Call Girls Service Chennai Jiya 7001305949 Independent Escort Service Chennai
Â
RSSDI
1. Insulin should be the
first drug in type 2
diabetes
Against the motion …..
Dr Mathew John, MD, DM, DNB
Consultant Endocrinologist
Providence Endocrine & Diabetes Specialty Centre
Trivandrum
www.providence.co.in
2. How will you treat your newly diagnosed
patient with type 2 diabetes ?
A. Insulin
B. Oral hypoglycemic agents
4. 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 ?
5. Ominous Octet
The 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
Insulin
SU
GLP-1 GLP-1
GLP-1
GRA
GLP-1
Metformin
Cabergoline
TZD
7. 0%
20%
40%
60%
0 3 6 9 12 15
Proportionofpatientswithevent
Years from randomization
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
UKPDS: Any Diabetes-Related
Endpoint in Metformin Study
M vs I
P=0.0034
M vs C
P=0.0023
UKPDS Group. Lancet. 1998;352:854-865.
8. 0%
10%
20%
30%
35%
0 3 6 9 12 15
Proportionofpatientswithevents
Years from randomization
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
UKPDS: Diabetes-Related Deaths
in Metformin Study
M vs I
P=0.11
M vs C
P=0.017
UKPDS Group. Lancet. 1998;352:854-865.
9. 0%
10%
20%
25%
0 3 6 9 12 15
Proportionofpatientswithevents
Years from randomization
Conventional (n=411)
Intensive (n=951)
Metformin (n=342)
UKPDS: Microvascular Endpoints
in Metformin Study
M vs I
P=0.39
M vs C
P=0.19
UKPDS Group. Lancet. 1998;352:854-865.
10. M vs. I
P=0.12
0%
10%
20%
30%
35%
0 3 6 9 12 15
Proportionofpatientswithevents
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.
11. UKPDS: Comparison of Metformin
vs. Intensive Therapy Results
Favors
conventional
0.2 1 5
Reduced
risk
Increased
risk
M vs Int RR P value*
Any diabetes-related endpoint
Metformin
Intensive
P =0.0034
0.68
0.93
0.0023
0.46
Diabetes-related deaths
Metformin
Intensive
P =0.11
0.58
0.80
0.017
0.19
All-cause mortality
Metformin
Intensive
P =0.021
0.64
0.92
0.011
0.49
Myocardial infarction
Metformin
Intensive
P =0.12
0.61
0.79
0.01
0.11
Relative risk* (95% CI)
Favors
metformin
*Vs conventional policy.
UKPDS Group. Lancet. 1998;352:854-865.
13. Any episode
Major episodes
UKPDS: Hypoglycemic Episodes
in Metformin Study
Actual Therapy Analysis
0
10
20
30
40
50
0 2 4 6 8 10
Proportionofpatients(%)
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
14. 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
15. 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
Meanchangeinweight(kg)
Conventional Insulin Chlorpropamide
Glibenclamide
UKPDS Group. Lancet. 1998;352:837-853.
16. 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
17. Diabetes therapies and cancer
Kaplan–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
18. Risk of cancer and duration of
insulin
0
1
2
3
4
5
<3 yrs 3-5 yrs > 5 yrs
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
19. What do guidelines say ?
• ADA/EASD
• IDF
• AACE
• NICE METFORMIN
22. 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
23. 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
24. 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
25. 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
27. 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
28. 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
29. 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: 2-12
Weng J, Li Y et al Lancet. 2008 May 24;371(9626):1753-60
30. 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.
31. Ominous Octet
The 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
Insulin
SU
GLP-1
GLP-1
GLP-1
GRA
GLP-1
Metformin
Cabergoline
TZD
32. 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.
Hinweis der Redaktion
This Kaplan-Meier plot shows the proportion of diabetes-related endpoints in patients assigned to conventional, intensive (a sulfonylurea or insulin), or metformin treatment. These diabetes-related endpoints include microvascular and macrovascular complications.2
Patients assigned to intensive blood glucose control with metformin had a significant 32% lower risk of developing any diabetes-related endpoint than patients assigned to conventional treatment (P=0.0023). The metformin group also had significantly greater risk reduction than the group assigned to intensive therapy with a sulfonylurea or insulin (P=0.0034).2
This Kaplan-Meier plot shows that patients treated with metformin had a 42% lower risk of diabetes-related death (P=0.017) than patients assigned to conventional treatment. There were no significant differences in the risk of diabetes-related deaths between those assigned to intensive therapy with metformin and those given sulfonylureas or insulin.2
Metformin-treated patients also had a 36% lower risk of all-cause mortality compared with patients assigned to conventional treatment (P=0.011). This risk reduction with metformin treatment was also greater than in patients treated with a sulfonylurea or insulin (P=0.021).2
This Kaplan-Meier plot shows microvascular endpoints in patients assigned to conventional treatment, intensive treatment with a sulfonylurea or insulin, or intensive treatment with metformin. Microvascular endpoints included retinopathy events and renal failure.2
Microvascular endpoints decreased 29% in overweight patients assigned to metformin therapy (P=0.19). Overweight patients treated with sulfonylureas and insulin exhibited a 16% decrease in microvascular complications (P=0.38).2
Patients assigned metformin treatment had a lower rate of progression to retinopathy at 9 years (P=0.44) than patients assigned conventional treatment. This result was similar to that in the sulfonylurea/insulin intensive therapy group. The proportion of patients with urinary albumin >50 mg/L did not differ among the intensive, metformin, or conventional-treatment groups.2
This Kaplan-Meier plot shows the proportion of patients experiencing myocardial infarction. Cardiovascular disease accounted for 62% of the mortality in overweight patients assigned to conventional treatment.
Patients assigned to the metformin group had a significant 39% lower risk of myocardial infarction than patients assigned to conventional treatment (P=0.01), but this risk reduction was not significantly different from that of the intensive-treatment group.2
For all macrovascular diseases together (myocardial infarction, sudden death, angina, stroke, peripheral vascular disease), metformin-treated patients had a 30% lower risk (P=0.020) than the conventional-treatment group.2
Assigning treatment with metformin to overweight patients significantly reduced the risk of developing any diabetes-related endpoint, experiencing a myocardial infarction, diabetes-related death, and death from any cause. When compared with intensive treatment (sulfonylurea or insulin), metformin significantly reduced the risk of developing any diabetes-related endpoint and all-cause mortality.2
Overweight patients allocated to metformin had a risk reduction in any diabetes-related endpoint of 32% compared with a 7% reduction for patients assigned to intensive therapy with sulfonylureas or insulin (P=0.0034). Patients treated with metformin had a 42% lower risk of diabetes-related death. There were no significant differences in diabetes-related death between those assigned to intensive therapy with metformin and those assigned to other intensive therapy (P=0.11).2
The reduction in risk for all-cause mortality was significant between groups (P=0.021), with a risk reduction vs conventional therapy of 36% for the metformin group and 8% for the intensive-therapy group (P=0.021). The risk of myocardial infarction was reduced by 39% in the group assigned to metformin therapy and by 21% in the group assigned to other intensive therapies (P=0.12).2
This slide shows the proportion of patients experiencing one or more major hypoglycemic episodes (ie, requiring third-party assistance or medical intervention) and those with any hypoglycemic episode, as based on actual therapy analysis rather than intention-to-treat analysis. All hypoglycemic episodes were most common in patients on insulin therapy; during the first few years of therapy, hypoglycemic episodes were also frequent in patients on chlorpropamide or glibenclamide but the number of episodes fell as FPG increased. The proportion of patients experiencing episodes of hypoglycemia was generally similar in patients on metformin and conventional treatments. There were fewer episodes of hypoglycemia with metformin than with any other intensive therapy.2
Over 10 years of follow-up, the proportions of patients per year taking the allocated treatment who had at least one major hypoglycemic episode were 0.7%, 0.6%, 2.5%, 0.3%, and 0% for patients on conventional, chlorpropamide, glibenclamide, insulin, and metformin therapy, respectively. The corresponding proportions for any hypoglycemic episode were 0.9%, 12.1%, 17.5%, 34.0%, and 4.2%, respectively.2
Patients on intensive therapy gained more weight than those on conventional therapy (white), with insulin therapy resulting in the greatest weight gain. Significantly, at 11 years, those on chlorpropamide gained about 2.6 kg (5.7 lb), those on glibenclamide gained about 1.7 kg (3.8 lb), and those on insulin gained about 4.0 kg (8.8 lb) more than those patients on conventional therapy.1
Rate of progression of solid tumour cancers in people with diabetes receiving alternative glucose-lowering therapies (metformin monotherapy, black lines; sulfonylurea monotherapy, green lines; sulfonylurea plus metformin, blue lines; insulin-based therapy, red lines) and a group with no diabetes treatment exposure (grey lines). a
Unadjusted (Kaplan–Meier curve). b Adjusted for confounding factors (age, sex, smoking status and prior cancer) using a Cox proportional hazards model
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). Those with fewer than three years of insulin therapy had an adjusted OR for CRC of 1.4 (95% CI, 0.6 - 2.9; P = 0.5), while those with three to five years of insulin exposure were at significantly higher risk (OR, 2.9; 95% CI, 1.1 - 7.7; P = .03). Those with more than five years of insulin use were at the greatest risk of developing CRC (OR, 4.7; 95% CI, 1.3 - 16.7; P = .02).