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- 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
- 3. Management of diabetes: Comprehensive benefits of therapies Hyperglycemia Blood Pressure ObesityLipids Beta cell protection CV friendly
- 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
- 6. From an outcome perspective …. UKPDS Metformin arm
- 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
- 20. Cost of therapy Insulin Add monitoring costs Delivery costs Storage costs Metformin Sulphonylurea
- 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
- 26. Thank you
- 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.
Notes de l'éditeur
- 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).