Barriers to initiation and

intensification of insulin

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 Results from a dietary survey in an Indian
T2DM population : a STARCH study
Region-wise macronutrient
North
15% intake in T2DM group
22%
63%

CONCLUSION
East Data from the present cross-sectional study show that CHO
West 16% constitutes 64.1% of total energy from diet in the T2DM
14% 19%
25% 65%
group, which is higher than the recommended level. There
61% Central was clear non-adherence (self-reported) to dietary advice in
14%
19% the T2DM group. Our findings need to be confirmed in a
67%
larger epidemiological survey.

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South Total carbohydrates (%)
14%
22% Total proteins (%)
64%
Total fats (%)

Joshi SR, et al. BMJ Open 2014;4:e005138

Indian Patients Show Higher PPG Levels
Before Insulin Initiation1

300
279

250 214 218 212

209

200
176

150

100

50

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0
India Italy Poland Canada Russia Greece

Valensi P et al. Int J Clin Pract 2009;63(3):522–31.

Clinical Challenge : T2DM with 2-OAD Failure (HbA1c Is 9.4%*)

Case Presentation:
 Age: 52 years Lab Results:
 Duration of type 2 diabetes: 10 years  FPG: 148 mg%
 FPG = 140-160 mg/dL over 2 mon.  2-hour PPG: 240 mg%
 Weight: 75 kg  TC: 181.5 mg%
 BMI: 23.8 kg/m2  TG: 168.1 mg%
 BP: 135/85 mmHg  HbA1c: 9.1%
 Current Rx:  Microalbuminuria : 18 mg/24 hr
Glimepiride 6mg + Metformin 1000 mg BID

Patient Perspective:

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 For glycemic control … is willing for injectable therapy … but wants minimal injections
 Has predictable daily routine, including meal composition

*Hypothetical patient case.

BID = two times per day; BMI = body mass index; FPG = fasting plasma glucose; PPG = postprandial plasma glucose; QD = four
times per day.
Treatment Strategies Glucose Triad
Treatment strategy should target all three components.
HbA1c

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FPG PPG

FPG = fasting plasma glucose; PPG = postprandial plasma glucose

Ceriello A, Colagiuri S. Diabet Med. 2008;25(10):1151-1156.
Treatment Strategies: Non-Insulins

A. TZD : Will target insulin resistance, CVD risk?

B. DPP4-I : Good option if pt. is needle-averse … but Long-standing diabetes?

Chances of achieving goal ?

C. Stop OAD & start basal/bolus insulin therapy

 Will target both FPG & PPG but multiple daily injections

D. Add a GLP-1 receptor agonist … Good A1c drop but expensive … Long

PP-HI-IN-0110
standing diabetes? Is wt. loss a goal for this patient ?

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; TZD = thiazolidinedione.

Treatment Strategies:
Insulins

• Basal insulin: targets FPG > PPG

• Benefit: Only 1-2 inj/day
• Drawback: Patients may require prandial insulin to reach HbA1c targets

• Premixed insulin: targets both FPG and PPG

• Benefit: Fewer injections than prandial
• Drawback: Unable to adjust components separately

• Prandial (mealtime) insulin: targets PPG > FPG

• Benefit: Most physiologic; best at targeting PPG

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• Drawback: More injections; additional basal insulin required for FPG

Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000.

Why Insulin Mixtures?

• Lispro Mix25, in a BD regimen…

• … provides both basal and rapid-acting insulin, which supplements
1st-phase insulin response & suppresses glucagon production3,4
• … targets both FPG & PPG
• … lowers HbA1c more effectively
• … can be taken just before or immediately after meals.

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1. Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. 2. Unger RH. N Engl J Med. 1971;285(8):443-449. 3. Bruttomesso D, et
al. Diabetes. 1999;48(1):99-105. 4. Roach P, Woodworth JR. Clin Pharmacokinet. 2002;41(13):1043-1057. 5. IDF. Available at:
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 23 March 2012.
Outcome Scenarios on Insulin
Achieve good
glycemic control

Patients who
progress on
therapy
Initial insulin Do not achieve good
therapy glycemic control

Patients who
do not progress
on therapy
Achieve good
glycemic control

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Clinical, humanistic and economic outcomes / predictors

Clinical Diabetes 2005 Apr; 23(2): 78-86.

Effect of Various Insulin Regimen in T2DM
patients with Secondary OHA failure
PPG excursion not normalized

Meal Meal Meal Meal Meal Meal Meal Meal Meal

A 400 B 400 C 400

350 350 350

300 300 300

250 250 250

Glucose Postprandial Excursion: Glucose Glucose
200 130 mg/dL 200 200
(mg/dL) (mg/dL) (mg/dL)
150 150 150
Fasting High:
220 mg/dL Postprandial Excursion:
100 100 85 mg/dL 100 Postprandial Excursion:
Normalized
Fasting Normalized Fasting High:
50 50 50 Normalized

0 0 0

0600 1000 1400 1800 2200 0200 0600 0600 1000 1400 1800 2200 0200 0600 0600 1000 1400 1800 2200 0200 0600

Time of Day Time of Day Time of Day

Untreated Basal Only Pre-mix or Basal

Bolus

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Clinical Diabetes 2005 Apr; 23(2): 78-86.
What comes with Clinical inertia ?

• Prolonged periods of uncontrolled hyperglycemia (if HbA1C persists > 7.0%) …

• Increased risk of complications (MI, HF, stroke, kidney disease) & CV
Mortality

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Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
Levels of clinical inertia in diabetes

NORMAL GLUCOSE PRE-DIABETES CLINICAL DIABETES COMPLICATIONS

TOLERANCE (NGT) [IMPAIRED FASTING GLUCOSE OF (IFG)/
IMPAIRED GLUCOSE TOLERANCE (IGT)]

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PRIMORDIAL PRIMARY SECONDARY TERTIARY
REVENTION PREVENTION PREVENTION PREVENTION

CLINICAL INERTIA

V Mohan et al. Expanding the concept of ‘Clinical Inertia’ in diabetes 2019

Causes Of Clinical & Therapeutic Inertia

Patient-
Related

Clinical
Inertia

Physician-
Related Health-care System -
related

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Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
CLINICAL INERTIA : Patient Related

• Denial of disease
• Lack of awareness of progressive nature of disease leading to feeling of ‘failure’
• Lack of awareness of implications of poor glycemic control
• Fear of side effects (hypoglycaemia, weight gain)
• Concerns over ability to manage more complicated treatment regimens
• Too many medicines
• Treatment costs
• Poor communication with physician
• Lack of support

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• Lack of trust in physician

Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
CLINICAL INERTIA : Health System Related

• No clinical guidelines
• No disease registry
• No visit planning
• No active outreach to patients
• No decision support
• No team approach to care
• Poor communication between physician and staff

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Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
CLINICAL INERTIA : Physician Related
• Time constraints
• Lack of support from e.g. nursing staff
• Concerns over costs of treatment/testing etc.
• Reactive rather than proactive care
• Underestimation of patient’s needs
• Difficulties navigating guidelines and algorithms
• Lack of information or understanding of new treatment options and potential
benefits
• Lack of information on side effects/fear of causing harm (i.e. hypoglycemia)
• Lack of clear guidance on individualizing treatment
• Concerns over patient’s ability to manage more complicated treatment regimens

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• Concerns over patient adherence

Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
When are doctors thinking of using Insulin in
India
IMPROVE™ Study

North South East West

Parameter
n=3031 n=8616 n=1729 n=4619

HbA1c, % 9.2% 9.20 (±1.68) 9.31 (±1.63) 9.44 (±1.82) 9.42 (±1.88)

FBG, mmol/L 194 mg/dL 9.71 (±2.20) 10.63 (±2.99) 11.51 (±3.68) 10.79 (±3.19)
PPBG, mmol/L 285.5 mg/dL
Breakfast 14.24 (±3.28) 15.54 (±3.97) 16.15 (±4.19) 15.78 (±4.10)
Lunch 15.36 (±2.86) 15.86 (±4.25) 16.88 (±4.55) 15.01 (±4.37)
Finner - 10.86 (±2.34) - 13.20 (±2.15)

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Siddharth Shah ∙ A. K. Das ∙ Ajay Kumar ∙ A. G. Unnikrishnan ∙ Sanjay Kalra ∙ M. P. Baruah ∙ B. Ganapathi ∙ R. K. Sahay.
Adv Ther (2009) 26(3):325-335
Tackling clinician barriers

• Setting up channels of computer-based direction and/or specialist feedback to assist GPs who
correctly identified a glycemic anomaly and proceeded with the appropriate treatment regimen.

• Other methods to support GPs have included case management with :

 Practice nurse or pharmacist directing treatment decisions according to an approved

 Detailed treatment algorithm under the supervision of a physician
 Automated appointment reminders for patients.

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Khunti S, Davies MJ, Khunti K. Clinical inertia in the management of type 2 diabetes mellitus: a focused literature review. Br J Diabetes Vasc Dis. 2015;15:65–9.
Tackling patient-level barriers

• Improving patient education … including early initiation

• Improving HCP-Patient communication
• Explaining, at diagnosis, the progressive nature of T2DM and the
possibility of eventual insulin

PP-HI-IN-0110
Khunti S, Davies MJ, Khunti K. Clinical inertia in the management of type 2 diabetes mellitus: a focused literature review. Br J Diabetes Vasc Dis. 2015;15:65–9
Tackling therapeutic barriers

• Keep focus on QOL of patient

• Consider longer-acting insulins (lower risk of hypoglycaemia).
• Combination therapy of INSULIN with the newer classes of
drugs (SGLT2i, GLP-1RAs and DPP4-i) has widened the
options for intensification.
• Fixed-ratio products could be considered as a single daily
injection, simplifying the regimen.

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Khunti S, Davies MJ, Khunti K. Clinical inertia in the management of type 2 diabetes mellitus: a focused literature review. Br J Diabetes Vasc Dis. 2015;15:65–9
 References……….
• Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745.
• Joshi SR, et al,BMJ Open 2014;e005138
• Valensi P et al. Int J Clin Pract 2009;63(3):522–31.
• Schwartz S, et al. Diabetologia. 2003;46(suppl 2):A267.
• Schwartz S, et al. Clin Ther. 2006;28:1649-1657.
• Ceriello A, Colagiuri S. Diabet Med. 2008;25(10):1151-1156
• Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000
• 1. Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. 2. Unger RH. N Engl J Med. 1971;285(8):443-449. 3. Bruttomesso D, et al. Diabetes.
1999;48(1):99-105. 4. Roach P, Woodworth JR. Clin Pharmacokinet. 2002;41(13):1043-1057. 5. IDF. Available at:
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 23 March 2012.
• Clinical Diabetes 2005 Apr; 23(2): 78-86
• Strain et al. Diabetes Ther. 2014 Dec; 5(2): 347–354.
• Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
• V Mohan et al. Expanding the concept of ‘Clinical Inertia’ in diabetes 2019
• Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
• Khunti S, Davies MJ, Khunti K. Clinical inertia in the management of type 2 diabetes mellitus: a focused literature review. Br J Diabetes Vasc Dis.
2015;15:65–9.
 Thank you!

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PP-HI-IN-0110
 Introduction

• Diabetes Rx gaining momentum in India and globally …

• Despite this, glycemic goals not achieved …

• One major reason could be “ Clinical or Therapeutic Inertia”

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Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745.
Levels and consequences of clinical inertia at each
stage of natural history of diabetes
Levels of clinical inertia Consequence

At population level: Not taking steps to improve physical Increases risk of type 2 diabetes in the population
activity or encouraging healthy eating and reducing obesity
rates

In high-risk groups e.g., pre-diabetes: Not doing Losing the opportunity to prevent diabetes
community-based screening to identify pre-diabetes and
altering lifestyle in those with pre-diabetes

In those with new-onset diabetes: Not identifying diabetes Delay in diagnosis which increases the risk of developing
early complications

In those with established diabetes: Not treating diabetes This leads to ‘bad metabolic memory’ or ‘legacy effect’
aggressively in early stages increasing the chances of developing complications of
diabetes

In those with long duration of diabetes: Not screening for Missing the opportunity to identify complications of diabetes at
complications on an annual basis early stages

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In those with early complications: Not aggressively treating the Leads to end-stage complications e.g., renal failure,
complications sets in amputations, heart attacks and strokes

V Mohan et al. Expanding the concept of ‘Clinical Inertia’ in diabetes 2019

What Would Be the Next Step in Therapy for this Patient?

A. No change to therapy – monitor HbA1c again in 3 months

B. Add an additional oral agent (ex: TZD, DPP-4 inhibitor)
C. Add a basal insulin at bedtime
D. Begin a premixed insulin analogue therapy
E. Stop OAD and start basal/bolus insulin therapy
F. Add a GLP-1 receptor agonist

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DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; TZD = thiazolidinedione.
Commonly Used Insulin Régimes in Reality & Issues
? Can we
start once
daily with
Patients failing oral combined treatment premixes?
?
Is OD Basal 1 injection basal insulin 2 injections human mixtures
adequate?
3 2 1

Add one fast-acting insulin

at a time (Basal-plus regimen) 2 injections analog mixtures (Mix25)

3
Hypo &
3 ? Weight gain
4
Basal-prandial regimen (4 injections) = 3 injections analog mixture (Mix25-50)

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Mix 50 initiate
? or intensify?
BASAL-PRANDIAL MIXTURES

Clinical Diabetes 2005 Apr; 23(2): 78-86.

 Clinical or Therapeutic Inertia

DEFINITION
… failure to establish appropriate targets and escalate treatment to
achieve treatment goals.
OR
The failure of healthcare providers to initiate or intensify therapy
when indicated. Physician-, patient- and healthcare-system-related
factors all contribute to clinical inertia.

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Strain et al. Diabetes Ther. 2014 Dec; 5(2): 347–354.
Solution to Clinical inertia ?

ADA guidelines:
Uncontrolled HbA1C requires further intensification to target PPG…
… by addition of a single injection of rapid-acting insulin analogue or a
GLP-1 RA

PP-HI-IN-0110
Okemah J, Peng J, Quiñones M. Addressing Clinical Inertia in Type 2 Diabetes Mellitus: A Review. Advances in Therapy. 2018;35(11):1735-1745
 DISCLAIMER

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When Evaluating Treatment Choices at this Stage, What Do You
Think May Be Your Patient’s Primary Concern?

A. Feelings of guilt or failure

B. Fear of weight gain or hypoglycaemia
C. Misconception of risks
D. Beliefs on treatment efficacy
E. Psychological barriers to insulin therapy

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