Monday, December 3, 2018

Kamlesh KhuntiUniversity of Leicester, UK

© Leicester Diabetes Centre at University Hospitals of Leicester NHS Trust, 2018.

Not to be reproduced in whole or in part without the permission of the copyright owner.

Therapeutic Inertia: prevalence,

consequences and solutions

Presenter Disclosure

Consultant: Amgen, Abbott, AstraZeneca, Bayer, BMS,

Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Novo

Nordisk, Roche, Sanofi and Servier.

Research Support: AstraZeneca, Boehringer Ingelheim,

Lilly, MSD, Novartis, Janssen, Novo Nordisk, Roche and Sanofi

Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Janssen,

Lilly, MSD, Novartis, Novo Nordisk and Sanofi

Leicester

Leicester Diabetes Centre

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

a In type 1 diabetes.

CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications.

UKPDS 34. Lancet. 1998;352:854. Holman RR, et al. N Engl J Med. 2008;359:1577-89.

DCCT Research Group. N Engl J Med. 1993;329;977-86. DCCT/EDIC Study Group. N Engl J Med. 2005;353:2643–53.

ACCORD Study Group. N Engl J Med. 2008;358:2545-59. Ismail-Beigi F, et al. Lancet. 2010;376:419–430.

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

Duckworth W, et al. N Engl J Med. 2009;360:129-39. Moritz T. N Engl J Med. 2009;361:1024-25. Hayward RA, et al N Engl J Med. 2015;372:2197-206.

Impact of intensive therapy for diabetes: summary of major clinical trials

Study Microvascular CVD Mortality

UKPDS

DCCT/EDICa

ACCORD

ADVANCE

VADT

Long-term

follow-up

Initial trial

Targeting: Achieving early glycaemic control which may generate a good legacy effect

Med

ian

Hb

A1c (

%)

0

6

7

8

9

UKPDS 1998

ConventionalMetformin

Holman et al 2008

Legacy effect

1997

Difference in HbA1c was lost after first

year but patients in the initial intensive arm

still had lower incidence of any complication:

• 24% reduction in microvascular

complications

• 15% reduction in MI

• 13% reduction in all-cause mortality

2007

MI, myocardial infarction

Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/.

Accessed 12 September, 2008;

Adapted from Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

DeFronzo RA, et al. 52nd EASD Annual Meeting 2016, Munich, Germany; Abstract and poster presentation

794. Available at: www.easdvirtualmeeting.org, last accessed 01 March, 2017

Treatment failure defined as HbA1c >6.5%;

Despite lower HbA1c, subjects receiving Triple Therapy experienced 7-fold lower

rate of hypoglycemia versus subjects receiving Conventional Therapy

Early, combination therapy (EDICT Study): Initial triple therapy vs stepwise approach

EDICT study: drug-naïve, newly-diagnosed T2DM patients randomized to MET/PIO/EXE BID

(triple therapy; N=86) or an escalating dose of MET followed by sequential add-on of SU and

insulin glargine

(conventional therapy; N=89) to maintain HbA1c levels at <6.5% for 3 years

Time (months)

0 6 12 18 4842363024

Cu

mm

ula

tive S

urv

ival

Follow-up (months)

6 12 18 363024

0.5

0.6

0.7

0.8

1.0

0.9

0

Hb

A1c

(%)

6

7

8

9Triple Therapy

Conventional Therapy

p < 0.0001

# p < 0.05

* p < 0.01

## * *

**

**

Triple Therapy

Conventional Therapy

ADA Standards of Care Treatment Algorithm 2018

American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes

2018. Diabetes Care 2018;41(Suppl. 1):S73–S85.

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Achievements of A1c in Europe: GUIDANCE Study

0

10

20

30

40

50

60

70

80

90

100

Belgium

Franc

e

Ger

man

y

Ireland

Italy

Net

herla

nds

Swed

en

UK

Tota

l sam

ple

HbA1c checked

Met HbA1c target

GUIDANCE, Guideline Adherence to Enhance Care; HbA1c, glycated haemoglobin A1c.

Perc

en

t, %

GUIDANCE study 7,597 patients with type 2 diabetes Gap exists between checking HbA1c and achieving target HbA1c < 7.0%

Stone MA, et al. Diabetes Care. 2013;36:2628-38.

Urgent need to overcome inertia

Therapeutic inertia

“failure to advance therapy or to de-intensify

therapy when appropriate to do so”

Khunti K , Davies MJ. Prim Care Diab 2017; 11: 105-106

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Therapeutic Inertia in Stepwise Management of T2DM

Diet

and exercise

Oral

monotherapy

Oral

combination

Oral plus

insulin

Insulin

intensification

Main clinical hurdle?

Intensification inertia?

Treatment Inertia in T2DM over the lifecourse

Data for a subgroup of more than 55,000 participants with HbA1c ≥ 7.5% (58 mmol/mol) having any intensification to their treatment at end of follow-up within a

retrospective cohort of over 80,000 people

HbA1c, glycated hemoglobin; OAD, oral antidiabetes drug

81,573 people in the UK

Time to treatment intensification from first HbA1c ≥ 7.5% (58 mmol/mol) by number of OADs and type of intensification

Time from HbA1c above 7.5% (years) Time from HbA1c above 7.5% (years) Time from HbA1c above 7.5% (years)

Intensification by one OAD Intensification by two OADs Intensification by three OADs

Median time to intensification

from HbA1c cut-off ≥ 7.5%: >7.2 years

Median time to intensification

from HbA1c cut-off ≥7.5%: 1.9 years

OAD or insulin

OAD

Insulin

Median time to intensification

from HbA1c cut-off ≥7.5%: >6.1 years

1.0

0.8

0.6

0.4

0.2

0.0

76543210 876543210 876543210

Pro

bab

ilit

y

8

Khunti K, et al. Diabetes Care 2013;36:3411–7

Insulin initiation is delayed in clinical practice

Khunti K, et al. Diab Obes Metabolism. 2012;14:1129‒36

Mean pre-insulin HbA1c by country

8.9

8.38.5

9.49.2

8.4

9.18.9

9.8 9.8

7.5

8.0

8.5

9.0

9.5

10.0

Pa

tie

nts

, %

Patients remain poorly

controlled on OAD treatment for

prolonged periods of time

At insulin initiation in SOLVE,

mean pre-insulin HbA1c range

was between 8.3% (China) and

9.8% (Turkey/UK)

SOLVE: 24-week observational study involving 10 countries that assessed safety and effectiveness

of initiating QD insulin detemir in patients with T2DM treated with ≥1 OADs

Titration inertia: patients remain at low basal insulin dose

1. Khunti K, et al. Diabetes Obes Metab 2012;14:654–661

2. Khunti K, et al. Diabetes Obes Metab 2012;14:1129–36

3. Rosenstock J, et al. Diabetologia 2008;51:408–16

0.00

0.10

0.20

0.30

0.40

0.50

Insu

lin

do

se,

U/k

g

Insulin at start

Final visit dose

n = 17,374

SOLVE:1,2 24 week observational study of once-daily (QD) insulin detemir in patients with T2DM receiving OADs

Treat-to-target trials often report higher

insulin doses compared to those

recorded in observational trials, such

as SOLVE

In one treat-to-target trial, insulin-naïve

patients were titrated to receive insulin

determir QD or glargine QD3

After 52 weeks, the mean daily insulin

detemir dose (n=227) was 0.78 U/kg

U Desai et al, Diabetes Care 2018; dc170662

Earlier treatment intensification is associated with

shorter time to subsequent glycaemic control

Patients do not reach individualised HbA1c targets in real world setting: DUNE StudyProspective observational study of patients initiated on basal insulin in 28 countries

27.923.5

26.820.2

0

20

40

60

80

100

Yes Yes, without hypoglycaemia*

Part

icip

an

ts (

%)

Newly initiated (n=1716) Previously initiated (n=1423)

27.4% of all participants achieved their personalised physician-set HbA1c target after 12 week

*Symptomatic

Meneghini L, et al. AhypoglycaemiaDA 77th Scientific Sessions 2017; Poster 990-P

EU5 and US real-world data in 40627 patients with type 2 diabetes initiating basal insulin 2008–2012

Mauricio D, et al. Diabet Obes Metab 2017;19:1155–64

Target achievement at 3 months is predictive of target achievement at 24 months

Observational, retrospective analysis of electronic medical records from 5 EU countries and US to assess glycaemic control and hypoglycaemia in insulin-naïve adults (≥30 years old)

initiating basal insulin with or without OADs

(N = 2264)

(N = 2330)

(N = 1228)

(N = 1117)

(N = 3468)

(N = 30,220)

(N = 40,627)

Country OR 95% CI

France (N=2264) 5.04 3.53, 7.18

Germany (N=2330) 3.71 2.84, 4.85

Italy (N=1228) 5.22 3.19, 8.52

Spain (N=1117) 3.50 1.85, 6.62

UK (N=3468) 5.51 3.73, 8.13

USA (N=30,220) 3.51 3.21, 3.84

Overall (N=40,627) 3.70 3.41, 4.00

0.6 1 6 12

Odds ratio (95% CI)

Mauricio D, et al. Diabet Obes Metab 2017;19:1155–64

Time from initiation of basal insulin therapy to intensification with bolus or premix insulin or GLP-1(n= 11,696)

a ≥ 6 months after starting basal insulin

.

Khunti K, et al. Diabetes Obes Metab. 2016. DOI:10.1111/dom.12626.

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al

pro

bab

ilit

y

Time from HbA1c ≥ 7.5% (58 mmol/mol)

to intensification with bolus, premix, or GLP-1 (years)

Product-limit survival estimate,

with number of patients at risk

0

6,072 At risk (n)1,652 461 137 27 04632568723,066

8642 10

Survival

probability:

0.5

30.9% intensified therapy

32.1% stopped basal insulin

Median time from initiation of

basal insulin to intensification was

3.7 years [95% CI: 3.4;4.0]

3.7 years

[95 CI: 3.4; 4.0]

Patients with HbA1c ≥ 7.5%a

Post insulin Intensification Inertia

1.2

1.8

0.7

0.4

1.0

2.7

2.0

1.3

1.2

1.5

3.7

3.2

0.0 1.0 2.0 3.0 4.0Median to treatment intensification, years

Reference

Index

treatmen

t

Addition to

index treatment

HbA1c

threshold

Fu, 2011 Metformin OAD or injectable

≥7.0%

7.0–7.9%

8.0–8.9%

≥9.0%

Yu, 2016 Metformin OAD or injectable >7.0%

Conthe, 2011 1 OAD OAD or injectable≥6.5%

≥7.0%

Paul, 2015 1 OAD OAD or insulin≥7.0%

≥7.5%

Ajmera, 2015 2 OADs OAD or insulin ≥8.0%

Khunti, 2016Basal

insulin

Bolus or premix

insulin or GLP-1 RA

≥7.5%

≥8.0%

Median time to treatment intensification(after one HbA1c measurement above target –Selected studies)

GLP-1 RA, glucagon-like receptor agonist; HbA1c, glycated haemoglobin; OAD,

oral antidiabetic drug

1 OAD

2 OADs

Insulin

Index treatment

Khunti K et al. Diab Obes Metab (2017 online)

Overcome therapeutic inertia for quaternary prevention

Therapeutic inertia

“failure to advance therapy or to de-intensify

therapy when appropriate to do so”

Quaternary Prevention: interventions that protect a group at risk of over-medicalisation

Khunti K , Davies MJ. Prim Care Diab 2017; 11: 105-106

Khunti K, Davies MJ. Lancet Diab & Endoc 2017;6:266-268

Potential overtreatment of T2DM in older adults

Lipska KJ et al JAMA Intern Med 2015 175(3) :356-362

No statistical

difference in

achieved

glycaemic control

across health

status (p 0.43)

Potential overtreatment of T2DM in older adults

No statistical

difference in type

of treatment

across health

status across

health status

(p 0.43)

Lipska KJ et al JAMA Intern Med 2015 175(3) :356-362

Overtreatment in UK

Hambling C et al. Diab Med 2017;34:1219–1227

3862 patients with T2DM of whom 1379 (35.7%) prescribed SU or insulin therapies.

Median age 78 years; 48% CKD

Absolute number of admissions with

hypoglycaemia

by age and year (2005-2014) 2

1. Lipska KJ et al. Diabetes Care 2017;40:468-475

2. Zaccardi F et al. Lancet Diab & Endoc 2016;4:677-85

Change in patterns of glucose lowering agents but glycaemic

control and rates of hypoglycaemia unchanged1

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Barriers

Patient perceptions of

insulin treatment and outcomes

Hypoglycaemia

Impaired quality of life

Lack of patient adherence to

treatment

Financial restrictions

Beliefs about patient

competence

Resource issue

Risks in patients with comorbidities

Complex regimens

Excess weight gain

Lack of appropriate education

Clinical inertia: patient and physician barriers

Peyrot et al. Diabetes Care 2005;28:2673–9; Elgrably et al. Diabet Med 1991;8:773–7; Wallace &

Matthews. QJM 2000;93:369–74; Kunt & Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10 Zafar A

et al. Diabetic Med 2015;32:407-413

Efficacy to effectiveness gap

RCTs are typically highly selective, often excluding:1

Elderly patients (aged 65 and older)

Patients with comorbidities

Patients taking other drugs

Patients seen in real-world practice may be:

Mostly older than 65 years

Suffering from several diseases

Taking multiple drugs

“Diverse and complex”

BP, blood pressure; CVD, cardiovascular disease; RCT, randomized controlled trial

1. Saturni S, et al. Pulm Pharmacol Ther 2014;27:129–38

• How can I be sure that RCT results are applicable to my patients?

• Does your drug work in the real world?

Comorbidity of top 10 common conditions

Guthrie B, et al. BMJ 2012;345:e6341

Fear of

hypoglycaemia

Where are the barriers to insulin initiation: physicians or patients?

Nakar S, et al. J Diabetes Complications. 2007;21:220-6.

“Insulin makes

you fat”

Pain from

injection

Pain from

blood tests

Patients not treated with insulin

Pati

en

ts,

%

Fear of

hypoglycemia

“Insulin makes

you fat”

Pain from

injection

Pain from

blood tests

Patients not treated with insulin Physicians

p < 0.001

p = 0.01

p = 0.01p = 0.01

Pati

en

ts,

%

Where are the barriers to insulin initiation: physicians or patients?

Nakar S, et al. J Diabetes Complications. 2007;21:220-6.

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Longitudinal HbA1c changes in patients on GLP1-RA

no Insulin within 24 months

added Insulin within 24 months

-1.15%

Earlier intensification by 6 months is associated with 18% higher odds of lowering HbA1c below 7% at 24 months

Montvida O et al. Diab Obes Met 2016 (online)

66,583 patients

Mean age 56 years

87% Obese

Longitudinal HbA1c changes

Delays in recognising glycaemic failure (therapeutic inertia)

no Insulin within 24 months

added Insulin within 24 months

switched to Insulin within 24 months

Montvida O et al. Diab Obes Met 2016 (online)

Consequences of Inertia: Retinopathy

Significantly shorter median time to progression of diabetic retinopathy

The adjusted incidence rate for diabetic retinopathy progression in clinical inertia: 4.9 (95% CI; 1.1, 21.8)

Osataphan S, et al. J Diabetes 2016;9:267–74

0.00

0.25

0.50

0.75

1.00

0 20 40 60

Non-clinical inertia

Clinical inertia

Kaplan-Meier survival estimates

Port

ions o

f th

e p

atie

nts

who a

re liv

ing w

ithout D

R

Analysis time (months)

Log rank test P=0.02

Consequences of inertia: Cardiovascular complications

Paul S, et al. Cardiovasc Diabetol 2015;14:100 doi:10.1186/s12933-015-0260-x

8.5

8.0

7.5

7.0

6.5

6 12 54 6048

Months

HbA

1c,

%

Patients with HbA1c ≥7% not

receiving IT within 1 year

Patients with HbA1c <7% who

received IT before 1 year of diagnosis

At 5.3 years, significantly

increased risk of:

• MI 67% (CI 39–101%)

• Stroke 51% (CI 25–83%)

• HF 64% (CI 40–91%)

• Composite CVE 62% (CI 46–

80%)

CVE, cardiovascular endpoint; HF, heart failure; IT, treatment intensification; MI, myocardial infarction

Dyglycaemic

“legacy”Drive risk for

complications

26%

Outline

Evidence for early tight glycaemic control

Therapeutic inertia

Definition

Extent of the problem

Reasons for inertia

Consequences of inertia

Potential solutions

Summary

Interventions to overcome Inertia

Developing quality

measures

Education (CME)

Motivating and

supporting patients

on self-management

Personal

feedback to

HCPs

Adherence to

guidelines

Adherence to

medications

Effective use of

information

systems

CME, continuing medical education.

Zafar A, et al. Prim Care Diabetes. 2010;4:203-7.

Overcoming barriers to injectable therapies

Russell-Jones D, Pouwer F, Khunti K. Diab Obes Met 2017 (online)

Stepping Up trial: logic model

Aim: To test the effectiveness of the

Stepping Up model of care compared

to usual care for T2D in GP

Education and training of PN, GP

Increased confidence and skills of PN

Improved capacity in practice to manage the clinical

work of insulin initiation

Increased numbers of people starting

insulin

Secondary outcome:

Number of patients commencing

insulin Improved glycaemic

outcomes

Primary outcome:

Change in HbA1c

Other outcomes

• Proportion reaching HbA1c ≤ 7%

• Psychometric scores: PHQ-9, PAID,

AQoL-8D

• HypoglycaemiaFurler J et al. BMJ 2017;356:j783

Results – Primary outcome: HbA1c (ITT)

Mixed effects multilevel regression with

adjustment for clustering at the practice level

indicated a 0.7% reduction in HbA1c in the

intervention group compared to the control

group (β -0.7, 95%CI -1.1, -0.4, p<0.001)

Intervention Control

Baseline HbA1c (%) 8.7 (8.1, 9.7) 8.5 (8, 9.6)

12 month HbA1c (%) 7.4 (6.9, 8.2) 8.0 (7.1, 9)

∆ HbA1c (%) -1.3 (1.4) -0.6 (1.5)

Furler J et al. BMJ 2017;356:j783

Significantly more participants in the intervention group commenced insulin

Control Group

ODDS RATIO (95% CI): 8.3 (4.5, 15.4); p<0.001

Intervention Group

25/115 (21.7%) commenced insulin

105/151 (69.5%) commenced insulin

0.7% reduction in HbA1c in the intervention group compared to

the control group (p<0.001)

Furler J et al. BMJ 2017;356:j783

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

Baseline 6 months 12 months 18 months

Intervention Control

Overall effect: –0.48

( –0.76 to –0.21), p = 0.001

Adapted from Crasto M, et al. Diabet Res Clin Pract. 2011;93:328-36.

Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: MEMO study

Ch

an

ge in

Hb

A1c,

%

Impact of education on hypoglycaemia

32.5 29

6.3

42.4

11.2

0 0

10

20

30

40

50

Grade 1 (mild)

Grade 2 (moderate)

Grade 3 (severe)

Hyp

og

lyc

aem

ia e

ve

nts

, %

Control group Intensive group

p < 0.05.

Grade 1 (minor) hypoglycaemia was defined as the presence of hypoglycaemic symptoms with a self-measured capillary blood glucose of

3.1 mmol/L and self-treated; Grade 2 (moderate) hypoglycaemia was defined as a self-measured plasma glucose of < 3.1 mmol/L and self-treated; Grade 3

(major) hypoglycaemia was defined as requiring the assistance of another person.

Crasto M, et al. Diabet Res Clin Pract. 2011;93:328-36.

Actual Costs per Annum of Interventions (£)

£0

£200

£400

£600

£800

£1,000

Conv MF SU

(Glimepiride)

DESMOND (1) Modified

Release

Metformin

SMBG x 1 day Sitagliptin SMBG x 3 day Exenatide

Khunti K et al. Lancet Diab & Endo 2016

Access to structured education poor globally

Summary

T2DM Progressive disease

Tight glycaemic control early associated with longer term benefits

Therapeutic inertia across treatment paradigm common in practice

Many barriers to achieving tight glycaemic targets

Different solutions are needed for different settings

Key issue is INDIVIDUALISING therapies

Earlier and appropriate intervention may improve patients’ chances of reaching goal

Adapted from: Khunti K, et al. Diab Care 2013;36:3411–7;’ Del Prato S, et al. Int J Clin Pract 2005;59:1345–1355

HbA

1c

Time

OAD

monotherapyOAD triple

combination

OAD dual

combinationInsulin

Conventional stepwisetreatment approach

Earlier and more aggressive intervention approach

10

9

8

7

6

8.7%

9.1%

9.7%

8.5%

For all patients

2.9 years 7.2 years

6.7 years

8.4% 8.8%9.0%

For those with

HbA1c ≥7%

Thank you

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