Timely Insulin Initiation

Act Timely ...

Avoid Glycaemic Memory…
 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Introduction

• Type 2 diabetes mellitus (T2DM) is characterised by progressive β-cell failure and

worsening of glycaemic control leading to chronic complications
– At time of clinical diagnosis of Type 2 DM beta cell function is only 50%
– UKPDS showed that this continues to deteriorate over time despite:
 Diet
 Exercise
 Anti diabetes medications Diet therapy group

• Insulin is the most effective drug for glycaemic

control
• Numerous barriers delay the use of insulins
• Up to 60% of patients will require insulin within
6 to 10 years of initial diagnosis
Fonseca V. Insulin. 2006;1(2):51-60
Barag SH. J Am Osteopath Assoc. 2011;111(7 Suppl 5):S13-9. 3
 ADA 2017 Guidelines

Usually insulin is not preferred as second or third choice

even though the guidelines suggest

American Diabetes
Association. Diabetes Care
2017;40(Suppl. 1):S64–S74 4
 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Risks Associated with Delaying Insulins

OAD OAD + OAD +

Diet and OAD monotherapy OAD basal multiple daily
10 exercise monotherapy uptitration combination insulin insulin injections

9
HbA1c(%)

Mean

6
Duration of diabetes

Complications

Campbell IW. Br J Cardiol 2000;7:625–631. | 2. Stratton IM, et al. BMJ 2000;321:405–412 6

Unnikrishnan IR, et al. J Assoc Physicians India. 2011;59 (Suppl):8–12
 Risks Associated with Delaying Insulins:
Poor Glycaemic Control

7
Brown JB, et al. Diabetes Care. 2004;27(7):1535–1540
 Real and Ideal Course of Treated T2DM

(First) cardiovascular event

e.g. Myocardial Infarction
9,5  New therapy attempt

Real course
9,0 Build-up of
metabolic memory Ideal course
8,5
HbA1c (%)

8,0 Increasing the risk of

diabetic late
7,5 complications

7,0

6,5

6,0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time (years after diagnosis)

Del Prato, Diabetologia (2009) 52(7),1219- 1226

 Risks Associated with Delaying Insulins:
Ticking Clock Hypothesis

For The “clock starts ticking”

Microvascular At onset of hyperglycemia

complications

Macrovascular Before the onset of

complications hyperglycemia

Diabetes Drafting Group. Diabetologia. 1985;28(suppl):615–640 | Haffner SM, et al. JAMA. 1990;263(21):2893–2898. 10
 Risks Associated with Delaying Insulins:
Increased Complications
Prevalence of complications of diabetes in people with T2DM at the time of initiating
insulin
China S. Asia E. Asia N. Africa Mid East Lat. Amer. Russia
n 9493 21107 9062 3623 11971 1032 2954
Duration of Diabetes (Yrs) 7.9 6.7 12.5 11.4 10.2 15.5 9.6

People with complication (%) 86.1 94 90.3 89.7 79.9 90.7 96.1

Cardiovascular disease (%) 22.9 32.5 29.4 48.5 30.5 35.3 74.6

Renal disease (%) 26.1 28.7 34.6 36.5 43.6 41.8 41.7
Eye Problems (%) 25.6 22 29.9 41.2 36.8 41.2 71
Foot ulcer (%) 2.5 6.5 5.8 3.5 8.7 7.7 5.1
Neuropathy (%) 33.7 29.4 40.1 38.9 56 47.6 84.4
Zilov AV, et al. Diabetes. 2011;60(Suppl. 1):A656:2486-PO 11
 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Patients Barriers

• Myths among patients (Insulin causes blindness, renal failure, amputations, heart
attacks or strokes)
• Sense of personal failure
• Low self-confidence
• Low confidence in therapy
• Injection phobia
• Hypoglycaemia concerns
Feeling that diabetes is a serious cause of concern
• Negative impact on social life and job
• Inadequate health literacy
• Health care provider inadequately explaining risks/benefits
• Limited insulin self management training
Kumar A, et al. JAPI. 2011;59.17–22 13
 Physicians barriers

• Concerns over patients with comorbidities

• Excess weight gain in already overweight patients
• Concerns about patient non-compliance
• Risk of severe hypoglycaemia/adverse effects on QoL
• Lack of resources – drug costs, staff, skills
• Patient refusal

Kumar A, et al. JAPI. 2011;59.17–22 14

 Patient and Physician Beliefs on Insulin
Therapy (GAPP Study)
Reasons for insulin omission/non-adherence
Reason Patients (%) Rank Physicians (%) Rank
Too busy 18.9 1 41.9 3
Travelling 16.2 2 43.6 2
Skipped meal 15.0 3 44.8 1
Stress or emotional problems 11.7 4 32.2 5
Embarrassing to inject in public 9.7 5 36.8 4
Challenging to take it at the same time
9.4 6 29.1 6
everyday
Forgot 7.4 7 2.0 11
Too many injections 6.0 8 26.4 7
Avoid weight gain 4.0 9 13.4 9
Regimen is too complicated 3.8 10 16.8 8
Injections are painful 2.6 11 7.8 10
Peyrot M, et al. Diabet Med. 2012;29(5):682–689 15
 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Earlier intensification of therapy
“improves long-term outcomes”!
OAD plus
multiple
Diet OAD OAD dose OAD OAD plus insulin
and monotherapy increases combination basal insulin injections
exercise per day

10
HbA1c (%)

8
Achieved
mean
HbA1c-values 7

6 Time

Duration of Diabetes

Mod. Campbell IW. Need for intensive, early glycaemic control in patients with Typ-2-Diabetes.
Br J Cardiol. 2000;7(10):625–631. Del Prato S et al., Int J Clin Pract. 2005;59:1345–1355.
 ADA 2017 Guidelines

18
American Diabetes Association. Diabetes Care 2017;40(Suppl. 1):S64–S74
 Benefits of Early Initiation of Insulin

• Early use of insulin shown to improve β cell function

• Insulin therapy early in T2DM shown to induce temporary “remission” of diabetes,

allowing control with diet alone

• Intensive insulin therapy significantly improves β cell function in patients who have
failed maximal doses of OADs

1. Meneghini L. South Med J. 2007;100:164-74 | 2. Chen HS, et al. Diabetes Care 2008;31:1927-32
3. Unnikrishnan IR, et al. J Assoc Physicians India. 2011;59 Suppl:8–12 19
 Benefits of Early Initiation of Insulin:
Mechanisms of β-cell dysfunction

• Increases beta cell mass*

– Decreased apoptosis
– Increased regeneration

• Glucotoxicity#
• Lipotoxicity#
• β-cell exhaustion*#
• Amyloid deposition*
• Oxidative stress#
* worsened by sulfonylurea administration
#improved by insulin

20
 Benefits of Early Initiation of Insulin:
β-cell Rest

• Early intensive insulin therapy in newly diagnosed T2DM patients:

– Favourable outcomes on recovery and maintenance of β-cell function
– Protracted glycaemic remission compared to OADs
– Reverse some effects of glucose toxicity and lipotoxicity
– Improve both insulin sensitivity and insulin secretion

• Short-term insulin treatment may have long-lasting effects when introduced in the
early stages of T2DM

Weng J, et al. Lancet. 2008;371(9626):1753–1760

Palumbo PJ. Cleve Clin J Med. 2004;71(5):385-386,391-392,394,397,400-401,405 21
 Benefits of Early Initiation of Insulin

Insulin alters progression of T2DM

Vinik AI. Insulin. 2006;1(1):2–12 22

 Benefits of Early Initiation of Insulin

UKPDS: effects of management on microvascular endpoints

People with event (%) 30

25% risk
20 reduction
P<0.01
Conventional

10 Intensive

0
0 3 6 9 12 15
Years from randomization

UKPDS Group. Lancet. 1998;352(9131):837–853 23

 Benefits of Early Initiation of Insulin

UKPDS: Effects of treatment on myocardial infarction in T2DM

30
16% risk
People with event (%)

reduction
20 Conventional P=0.052

10 Intensive

0
0 3 6 9 12 15
Years from randomization
Years from randomization
UKPDS Group. Lancet. 1998;352(9131):837–853 24
 Other Benefits of Insulins

• Vasodilation, platelet inhibition

• Antioxidant
• Anti-inflammatory
• Cardioprotective
• Neuroprotective
• Antiapoptotic
• Antithrombotic

Davis SN, et al. Clin Cornerstone. 2008;9(Suppl 1):S28–S40. 26

 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Overcoming barriers to insulin initiation

• Identify patients personal obstructions

– Prompt patient’s thinking with open-ended questions and detailed conversations

• Restore patient’s sense of personal control

– Introduce insulin as a brief, temporary experiment

• Enhance self-efficacy
– Demonstrate insulin use
– Encourage practice before returning home

Polonsky W and Jackson R. Clinical Diabetes. 2004;22:147–150.

 Overcoming barriers to insulin initiation

• Keep things flexible and simple

– Minimise behavioural change recommendations
– Start with a single shot of insulin in combination with oral agents
– Quick follow-up to detect glycaemic improvements or sub-optimal dosing

• Consider insulin pens

– Easier to operate
– Appear less forbidding

Polonsky W and Jackson R. Clinical Diabetes. 2004;22:147–150.

 Overcoming barriers to insulin initiation

• Discuss the real risks of hypoglycaemia

– Hypoglycaemia facts - rare in patients with type 2 diabetes
– Reassurance and education
 Symptom recognition
 More frequent glucose monitoring

• Tackle injection phobias

– Referral for cognitive behavioural therapy

• Review positive benefits of therapy

– Improvements in glycaemic control, mood, and energy levels

Polonsky W and Jackson R. Clinical Diabetes. 2004;22:147–150.

 Overcoming barriers to insulin initiation

Patient Concerns How a Physician Can Respond

Fear: “I’m afraid of needles.” Insulin pens and smaller, thinner needles make injections
almost painless.
Failure: “Going on insulin proves I can’t take control of my The natural course of diabetes is to worsen over time, but
disease.” controlling your blood glucose levels with insulin can slow
that process down.

Stigma: “If people see me taking an insulin shot, they’ll think
I’m a sick person.”
Weight gain: “Insulin will make me fat.”
New injection devices like insulin pens are not very
noticeable, and the needles are smaller and thinner than
they used to be.
I’ll help you find a nutritionist who can teach you how to eat
healthier foods and develop an active lifestyle that helps
keep you trim. And insulin is no more likely to make you fat
than some of the oral agents you’ve been using.

Dushay J, Abrahamson MJ. The Journal of Family Practice. 2010;59(4): E1–E8.

 Overcoming barriers to insulin initiation

Patient Concerns How a Physician Can Respond

Hypoglycemia: “I’ve heard that diabetics who use insulin can pass That’s less likely to happen with the newer forms of insulin we use
out suddenly, or even go into a coma. I think it’s called now. And if you do have a hypoglycemic episode, it will probably be
hypoglycemia, and it scares me.” something mild you can treat yourself. I can teach you how to
recognize what’s happening and what to do about it.

Complexity: “It all sounds too difficult for me to manage on my We have new, step-by-step instructions you can follow when you
own.” start insulin therapy and when you need to make changes.

Complications: “I know people on insulin who have serious
complications like heart attacks and kidney disease. Will that
happen to me?”
Diabetes-related complications are the result of inadequate control
of blood sugar levels. Insulin provides more intensive glycemic
control than you’ve been achieving, and that helps avoid the
complications you’re concerned about. That’s why I recommend you
start using insulin.

Dushay J, Abrahamson MJ. The Journal of Family Practice. 2010;59(4): E1–E8.

 Overcoming barriers to insulin initiation

• Addressing patient’s concerns about hypoglycaemia

• Educating patients regarding symptoms
• Advising frequent blood glucose monitoring
• Dispelling myths
– Most hypoglycaemic episodes are mild to moderate
– Severe episodes are less common in Type 2 diabetes

• Balancing risk of hypoglycaemia against greater risk of diabetes complications

• Using different insulin regimens and formulations that are less invasive and allow
for fewer injections

Korytkowski M. Int J Obes. 2002;26(suppl 3):S18–S24 | Palumbo PJ. Clevel Clinic J of Med. 2004;71(5):385:405.
 Overcoming barriers to insulin initiation

• Addressing patient’s concerns about weight gain

– Dispelling myths
 Insulin associated with weight gain of ~2–4 Kg
 Proportional to the correction of glycaemia
 Predominantly the result of reduction of glycosuria

– Appropriate dietary advise and effective patient education

– Benefits of stringent glycaemic control offset the impact of weight gain

– Use of metformin with insulin helps limit weight gain

Korytkowski M. Int J Obes. 2002;26(suppl 3):S18–S24 | Palumbo PJ. Clevel Clinic J of Med. 2004;71(5):385:405.
 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Initiation and Titration of Premixed Insulin

• Start with 10 U either in the morning (if night-time glucose is high) or at night (if
morning glucose is high)
• If the total insulin dose exceeds 20 U or pre-dinner blood glucose persists >150
mg/dL, then premix insulin can be given twice daily

Time Dose divison

Before breakfast 2/3 total daily dose
Before dinner 1/3 total daily dose

Indian National Consensus Group. JAPI. 2009:57(Suppl.1):42–6 36

 Initiation and Titration of Premixed Insulin

Titrate at regular interval (at least weekly) until

glycaemic goals are achieved

Pre-meal Blood Glucose Change in Insulin Dose (U)

(mg/dL)
≤100 -2
100-110 0
110-140 +2
140-180 +4
≥180 +6

Indian National Consensus Group. JAPI. 2009:57(Suppl.1):42–6 37

 Agenda

• Introduction
• Risks Associated with Delaying of Insulins
• Barriers to initiation of insulin
• Benefits of Early Initiation of Insulin
• Overcoming the barriers
• Initiation and Titration of Premixed Insulin
• Summary
 Summary

• As per guidelines there is a need to aggressively treat diabetes.

• When lifestyle therapy, diet and oral anti-diabetic combination fail to achieve
desired glycemic levels, insulin is advised.
• Early use of insulin is advocated
• Use of insulin helps in Beta cell salvage
• Insulin helps in reduction of the complications associated with diabetes
• Treatment with insulin is associated with greater clinical experience
• It can bring about reduction from any level of elevated HbA1c to/close to goal
• There is no maximum limit of dose for hyperglycemic action
• Insulin has added beneficial effect on lipid profile

39
Thank You