Early Initiation of Insulin

Early Use of Insulin

WHY HOW When How long?

Robert Turner MA, MD, FRCP Professor of Medicine University of Oxford 1938-1999

We dont start insulin early enough, or use it aggressively enough

63% Of Patients with Diabetes Are Not at ADA A1C Goal <7%
Adults aged 20-74 years with previously diagnosed diabetes who participated in the interview and examination components of the National Health And Nutrition Examination Survey (NHANES), 1999-2000
100 80
12.4%
7.8% A1C >10%
>9% >8% 7-8% <7%

% of Subjects 60 n=404 40
20 0

63% 7%

17.0% 25.8%

37.2% >8%

37.0%

Saydah SH et al. JAMA 2004;291:335

Clinical Inertia: Failure to Advance Therapy When Required

Percentage of subjects advancing when A1C < 8%
100 80 % of Subjects 60
35.3%
66.6% 44.6%

At insulin initiation, the average patient had: 5 years with A1C > 8% 10 years with A1C > 7%

40
20 0
Diet Sulfonylurea Metformin Combination 18.6%

Brown JB et al. Diabetes Care 2004;27:1535-1540.

Insulin Glargine Trials Showing Effective Reduction in HbA1c

10 9.5 9 8.61 8.71 8.85 8.80

8.80

HbA1c (%)

8 6.96 7.14 6.96 7.15 7.14 6.80

5
Treat-ToTarget LANMET APOLLO LAPTOP Triple Therapy INITIATE

Baseline

Study endpoint

Insulin Glargine Trials Showing Effective Reduction in HbA1c

10 9.5 9 8.61 8.71 8.85 8.80

8.80

HbA1c (%)

8 6.96 7.14 6.96 7.15 7.14 6.80

5
Treat-ToTarget LANMET APOLLO LAPTOP Triple Therapy INITIATE

Baseline

Study endpoint

Less Hypoglycemia with Insulin Glargine vs NPH

3500 Hypoglycemia events per 100 patient-years 3000 2500 2000 1500 1000 T1DM NPH Insulin glargine

p=0.004 between treatments

6
200 Hypoglycemia events per 100 patient-years 150

8 HbA1c

10

T2DM

p=0.021 between treatments

100
50 0 6 7

Mullins P et al. Clin Ther 2007;29:160719.

8 HbA1c

10

Combined Effects of Metformin with Insulin Therapy in Type 2 Diabetes

Sasali A and Leahy JL. Curr Diab Rep 2003;3:378-

LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures

N=371 insulin-nave patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks Hypoglycaemia* (events/patient year)

Twice-daily premixed insulin Insulin glargine + OADs

p=0.0003 9 8
HbA1c (%)

1.3%

1.7%

5 4 3 2 1

5.7

7 6 5

7.5%

p=0.0009 2.6

7.2%

*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])

Janka H et al. Diabetes Care 2005;28:254259.

Tier 1 : Well-validated core therapies

At diagnosis:
Lifestyle + Metformin Step 1 Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Sulphonlyureasa Step 2

ADA/EASD Revised Consensus Statement (2009)

Lifestyle + Metformin + Intensive Insulin

Step 3

Tier 2 : Less wellvalidated core therapies Lifestyle + Metformin

+ Pioglitazone
No hypglycemia Oedema/CHF Bone loss

Lifestyle + Metformin + Pioglitazone + Sulphonylureas Lifestyle + Metformin + Basal insulin

b

Lifestyle + Metformin + GLP-1 agonistb

David Nathan et al. Diabetes Care 2009; 32:193-203
a

No hypglycemia Weight loss Nausea/Vomitting

A Sulphonylurea other than Glibenclamide or Chlorpropamide

Insufficient clinical use to be confident regarding saf

Tier 1 : Well-validated core therapies

At diagnosis:
Lifestyle + Metformin Step 1 Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Sulphonlyureasa Step 2

ADA/EASD Revised Consensus Statement (2009)

Lifestyle + Metformin + Intensive Insulin

Step 3

Tier 2 : Less well-validated core therapies Lifestyle + Metformin

+ Pioglitazone
No hypglycemia Oedema/CHF Bone loss

Lifestyle + Metformin + Pioglitazone + Sulphonylureas Lifestyle + Metformin + Basal insulin

Lifestyle + Metformin + GLP-1 agonistb

David Nathan et al. Diabetes Care 2009; 32:193-203
a

No hypglycemia Weight loss Nausea/Vomitting

A Sulphonylurea other than Glibenclamide or Chlorpropamide

Insufficient clinical use to be confident regarding saf

The contribution of postprandial glucose excursions and fasting Hyperglycemia is very different at lower and higher HbA1c levels
In early diabetes PPG contributes up to 70% of glucose load
80

At high HbA1c levels fasting hyperglycemia is predominant

Relative contribution (%)

60

50:5 0

Postprandial Excursions Fasting Hyperglycemia

40

20

290 Patients with Type 2 Diabetes

Mean Diabetes Duration 8.8 years

1
(<7,3)

2
(7,3-8,4)

3
(8,5-9,2)

4
(9,3-10,2)

5
(>10,2)

Mean HbA1c: 8.8%

HbA1c quintiles

Monnier L et al. Diabetes Care 2003; 26:88

Area under the Curve

Impact of Postprandial and Fasting Glucose Concentrations on HbA1c Level in Patients with Type 2 Diabetes (n=973) 100 100
90 80

90
80 70 60

70
60 50 40

50
40 30 20 10 0 <6.5% (n=35) 6.5-6.9% (n=246) 7.0-7.9% (n=461) 8.0-8.9% (n=212) 9.0% (n=19)

30
20 10 0

AUC ppg AUC total % ppg

Baseline HbA1C category

Schernthaner G et al. Diabetes, Metabolism & Obesity 2010 (in p

%ppg [%]

What should I tell people with Type 2 diabetes about insulin?

Most people with Type 2 diabetes eventually need insulin because their own production of insulin falls off with time and they therefore inevitably become insulin deficient Diabetes is caused by a progressive failure of insulin production in people who are usually insulin insensitive (overweight)

What should I tell people with Type 2 diabetes about insulin?

If you need insulin, it doesnt mean you failed. Tablets cannot control blood glucose forever, because they dont stop the problem of your own declining insulin production getting worse

Islet -cell dysfunction worsens over time, regardless of therapy

Characteristics of Type 2 Diabetes: Overview

Absolute or relative insulin deficiency

Impaired beta cell function Insulin resistance

Over time, many patients require insulin

Twin components

Fasting hyperglycemia Postprandial hyperglycemia

Different agents may be needed to treat both aspects

Associated disturbances

Hypertension Fasting and postprandial dyslipdemia Atherothrombotic changes

Multiple interventions may be required

Characteristics of Type 2 Diabetes: Overview

Absolute or relative insulin deficiency

Impaired beta cell function Insulin resistance

Over time, many patients require insulin

Twin components

Fasting hyperglycemia Postprandial hyperglycemia

Different agents may be needed to treat both aspects

Associated disturbances

Hypertension Fasting and postprandial dyslipdemia Atherothrombotic changes

Multiple interventions may be required

Timeline for Utilization of Therapies

Case 1

42 year old male No past h/o DM H/o Balanoposthitis, Polyuria, polydipsia Casual Blood glucose 325 mg% Treatment ?

Case 1 contd.

Any Other Information needed ?

Case 1 contd.

HbA1C 7.5%

Case 1 Contd.

Scenario 2 HbA1c 12%

Type 2 Diabetes: Pathogenesis in a Nutshell (cont.)

Increased Insulin Secretion Following Elimination of Glucotoxicity

Case 2

52 yr Male Kn Diabetic Type2 10yrs On Tab Glimeperide 4 mg od Tab metformin 1000mg BD Tab Pioglitazone 30 mg od FPG 130 PPG 190 Next Action?

HbA1C 7.2 %

Alpha Glucosidase Inhibitor Insulin ( ? Which)

The contribution of postprandial glucose excursions and fasting Hyperglycemia is very different at lower and higher HbA1c levels
In early diabetes PPG contributes up to 70% of glucose load
80

At high HbA1c levels fasting hyperglycemia is predominant

Relative contribution (%)

60

50:5 0

Postprandial Excursions Fasting Hyperglycemia

40

20

290 Patients with Type 2 Diabetes

Mean Diabetes Duration 8.8 years

1
(<7,3)

2
(7,3-8,4)

3
(8,5-9,2)

4
(9,3-10,2)

5
(>10,2)

Mean HbA1c: 8.8%

HbA1c quintiles

Monnier L et al. Diabetes Care 2003; 26:88

Case 2 Contd

HbA1C 9.5%

Take Home Message

Start Insulin irrespective of previous treatment if HbA1C > 9-10% to reduce glucotoxicity Start Insulin when Sub maximal doses are unable to maintain HbA1C < 7%

Oral Meds What to Do When Insulin Started (General Rules)

Metformin

Continue unless contraindicated

Sulfonylureas
Continue with basals generally Stop if using large doses of insulin Stop if using premixed insulin

TZDs
Proceed with caution Exacerbates weight gain and edema

Barriers to physician uptake

Knowledge Attitudes Behaviour

Improved outcomes

I didnt know there were guidelines

Its all good in theory, but practice is different

My patients are happy with their care as it is

My patients are better controlled now

I havent read the guidelines

I know whats best for my patients

It takes time time I havent got

Im more confident Im doing the best for my patients

Adapted from Cabana MD et al. JAMA 1999; 282:14581465.

Effect of intensive insulin therapy on betacell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallelgroup trial. Lancet. 2008; 371(9626):1753-60 (ISSN: 1474547X)