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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
Years from randomization
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
UKPDS Group. Lancet. 1998;352:854-865.
0%
10%
20%
25%
0 3 6 9 12 15
Prop
ortio
n of
pati
ents
with
eve
nts
Years from randomization
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
UKPDS: Microvascular Endpoints in Metformin Study
M vs IP=0.39
M vs CP=0.19
UKPDS Group. Lancet. 1998;352:854-865.
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
Years from randomization
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
M vs. C P=0.01
UKPDS: Myocardial Infarction in Metformin Study
UKPDS Group. Lancet. 1998;352:854-865.
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.
UKPDS Group. Lancet. 1998;352:854-865.
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
(%)
Years from randomization
0
2
4
6
8
0 2 4 6 8 10
UKPDS Group. Lancet. 1998;352:854-865.
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
Years from randomization
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
UKPDS Group. Lancet. 1998;352:837-853.
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.