Why is Earlier and More Aggressive Treatment of T2 Diabetes Better?

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1 Blood glucose (mmol/l) Why is Earlier and More Aggressive Treatment of T2 Diabetes Better? Disclosures Dr Kennedy has provided CME, been on advisory boards or received travel or conference support from: Astra Zeneca, Bristol Myers-Squibb, Eli Lilly, Sanofi, Novo Nordisk, Takeda, Boehringer-Ingelheim and Merck. Clinical Associate Professor Mark Kennedy Department of General Practice, University of Melbourne Chair, Primary Care Diabetes Society of Australia Medical Director, Northern Bay Health Overview Diabetes natural history and complications Glycaemic control early in T2DM is critical to reduce risk for diabetes-related outcomes Also targeting risk factors such as hypertension and dyslipidaemia brings additional benefits Primary care is the ideal place manage early, uncomplicated diabetes and thus have significant impact on the long term trajectory of the disease T2DM is associated with serious complications 2- to 4-fold increase in cardiovascular mortality Retinopathy and stroke Leading cause of blindness in adults Cardiovascular Disease 8/ individuals with diabetes die from CV events Nephropathy Neuropathy Leading cause of end-stage renal disease Leading cause of non-traumatic lower extremity amputations Natural history of T2DM Progressive deterioration of β-cell consists of both presumed irreversible component (loss of β-cell mass) and reversible glucotoxicity effect caused by hyperglycaemia on β-cell secretory capacity Glycaemia and Vascular Risk Relationship between glucose levels and vascular risk factors well established Hyperglycaemia may negatively impact myocardium before the diagnosis of T2DM 1 retinopathy can develop as early as 7 years before diagnosis of T2DM 2 Microalbuminuria in up to 7% of patients at diagnosis of T2DM 3 Adapted from: 1. Kendall DM et al. Am J Med 9;122(6 Suppl):S Selvin et al., Circulation, 1(16), (14); 2. Fong et al., Diabetes Care, 27(), (4); 3. Adler et al., Kidney International, 63(1), (3) 1

2 Prevalence (%) Prevalence (%) Primary composite endpoint* (%) Effect of HbA 1c on complications in the UKPDS 6 Myocardial infarction Microvascular disease.% 6.% 7.% 8.% 9.%.% retinopathy even in early stages of T2DM Prevalence of diabetic retinopathy in the Diabetes Prevention Program cohort 7.9 IFG + IGT *Mean duration 3.1 years 12.6 Recent onset type 2 DM* More than 12% of people with recent-onset T2DM may already have diabetic retinopathy Adapted from: Stratton IM et al. BMJ ;32: 12. Diabetes Prevention Program Research Group. Diabet Med7;24: Early Intensive Insulin Use Intensive Insulin therapy for 2-3 weeks after diagnosis Improves β-cell function and insulin resistance Can induce drug-free remission drug-free remission in 46% at 12 months Remission rates higher when insulin used compared to oral agents suggesting perhaps additional benefits of early Insulin, antilipolytic, anti-inflammatory and anti-apoptic effects Kramer et al. The Lancet Diabetes & Endocrinology, Volume 1, Issue 1, 13, Pp STENO-2: multifactorial management significantly reduces risk of CV events in T2DM N = 16 Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%) P =.7 Conventional therapy Intensive therapy Time of follow-up (years) 3% risk reduction (Intensive vs. Conventional Therapy) P =.1 *Death from CV causes, non-fatal MI, CABG, PCI, non-fatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease. CABG, coronary artery bypass graft; MI, myocardial infarction; PCI, percutaneous coronary intervention. Adapted from: 1. Gaede P et al. N Engl J Med 3;348: Gaede P, et al. N Engl J Med 8;38:8 91. Intensive therapy involved behaviour modification and pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and microalbuminuria, with secondary prevention of CV disease with aspirin 1 Sustained benefit for CV events also observed in the intensive management group over an additional. years 2 STENO-2: Multifactorial management reduces the risk of microvascular complications in T2DM Relative risk of development or progression of microvascular complications with intensive management (n=8) vs conventional therapy (n=8) Variable Relative Risk p value Nephropathy.39 ( ).3 Retinopathy.42 ( ).2 Autonomic neuropathy Peripheral neuropathy.37 ( ) ( ).66 Intensive multifactorial management over a mean follow-up of 7.8 years was associated with significant reductions in risk of development or progression of nephropathy, retinopathy and autonomic neuropathy vs conventional therapy Gaede P, et al. N Engl J Med. 3;348: Intensive therapy better Conventional therapy better Steno-2 21 year follow up After original 7.8 years of intensified, multifactorial, target-driven treatment of type 2 diabetes with microalbuminuria At 21.2 years of follow-up: CVD events more than double in conventional treatment group Extra 7.9 years of life in intensive treatment group Matched by time free from incident CVD Reduced Microvascular complications: Autonomic neuropathy, Nephropathy Retinopathy and blindness 2

3 HbA 1c (%) Percentage decrease in relative risk Australian Diabetes Society HbA 1c targets Individualized Glycemic Targets: Why? Populations HbA 1c % SI units General 7% 3 mmol/l Diabetes of short duration and no clinical CVD Requiring lifestyle modification ± metformin 6.% 42 mmol/l Requiring any antidiabetic agents other than metformin or insulin 6.% 48 mmol/l Requiring insulin 7.% 3 mmol/l Pregnancy or planning pregnancy 6% 42 mmol/l Diabetes of longer duration or clinical CVD (any therapy) 7.% 3 mmol/l Recurrent severe hypoglycaemia or hypoglycaemia unawareness (any therapy) Major comorbidities likely to limit life expectancy (any therapy) 8.% 64 mmol/l Symptomatic therapy of hypoglycaemia UKPDS post-trial follow-up: differences in HbA 1c not maintained after RCT ceased Intervention trial Post-trial monitoring Pts followed for years Conventional Sulphonylurea-insulin Legacy Effect of Earlier Glucose Control After median 8. years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P:.29. Microvascular disease RRR: 2% 24% P:.99.1 Myocardial infarction RRR: 16% % P:.2.14 All-cause mortality RRR: 6% 13% P: Time from randomisation (years) Post-trial monitoring annual follow-up 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;32: Holman RR, et al. N Engl J Med 8;39: Holman R, et al. N Engl J Med 8;39. UKPDS hypertension sub-study: tight BP control reduces complications in T2DM Diabetes-related deaths 32% risk reduction P < Microvascular disease 37% risk reduction P < % risk reduction P = Less tight control: mean BP 4/87 mmhg Tight control with captopril or atenolol: mean BP 144/82 mmhg Targets for T2D A 1% reduction in HbA 1c and a sustained diastolic BP <8 mmhg Adapted from: UKPDS Group. BMJ 1998;317: Adapted from Stratton IM, et al. UKPDS 3. BMJ ; 321: 412. corresponding to a 1% decrease in HbA 1C 21% Observational analysis of HbA 1c decrease from UKPDS study data 21% All cause mortality 14% Myocardial infarction 14% Lower extremity amputation or fatal peripheral vascular disease *P =.3; P <.1 12% * Peripheral vascular disease 43% Any diabetesrelated endpoint Diabetesrelated death Microvascular disease 37% Cataract extraction 19% 3

4 In the ACCORD trial, intensive therapy resulted in more deaths at 3. years but patients in UKPDS and ACCORD had different baseline characteristics UKPDS ACCORD Age Median HbA1c Median duration of diabetes Newly diagnosed years Previous cardiovascular event (exclusion criteria) 3.2% ACCORD patients had: a longer history of T2DM and a higher rate of previous cardiovascular events compared to UKPDS patients ACCORD N Engl J Med 8;38:24-9 UKPDS Group. Lancet1998;32: ACCORD N Engl J Med 8;38:24-9 ORIGIN Trial Patients with prior CVD or at high CV risk and either prediabetes or diabetes Insulin glargine vs standard therapy for 6.2 years Results: Reduced incident diabetes in those starting with prediabetes No decrease in composite outcome of CV death, non-fatal MI and non-fatal CVA Intensive glucose control on microvascular outcomes in T2DM Four trials (ACCORD, ADVANCE, UKPDS, and VADT) participants. Median yr follow-up 9% mean HbA1c % less kidney events 13% less eye events No reduction for nerve events NNT 63 73T2DM patients to prevent one kidney or eye event 9% reduction in major cardiovascular events No reduction in all-cause mortality Increase in severe hypoglycaemia Sophia Zoungas, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a metaanalysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 17; : ADVANCE, VADT and ACCORD Long-term benefits of intensive glycaemic control on microvascular outcomes in ADVANCE and VADT But no significant reduction in the risk of macrovascular outcomes with intensive control in first 3..6 years of follow-up. Improvements in CV outcomes apparent after an additional ~ years in ACCORD and ~ years in VADT, similar to UKPDS, but not after 6 years of follow-up in ADVANCE ACCORD BP and lipid normalization also did not results in event reduction LOOK AHEAD no benefit of lifestyle change and weight loss Above interventions started too late so intervention should be early HbA 1c reduction and cardiovascular events in T2D Danish database 2472 adults with new T2DM. Median age 62. years Large decrease HbA 1c within 6 months of metformin initiation followed for 2.6 years Lower risk of cardiovascular events and CVD death in T2DM Less comorbidities Less need for preventive medications Svensson et al, Diabetes Care Jun 17, (6)

5 Delay in treatment intensification increases risks of cardiovascular events in T2DM Retrospective cohort study in UK of,477 T2DM patients diagnosed from 199 with follow-up data available until 12 Median follow-up.3 years In those newly diagnosed: 22% remained under poor glycaemic control over 2 years 26% never received treatment intensification Delay in treatment intensification by 1 year for those with poor glycaemic control: Increased the risk of MI, HF, stroke by >% Paul, et al., Cardiovasc Diabetol 14:. () Take-home messages Microvascular complications of diabetes may already be present at time of diabetes diagnosis Glycaemic control early in T2DM is critical to reduce risk for diabetesrelated outcomes Simultaneously targeting risk factors such as hypertension and dyslipidaemia brings additional benefits Having practice systems in place to detect diabetes early and regularly review control of CVD risk factors especially when newly diagnosed can bring benefits over decades Primary care is the ideal place manage early, uncomplicated diabetes and thus have significant impact on the long term trajectory of the disease