2015;373:2117 28. Slide 5 of 20
Patients with event (%) CV death JARDIANCE reduced the relative risk of CV death by 38% vs placebo on top of 9 Early standard * of sustained care patients # response with T2D and established CV disease (CAD, PAD, MI or stroke) Standard of care + HR 0.62 1. 8 Placebo p<0.001 7 6 5 4 3 2 1 0 0 6 12 18 Months 24 30 36 42 48 Adapted from Zinman B et al. 2015. 1 *Within 6 months from start. # Up to 48 months from start. CV death was a pre-specified secondary endpoint. Cumulative incidence function. HR, hazard ratio The absolute risk for CV death was 5.9% in patients receiving standard of care plus placebo and was reduced to 3.7% in patients receiving standard of care plus JARDIANCE (p<0.001). 1 1. Zinman B et al. N Engl J Med 2015;373:2117-28. Standard of care + JARDIANCE Results achieved on top of standard of care Antihypertensives Lipid lowering agents Anticoagulants Glucose lowering agents Slide 8 of 20
Patients with event (%) All-cause mortality JARDIANCE reduced the relative risk of all-cause mortality by 32% JARDIANCE is not indicated to reduce all-cause mortality vs placebo on top of standard of care in patients with T2D and established CV disease (CAD, PAD, MI or stroke) Early 14 * 1 and sustained # response 12 10 8 6 4 2 0 HR 0.68 p<0.001 0 6 12 18 Months 24 30 36 42 48 *Within 6 months from start. # Up to 48 months from start. Adapted from Zinman B et al. 2015. 1 All cause mortality was a pre-specified secondary endpoint. Kaplan-Meier estimate. HR, hazard ratio The absolute risk for all-cause mortality was 8.3% in patients receiving standard of care plus placebo and was reduced to 5.7% in patients receiving standard of care plus JARDIANCE (p<0.001). 1 1. Zinman B et al. N Engl J Med 2015;373:2117-28. Standard of care + Placebo Standard of care + JARDIANCE Results achieved on top of standard of care Antihypertensives Lipid lowering agents Anticoagulants Glucose lowering agents Slide 10 of 20
Patients with event (%) Hospitalisation for heart failure JARDIANCE reduced the relative risk of hospitalisation for heart failure by 35% vs placebo on top of standard of care in patients with T2D and established CV disease (CAD, JARDIANCE PAD, is MI not or indicated stroke) to 1 reduce hospitalisation for heart failure 7 Early * and sustained # response Standard of care + Placebo 6 5 4 3 2 1 0 HR 0.65 p=0.002 0 6 12 18 Months 24 30 36 42 48 Adapted from Zinman B et al. 2015. 1 *Within 6 months from start. # Up to 48 months from start. Hospitalisation for heart failure was a pre-specified secondary endpoint. Cumulative incidence function. HR, hazard ratio The absolute risk for hospitalisation for heart failure was 4.1% in patients receiving standard of care plus placebo and was reduced to 2.7% in patients receiving standard of care plus JARDIANCE (p<0.002). 1 1. Zinman B et al. N Engl J Med 2015;373:2117 28. Standard of care + JARDIANCE Results achieved on top of standard of care Antihypertensives Lipid lowering agents Anticoagulants Glucose lowering agents Slide 12 of 20
Number needed to treat (NNT) to save 1 life 4S 1 HOPE 2 Simvastatin 1 for 5.4 years 30 Ramipril 2 for 5 years 56 EMPA-REG OUTCOME 3 JARDIANCE 3 for 3.1 years 39 In high CV risk 5% diabetes, 26% hypertension In high CV risk 38% diabetes, 46% hypertension T2D with established CV disease (CAD, PAD, MI or stroke) on top of standard of care 92% hypertension Pre-statin era Pre-ACEi/ARB era <29% statin > 80% ACEi/ARB > 75% statin 199 4 2000 No w Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering therapies. 3 ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockers, 1. 4S investigators. Lancet 1994;344:1383-89. 2. HOPE investigators, N Engl J Med 2000;342:145-53. 3. Zinman B et al. N Engl J Med 2015;373:2117-28. Slide 14 of 20
JARDIANCE slowed the progression of renal indicators in the EMPA-REG OUTCOME study in patients with T2D and established CV disease (PAD, CAD, MI or stroke) on top of standard of care 1*# # JARDIANCE is not indicated to prevent decline in renal function *Incident or worsening nephropathy analysed in patients who did not have macroalbuminuria at baseline. Modified intention to treat analyses in patients who received 1 study drug. Defined as progression to macroalbuminuria (urinary albumin to-creatinine ratio, >300mg of albumin per gram of creatinine); a doubling of the serum creatinine level, accompanied by an egfr of 45 ml/min/1.73m 2, as calculated by the Modification of Diet in Renal Disease (MDRD) formula; the initiation of renal-replacement therapy; or death from renal disease. Death due to renal disease: 3 events on JARDIANCE and 0 on placebo. Slide 15 of 20 Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering agents. 2
Presentation title Date 57 Summary Diabetes prevalence is growing Strong evidence base or reduced complications with optimal management There remain substantive numbers of people not at/near target for management Therapy needs to multifactorial and introduced progressively and incrementally to manage diabetes over time reflecting the progressive pathogenesis Newer therapies offer several advantages including convenience, side effect profile and are showing superiority in studied populations for renal and CVD endpoints above standard care Maori and Pacifica are at particularly high risk for CVD and renal harm from diabetes Cost is an issue, but largely because of the high numbers with diabetes with suboptimal control currently, thus cost is likely to come with substantive benefit.