04-Sep-17. INERTIA a failure to initiate or modify treatment in a timely manner in people whose health is likely to improve with this modification

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1 PROF MERLIN THOMAS DIAttitude Study INERTIA a failure to initiate or modify treatment in a timely manner in people whose health is likely to improve with this modification 13% immediately 41% of patients with two HbA1c values above the recommended threshold still had not had their treatment intensified a year after the second high HbA1c value was recorded 39% by 6 months 59% by a year >8 > >7 >7.5 >8 Delayed actions can unnecessarily place patients at increased risk for negative clinical outcomes, increased healthcare utilization, and higher costs Median time to second line (years) Time from HbA 1c above target (years) Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people Diabetes Care (2013) 1

2 Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes 110,543 UK patients, treated between May 1990 and January 2010 Avoidable glycaemic burden Intensification (IT) 46% Clinical inertia may contribute to the large percentage of people with T2DM who live with suboptimal glycaemic control for years, and an avoidable risk of diabetic complications. Intensification 26% <6 months 36% <1 year 53% <2 years The overall median time to receiving 2 nd OAD was 22 months o S Paul. Cardiovascular Diabetology (2015) Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes 110,543 UK patients, treated between May 1990 and January 2010 Intensification (IT) 46% CV event rate 0.4 Intensification 8.4% compared to 5.5% MI HF Stroke IT<1 + A1c< 7% IT<1 + A1c>7% IT>1 + A1c > 7% o S Paul. Cardiovascular Diabetology (2015) o S Paul. Cardiovascular Diabetology (2015) Inherent uncertainties and complexities Competing goals (weight loss, fewer hypos, lower CV risk) Lack of confidence (once a failure, always a failure) Lack of resources (time, effort, support, education) Fear of side effects, interactions, polypharmacy burden & costs 2

3 HbA 1c (%) HbA 1c (%) 04-Sep-17 Titanic was in full compliance with maritime safety regulations of the time. Nihilism (near enough is good enough) Applicability (this patient has different needs) What harm will waiting really do? If asymptomatic Just following the guidelines The regulations required a vessel of 10,000 tons or more to carry 16 lifeboats. Titanic had 20! Early pro-active intervention (if current therapy is failing or likely to fail) Early combination therapy (to reduce the risk of failure) Targets are rarely achieved with monotherapy. Optimal BP control in high risk patients can only be achieved with combination therapy Earlier BP control improves outcomes Guidelines now mandate early aggressive intervention to reduce inertia and save lives Early intensive sequential approach to hyperglycaemia OAD OAD + Diet and OAD* monotherapy OAD OAD + multiple daily exercise monotherapy up-titration combination basal insulin insulin injections 10 9% HbA 1c = 7% 6 Duration of diabetes *OAD = oral antidiabetic Diet and exercise OAD* monotherapy OAD combinations OAD up-titration OAD + basal insulin OAD + multiple daily insulin injections ACTION POINT: HbA 1c = 7% HbA 1c = 6.5% Duration of diabetes *OAD = oral antidiabetic o Adapted from Adapted from Del Prato S et al Int J Clin Pract ;59(11): Adapted from Adapted from Del Prato S et al Int J Clin Pract ;59(11):

4 When do you know they are going to fail? Metformin monotherapy is a successful initial treatment strategy (HbA1c <7%) in only about half of all cases Predictors of success include: Compliance/tolerability Immediate prescription after diagnosis Low HbA1c before starting Lower BMI Older age Nichols GA, Connor C, Brown JB, Current Medical Research and Opinion. September 2010, Vol. 26, No. 9, Pages When do you know they are going to fail? In those (half) who initially achieve HbA1c < 7% one in six patients every year have a HbA1c <7.5% or need another agent By 3 years ~half are on another agent another agent Predictors of ongoing success include : Immediate prescription after diagnosis Lower HbA1c at baseline Younger age Significant weight loss Nichols GA, Connor C, Brown JB, Current Medical Research and Opinion. September 2010, Vol. 26, No. 9, Pages When do you know they are failing? Three quarters of all patients will need more than one agent because monotherapy does not achieve the target values of HbA 1c or sustain these levels for long o When the treatment goal of HbA 1C <7 % with metformin plus lifestyle intervention is not achieved within 3-6 months o In order to achieve the HbA 1C <7 % these glucose goals are usually necessary: Fasting glucose 4-7 mm Postprandial glucose (<10 mm) o If more than 20% are greater than this in a two week period you are not in control Turner et al JAMA. 1999;281(21): THE STOP RULE Review possible reasons for poor control before any move to second line therapy NON COMPLIANCE (pills,diet,lifestyle) SIDE EFFECTS (real or perceived risk for) STRESS & DEPRESSION INFECTION EXCESSIVE WEIGHT GAIN OTHER DRUGS HYPOTHYROIDISM RACGP Guidelines If sequential therapy was used appropriately and agents were added in a timely manner to minimize the time spent in a hyperglycaemic state, there may be little argument for initial combination therapy 4

5 Randomisation 04-Sep-17 Rationale for initial combination therapy Rationale for initial combination therapy Diabetes is a complex disease that stems from multiple metabolic defects So cannot be effectively treated with one agent Diabetes is not a one size fits all disease Diabetes almost always requires intensification of therapy over time in order to maintain adequate glycemic control Zinman B. Am J Med (2011) Early robust lowering of HbA 1c More likely to reach (earlier) targets for control Better sustain control (Less failure or escape) Avoid (delay) of clinical inertia Minimize complexity &improve compliance (by success) Potential to slow titration of metformin to minimise side effects & improve tolerability Potential to use less than maximal doses of individual agents to minimise side effects Zinman B. Am J Med (2011). When to consider combination therapy early? Initiate at or soon after diagnosis for those unlikely to achieve goals with metformin, diet & lifestyle Symptomatic Entry HbA 1c > 7.5% (AACE) Entry HbA 1c > 9.0% (XXX) Complications (CVD, eye, kidney, retinopathy, erectile dysfunction) What might be the downside? Additional side effects/cost for some patients. If side effects occur in initial combination therapy, which caused the side effects? Initial combination therapy may mask an excellent response to one or a poor response to another Overtreatment of individuals who may have maintained adequate glycemic control with one Vildagliptin Efficacy in combination with metformin For early treatment of type 2 diabetes mellitus Study design Initial combination vs Sequential addition MET 500 mg/d MET 1000 mg/d MET 1500 mg/d Period 1 Period 2 Period 3 Vilda 50 mg bid + MET Vilda 50 mg bid + MET + (basal) insulin* up to 1000 mg bid up to 1000 mg bid HbA1c >7.0% or 53 mmol/mol (twice) At investigator discretion Placebo bid + MET up to Vilda 50 mg bid + MET up to Screening Run in: 3 weeks 1000 mg bid 1000 mg bid 2 weeks Visits every 3 months Day 1 Patient population ADOPT-like design, ~2000 patients with newly diagnosed (<24 months) T2DM and HbA1c % Period 1 is double blinded (until the end of the study), period 2 is single blinded and period 3 is open label. Intensification of treatment with OAD instead of insulin in period 3 leads to study discontinuation + (basal) insulin* 5 years Primary objectives (co-primaries) Initial treatment failure and rate of loss in glycaemic control (HbA1c) over time Other endpoints Progression of and change in HbA1c, FPG, safety and tolerability, 2-h meal AUC glucose and annual 2-h meal ISR/G Adapted from: Del Prato S et al. Diabet Med. 2014;31:

6 THE VALUE OF EARY & AGGRESSIVE TREATMENT HI PROF MERLIN THOMAS 6