Real World Evidence for Insulin Treatment: focus on clinical inertia. Melanie Davies CBE

Transcription

1 Real World Evidence for Insulin Treatment: focus on clinical inertia Melanie Davies CBE

2 Learning objectives After this presentation, you should be able to: Have an understanding of real world data with insulin therapy Explain the role of clinical inertia in insulin management

3 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

4 ADA/EASD 2015: position statement for managing hyperglycaemia Healthy eating, weight control, increased physical activity Initial monotherapy Metformin Two-drug combinations SU TZD DPP-4i SGLT2i GLP-1 RA Insulin Three-drug combinations TZD DPP-4i SGLT2i GLP-1 RA Insulin SU DPP-4i SGLT2i GLP-1 RA Insulin SU TZD SGLT2i Insulin SU TZD DPP-4i Insulin SU TZD Insulin TZD DPP-4i SGLT2i GLP-1 RA More complex strategies Insulin (MDI) Escalate therapy at 3 months if target not achieved. Inzucchi SE, et al. Diabetes Care. 2015;38:140-9.

5 Individualization of targets Patient attitude and expected treatment efforts Risks potentially associated with hypoglycaemia, other adverse events More intensive Highly motivated, adherent, excellent self-care Low Less intensive Less motivated, non-adherent, poor self-care High Disease duration Newly diagnosed Long standing Life expectancy Long Short Important comorbidities Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Resources, support system Readily available Limited Inzucchi SE, et al. Diabetologia. 2012;55:

6 Clinical Assessment of Individualized Glycemic Goals in Patients with T2DM: Survey Among Leading Worldwide Diabetologists Cahn A, et al. Diabetes Care 2015;

7 The challenge when improving HbA1c

8 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

9 Clinical inertia in stepwise management of type 2 diabetes Biggest clinical hurdle? + + +

10 Intensification inertia + + +

11 Clinical inertia contributes to poor glycaemic control Khunti K, Davies MJ et al. Diabetes Care 2013; [Epub]

12 Clinical inertia: patient and physician barriers Lack of appropriate education Patient perceptions of insulin treatment and outcomes Hypoglycaemia Excess weight gain Impaired quality of life Complex regimens Barriers Lack of patient adherence to treatment Risks in patients with comorbidities Financial restrictions Resource issue Beliefs about patient competence Elgrably F, et al. Diabet Med. 1991;8: Kunt T, Snoek FJ. Int J Clin Pract. 2009;63(Suppl. 164):6-10. Peyrot M, et al. Diabetes Care. 2005;28: Wallace TM, Matthews DR. QJM. 2000;93: Zafar A, et al. Diabetic Med. 2015;32:

13 Consequences of clinical inertia 105,477 newly diagnosed type 2 diabetes cases One-year delay in intensification in patients with HbA1c 7.0% ( 53 mmol/mol) associated with: myocardial infarction: 67% (CI 1.39 to 2.01) stroke: 51% (1.25 to 1.83) heart failure: 64% (1.40 to 1.91) composite cardiovascular events: 62% (1.46 to 1.80) Paul SK, et al. Cardiovasc Diabetol. 2015;14:100.

14 Barriers to insulin initiation Percentage, % Insulin makes you fat Patients not treated with insulin Fear of hypoglycemia Pain from injection Pain from blood tests Nakar S, et al. J Diabetes Complications. 2007;21:220-6.

15 Barriers to insulin initiation 90 p = Percentage, % p < p =0.01 p = Insulin makes you fat Fear of hypoglycemia Pain from injection Pain from blood tests Patients not treated with insulin Physicians Nakar S, et al. J Diabetes Complications. 2007;21:220-6.

16 Patient-reported key barriers to initiating insulin When I think about using insulin, I think about succumbing to the disease Insulin as a last treatment resort If I have to take insulin, I probably haven t looked after myself. It s the last option Insulin as evidence of personal failure to self-manage diabetes If it gets too low, so that you faint. That s why I don t want it. Because I don t have anyone to look out for me, since I live on my own Concerns of hypoglycemia I ve heard that it s insulin that causes weight gain, rather than the tablets After my grandmother went on insulin, she suffered from all sorts of complications and health problems like amputations. I am afraid of the same thing happening to me Weight gain from insulin If I see a needle, it doesn t matter where, even at the dentist, it is hell for me. If possible, I would try to avoid it forever. Negative perceptions around insulin Injecting yourself is a bit of an awkward thing to do. It s a hassle, too, bringing it along, always. Treatment convenience Needles and injections Brod M, et al. Patient 2014; 7:

17 Non-Adherence a Problem of Epidemic Proportions Non-adherence in chronic diseases averages 50% by 1 year disease duration 1 In Europe, it costs 125 billion and contributes to 200,000 deaths/year 2 3/10 stop taking their medicines before their first supply runs out 3 25% take less than the recommended dose 3 33% do not fill the prescriptions they are given 3 1. WHO. Adherence to longterm therapies: Evidence for action Friends of Europe, Just what the Doctor Ordered: An EU Response to Medication Non-adherence National Council on Patient Information and Education. Enhancing Prescription Medicine Adherence: A National Action Plan

18 Non-adherence to insulin treatment 100 Cross-sectional multi-country survey (N=1530) 1 Patient-reported insulin non-adherence (%) Japan US UK Germany China Turkey Spain France An average of 33% of patients a reported insulin non-adherence; 1 insulin non-adherence rates in diabetes range from 20% to 38% 2 a T1DM or T2DM 1. Peyrot et al. Diabet Med 2012;29(5):682 9; 2. Doggrell, Chan. J Diabetes 2014;doi: /

19 Discontinuation with insulin therapy in T2DM Retrospective analysis from US claims database (N=74,399) 1 Probability of early discontinuation Days from index date to discontinuation Index date is date of first prescription 62% of patients initiating insulin discontinue in the first 3 months and 82% in the first year post-initiation 1 Ascher-Svanum et al. Diabetes Ther 2014;5(1):225 42

20 Positive Predictors of Adherence to Insulin ADHERENCE RATES 46 86% Older age Support from diabetic nurse specialist Physical disability Higher household income Following a healthy diet Perceived self-efficacy Hypoglycemia awareness Previous experience of liaison psychiatry Previous experience of cognitive behavioral therapy Davies MJ et al. Diabet Med. 2013;30:

21 Risks of Over Medicalization Protecting the person with diabetes from over medicalization is an important aspect of diabetes care Protect from medical invasion Person with diabetes is already living a medically invaded life Important not to unnecessarily intrude into a patient's life Can be helped by increasing self-management skills at every medical contact Kalra S, Sreedevi A, Unnikrishnan AG. J Pak Med Assoc Nov;64(11):1324-6

22 Emergency Hospitalisations for adverse Drug events in Older Americans 35 No. of hospitalizations per 10,000 outpatient medication visits Medication Most commonly implicated medications Annual National Estimate of Hospitalizations (N=99,628) Proportion of ER Visits Resulting in Hospitalization No. % (95% CI) % Warfarin 33, ( ) 46.2 Insulins 13, ( ) 40.6 Oral antiplatelet agents 13, ( ) 41.5 Oral hypoglycemic agents 10, ( ) Warfarin Insulins Oral antiplatelet Oral hypoglycemic agents agents Opioid analgesics Digoxin HEDIS Beers criteria Beers criteria excl. digoxin Commonly Implicated Agents High-Risk or Potentially Inappropriate Medications Budnitz DS et al N Engl J Med :21:

23 Glycaemic control and use of hypoglycaemic medications in older people with T2 DM and comorbid dementia Thorpe CT et al Diabetes Care 2015 Jan 15 doi /dc

24 Glycaemic control and use of hypoglycaemic medications in older people with T2 DM and comorbid dementia 52 % of patients had tight glycaemic control (< 7%) Among tightly controlled patients 75% used SUs and/or insulin Many older patients with T2DM and dementia are at high risk of hypoglycaemia associated with intense diabetes therapy De-intensification of therapy may be appropriate Thorpe CT et al Diabetes Care 2015 Jan 15 doi /dc

25 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

26 There is a need for earlier insulin initiation: baseline HbA1c Distribution of HbA1c at time of insulin initiation Patients, % % 41(%) 9.0% 22(%) 10.0% Clinical inertia exists despite: The benefits of timely glycaemic control Guidelines encouraging earlier use of insulin At insulin initiation in SOLVE : The average HbA1c was 8.9% % had HbA1c 9.0% 22% had HbA1c 10.0% Khunti K, et al. Diab Obes Metabolism. 2012;14:

27 There is a need for earlier insulin initiation: baseline HbA1c (countries) Mean pre-insulin HbA1c by country Patients, % Patients remain poorly controlled on OAD treatment for prolonged periods of time At insulin initiation in SOLVE, mean pre-insulin HbA1c range was: % (China) 9.8% (Turkey/UK) Khunti K, et al. Diab Obes Metabolism. 2012;14:

28 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

29 CREDIT Study choice of insulin regime Freemantle N et al DOM;14: 2012;

30 What regimen is used in the RW 60% 20% Freemantle N et al DOM 2012;14:

31 CREDIT Study choice of insulin regime Freemantle N et al DOM 2012;14:

32 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

33 Clinical inertia in type 2 diabetes in real-life clinical practice (at 24 weeks) 0.50 Insulin dose, U/kg Insulin at start Final visit dose 0.00 n = 17,374. Khunti K, et al. Diab Obes Metabolism. 2012;14:

34 Mean HbA1c and mean insulin dose in the total SOLVE cohort HbA1c Insulin dose Error bars represent ± SD HbA1c, % Insulin dose, U/kg Pre-insulin/ Insulin start Interim visit 0 Final visit Khunti K, et al. Diab Obes Metabolism. 2012;14:

35 Impact and efficacy of insulin in the RW Home P et al Dia Res Clin Pract 2011;94:

36 Impact and efficacy of insulin in the RW Home P et al Dia Res Clin Pract 2011;94:

37 Impact and efficacy of insulin in the RW Home P et al Dia Res Clin Pract 2011;94:

38 Impact and efficacy of insulin in the RWE Home P et al Dia Res Clin Pract 2011;94:

39 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

40 As beta-cell function declines, treatment intensification increases hypoglycaemia risk 100 Mild hypoglycaemia Beta-cell function (%) Diagnosis Proportion reporting 1 hypoglycaemic episode SU <2yr >5yr <5yr >15yr Years from diagnosis Type 2 Type 1 Adapted from Lebovitz Diab Rev 1999;7:139 53; UK Hypoglycaemia Study Group Diabetologia 2007;50:1140 7

41 The glycaemic threshold for hypoglycaemia symptom response alters with age In young adult males awareness of symptoms occurred when blood glucose was 3.6 mmol/l, but impairment in cognitive function occurred at 2.6 mmol/l In older males these thresholds are much closer together - awareness of symptoms occurred almost simultaneously with cognitive decline Blood glucose 3 (mmol/l) Glycaemic thresholds for subjective symptomatic awareness of hypoglycaemia and for the onset of cognitive dysfunction in young and elderly non-diabetic males symptoms symptoms reaction time younger men n=7 (22-26 years) older men n=7 (60-70 years) 2.5 reaction time (defined as 4-choice reaction time test) younger men 2 Hypoglycaemia and Clinical Diabetes, 2nd edition, Eds. Frier BM and Fisher M, 2007, John Wiley and Sons, Chichester (Adapted from: Matyka et al (1997) Diabetes Care 20: 135)

42 Prevalence and Incidence of Hypoglycaemia in T2 DMsystematic review and meta-analysis of population based studies 46 studies involving 532,542 subjects Prevalence of mild/moderate hypoglycaemia in T2DM 45% Prevalence of severe hypoglycaemia in T2DM 6% On average an individual with T2DM has 19 mild/moderate episodes and 0.8 severe episodes per year Eldridge C, Davies M and Khunti K PLoS One (6):e

43 HAT is the largest real-world hypoglycaemia study conducted to date countries N=27,585 Latin America South-East Asia Patients Eastern Europe EU countries N=5843 France N=3132 UK N=319 Russia Canada EU 0 HiT 1 DIALOG 2 UK Hypoglycaemia Study Group3 HAT 4 1. Orozco-Beltran D et al. ADA 2014 Abstract 394-P. 2. Cariou B et al. ADA 2013 Abstract 591; 3. UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140 7; 4. Khunti K et al,dom 2106;18:

44 Global HAT: retrospective and prospective hypoglycaemia rates in T2D T2D (n=19,563) Retrospective Hypoglycaemic events per patient year IRR 1.20 IRR 0.69 IRR 1.19 Any Nocturnal Severe Prospective Hypoglycaemia prevalence, % of patients Retrospective Prospective Any (4 wks) 51% 47% Nocturnal (4 wks) 22% 16% Severe (6 mths/4 wks) 16%* 9% Khunti K et al,dom 2106;18:

45 Hypoglycaemia rates vary by world region T1D T2D Overall hypoglycaemia rates for T1D and T2D are high in northern and eastern European (particularly Russian) populations, respectively European populations also display high rates of nocturnal hypoglycaemia T2D-associated nocturnal hypoglycaemia is most common in Russian patients PPY: per patient-year; T1D: type 1 diabetes; T2D: type 2 diabetes Khunti K et al. Diabetes Obes Metab 2016;18:907 15

46 Absolute number of admissions by age and year ( ) Zaccardi F et al. Lancet Diab & Endoc 2016;4:677-85

47 Patients increase blood glucose monitoring in response to hypoglycaemia - regional differences Latin America T1D T2D SE Asia Middle East Russia A high proportion of patients in all countries increased monitoring following hypoglycaemia Eastern Europe Northern Europe/Canada % of patients with a positive response Khunti K, et alposter presented at the World Diabetes Congress 2015, 30 November 4 December 2015, Vancouver, Canada.

48 Increased patient contact with medical personnel following hypoglycaemia Global Latin America SE Asia Middle East Russia Eastern Europe Northern Europe/Canada % patients requiring extra clinic visits Global Latin America SE Asia Middle East Russia Eastern Europe Northern Europe/Canada % patients requiring extra telephone contact with medical personnel Type 2 diabetes Type 1 diabetes Aronson R, Poster presented at the World Diabetes Congress 2015, 30 November 4 December 2015, Vancouver, Canada.

49 Incidence of CVD and mortality in patients experiencing hypoglycaemia CVD history 100 T1D No CVD history 100 T2D Incidence rate (per 1,000 person-years) Incidence rate (per 1,000 person-years) CV events All-cause mortality 0 CV events All-cause mortality CV, cardiovascular; CVD, cardiovascular disease; T1D, type 1 diabetes; T2D, type 2 diabetes Khunti et al. Diabetes Care 2015;38:316 22

50 Outline Guidelines for use of insulin Clinical inertia of initiation and intensification of insulin When is insulin started in the RW What regimens are chosen in the RW Impact and efficacy in the RW Rates of hypoglycaemia in the RW Summary

51 In the RW Summary Clinical inertia is a major problem in insulin initiation and intensification Poor adherence and persistence with insulin is the norm Insulin is started very late with high HbA1c and regional variations Once initiated insulin works well Hypoglycaemia is more of a problem in the RWE than in RCTs RCTs may underestimate to benefits of newer approaches to insulin therapy in the RWE

52 Thank you