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Insulin should be the first drug in type 2 diabetes

Against the motion …..

Dr Mathew John, MD, DM, DNBConsultant Endocrinologist

Providence Endocrine & Diabetes Specialty CentreTrivandrum

www.providence.co.in

How will you treat your newly diagnosed patient with type 2 diabetes ?

A. Insulin B. Oral hypoglycemic agents

Management of diabetes: Comprehensive benefits of therapies

Hyperglycemia

BloodPressure

Obesity Lipids

Beta cell protection CV friendly

Why insulin is not the choice ?

From a pathophysiological perspective ? From an evidence perspective ? From an outcome From the adverse event ? From a guideline perspective ?

Ominous OctetThe pathophysiology of type 2 diabetes

Ralph A. DeFronzo From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus DIABETES, VOL. 58, APRIL 2009

SGLT 2 blockers

TZD

InsulinSU

GLP-1 GLP-1

GLP-1 GRA

GLP-1 Metformin

CabergolineTZD

From an outcome perspective ….

UKPDS Metformin arm

0%

20%

40%

60%

0 3 6 9 12 15

Prop

ortio

n of

pati

ents

with

eve

nt

Years from randomization

Conventional (n=411)

Intensive (n=951)

Metformin (n=342)

UKPDS: Any Diabetes-Related Endpoint in Metformin Study

M vs IP=0.0034

M vs C P=0.0023

UKPDS Group. Lancet. 1998;352:854-865.

0%

10%

20%

30%

35%

0 3 6 9 12 15

Prop

ortio

n of

pati

ents

with

eve

nts


Conventional (n=411)Intensive (n=951)Metformin (n=342)

UKPDS: Diabetes-Related Deaths in Metformin Study

M vs IP=0.11

M vs C P=0.017


0%

10%

20%

25%

0 3 6 9 12 15

Prop

ortio

n of

pati

ents

with

eve

nts



Intensive (n=951)

Metformin (n=342)

UKPDS: Microvascular Endpoints in Metformin Study

M vs IP=0.39

M vs CP=0.19


M vs. IP=0.12

0%

10%

20%

30%

35%

0 3 6 9 12 15

Prop

ortio

n of

pati

ents

with

eve

nts



Intensive (n=951)

Metformin (n=342)

M vs. C P=0.01

UKPDS: Myocardial Infarction in Metformin Study


UKPDS: Comparison of Metforminvs. Intensive Therapy Results

Favors conventional

0.2 1 5Reducedrisk

IncreasedriskM vs Int RR P value*

Any diabetes-related endpoint Metformin Intensive

P =0.00340.680.93

0.00230.46

Diabetes-related deaths Metformin Intensive

P =0.110.580.80

0.0170.19

All-cause mortality Metformin Intensive

P =0.0210.640.92

0.0110.49

Myocardial infarction Metformin Intensive

P =0.120.610.79

0.010.11

Relative risk* (95% CI)

Favors metformin

*Vs conventional policy.


Adverse effect perspective

Any episodeMajor episodes

UKPDS: Hypoglycemic Episodes in Metformin Study

Actual Therapy Analysis

0

10

20

30

40

50

0 2 4 6 8 10

Prop

ortio

n of

pati

ents

(%)


0

2

4

6

8

0 2 4 6 8 10


Conventional InsulinChlorpropamide Glibenclamide Metformin

Insulin and hypoglycemia

Wrighta AD. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, Metformin, or insulin for 6 years from diagnosis: UKPDS73 Journal of Diabetes and Its Complications 20 (2006) 395– 401

Grade 1-4 hypoglycemia Grade 2-4 hypoglycemia


UKPDS: Change in Weight With Sulfonylureas vs. Insulin

Cohort, Mean Data

0.0

2.5

5.0

7.5

10.0

0 2 4 6 8 10

Mea

n ch

ange

in w

eigh

t (kg

)

Conventional Insulin Chlorpropamide

Glibenclamide


The graph illustrates that the QALY decrement associated with an increase in weight and hypoglycaemia by approximately 3 kg and 30%, respectively, will offset the QALY gain associated with a 1% reduction in HbA1c

(McEwan, Evans. Diab, Obesity and Metab; In Press)

Relationship between weight gain, hypoglycaemia and quality of life

QALY gain associated with 1 % improvement in HbA1c is offset by a 3 kg increase in weight

Diabetes therapies and cancerKaplan–Meier curves adjusted for confounding factors (age, sex, smoking

status and prior cancer) using a Cox proportional hazards model

Currie CJ, Poole CD, Gale EAM The influence of glucose-lowering therapies on cancer risk in type 2 diabetes Diabetologia (2009) 52:1766–1777

Metformin

No treatment

Sulphonylurea

Insulin

Risk of cancer and duration of insulin

<3 yrs 3-5 yrs > 5 yrs 0

0.51

1.52

2.53

3.54

4.55

The risk of CRC was found to increase with duration of exposure to insulin use, the odds ratio increasing by 1.21 for each additional year of insulin use (95% CI, 1.03 - 1.42; P = .02).

Gastroenterology 2004;127:1044-1050

What do guidelines say ?

• ADA/EASD• IDF • AACE • NICE METFORMIN

Cost of therapy

InsulinAdd monitoring costsDelivery costs Storage costs

Metformin

Sulphonylurea

Convenience of treatment

The argument always is

Newer insulin analogs reduce risk of hypoglycemia……….

• Evidence : “ Benefits in terms of reduced hypoglycaemia were inconsistent”

Newer methods of insulin delivery reduce further risk

“ I am waiting for close loop CSII”

Singh SR . Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis CMAJ 2009;180(4):385-97

Trials looking at “ Insulin as first drug in type 2 diabetes”

• Weng J, Li Y et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomized parallel-group trial. Lancet. 2008 May 24;371(9626):1753-60.

• Li Y, Xu W et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care. 2004 Nov;27(11):2597-602.

• Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. Diabetes Metab Res Rev. 2003 Mar-Apr;19(2):124-30

Summary of trials

• Short duration of intervention ( normoglycemia for 2 weeks)

• Follow up period : 1 year • Not blinded • Used CSII in significant number of patients

Why insulin is not the first drug in type 2 diabetes ?

• Pathophysiology • Evidence from trials • Adverse events • Guidelines • Why “ insulin first“ trials are not that great

Thank you

Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with

newly diagnosed type 2 diabetes

• More patients achieved target control in insulin group ( 97.1% , 95.2 % , 83.5 % CSII, MDI, OHA) • The control was achieved in less time ( 4 days, 5.6 days, 9.3 days )

• Remission rates were significantly higher in the insulin group (51.1 % in CSII, 44.9 % in MDI, 26.7 % in OHA p: 0.0012)

• Beta cell function as represented by HOMA B and acute insulin response improved after intensive interventions

• Acute insulin response was sustained in the insulin group but reduced in the OHA group at 1 year.

Weng J, Li Y et al Lancet. 2008 May 24;371(9626):1753-60

Other studies supporting use of insulin

as initial therapy in type 2 diabetes • 138 treatment naïve patients with type 2 diabetes • FPG > 200 mg/dl • CSII for 2 weeks • 126 achieved normoglycemia ( FPG < 110 mg/dl, PPG < 144 mg/dl) within

6.3 days

• % of patients maintaining euglycemia at 3, 6, 12 and 24 months were 72.6 % , 67 % , 47.1% and 42.3 %

• Patients who maintained normoglycemia > 12 months showed significant improvement in beta cell function especially FPIR

Li Y, Xu W Diabetes Care. 2004 Nov;27(11):2597-602

How does this work ?

• Beta cell rest • Reversing glucotoxicity• Reversing lipotoxicity • Ant apoptotic effect /anti inflammatory effect • Improved GLP –1 effect

Vinik A: benefits of early initiation of insulin , Insulin 2006;1: 2-12Weng J, Li Y et al Lancet. 2008 May 24;371(9626):1753-60

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type

2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

• 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years),

• Randomised to SU vs. Insulin vs. diet • Target FPG < 6 mmol/L • There was no difference in HbA1c among agents in the intensive group.

• Was no difference for any of the three aggregate endpoints between the three intensive agents ( any diabetes related end point, diabetes related death, all cause mortality )

• Weight gain was more with insulin

Lancet. 1998 Sep 12;352(9131):837-53.

Ominous OctetThe pathophysiology of type 2 diabetes

Ralph A. DeFronzo From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus DIABETES, VOL. 58, APRIL 2009

SGLT 2 blockers

TZD

InsulinSU

GLP-1

GLP-1

GLP-1 GRA

GLP-1 Metformin

CabergolineTZD

Disclaimer

The material for these slides were derived from various sources including pictures and cartoons from the world wide web. I have tried my best to acknowledge all possible sources and references. However, if I have overlooked any particular reference, it is not done intentionally. Anyone reproducing materials from this presentations should acknowledge the author of the original work.

Cartoons are made to simplify certain concepts. The presenter should attach explanations to all cartoons or else it will appear quite amateurish.

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