Professional Documents
Culture Documents
Diabetes Mellitus
More than 220 million people worldwide have diabetes. In 2004, an estimated 3.4 million people died from consequences of high blood sugar globally. More than 80% of diabetes deaths occur in lowand middle-income countries. WHO projects that diabetes deaths will double between 2005 and 2030 Type 2 diabetes comprises 90% of people with diabetes around the world.
WHO ,Jan 2011 report
18.5-24.9
1. Source: The Global Challenge of Obesity and the International Obesity Task Force http://www.iuns.org/features/obesity/tabfig.htm#Table 1
1. Source: http://www.who.int
1. Mokdad AH et al, Diabetes Care. 2000;23:1278-1283. 2. Mokdad et al. JAMA.1999;282:1519-1522. 3. Mokdad AH et al. JAMA .2001;286:1195-1200
Traditionally, the requirement for insulin was seen as a last resort, once maximal combination oral agent therapy has failed and usually more than 10 years after the diagnosis of T2DM .1
1. Rosenstock J, Wyne K. Insulin Treatment in Type 2 Diabetes. In: Goldstein BJ, Muller-Wieland D (Eds). Textbook of Type 2 Diabetes 2003, pp 131154.
1. King H, Aubert RE, Herman WH. Global burden of diabetes, 19952025: prevalence, numerical estimates, and projections. Diabetes Care 21: 14141431, 1998. 2. Green A, Hirsch NC, Pramming SK. The changing world demography of type 2 diabetes. Diabetes Metab Res Rev 19: 37, 2003. 3. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 10471053, 2004.
1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.J Clin Invest 104: 787794, 1999. 2. McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 718, 2002.
Evidence for B cell loss In a study of pancreatic tissue from 124 autopsies, relative b-cell volume, frequency of b-cell apoptosis, b- cell replication, and the formation of new islets from exocrine ducts were measured .1 I. Relative B-cell volume was decreased by 63 and 44% in both obese and lean persons with T2DM respectively, in comparison with healthy age- and weight-matched non-diabetic controls. II. In addition, subjects with prediabetes also exhibited a 40% decreased relative b-cell volume, suggesting this is etiologically important in the development of T2DM due to a predominance of b-cell apoptosis, which was increased 10-fold in lean subjects and threefold in obese subjects with T2DM.
1. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased betacell apoptosis in humans with type 2 diabetes. Diabetes 52: 102110, 2003.
Early feature of pathogenesis : B cell loss Glucotoxicity + lipotoxicity = B cell apoptosis B cell dysfunction /b cell loss
Indeed, insulin therapy in T2DM can improve peripheral insulin action by correcting glucotoxicity and lipotoxicity and, by also inducing b-cell rest, can potentially enhance insulin secretion and thereby potentially reduce b-cell loss and/or preserve bcell integrity.
Israeli study : 2-week period of intensive insulin therapy. Once the intensive insulin therapy was stopped, most of the patients continued with sustained adequate glycemic control for long periods of time (9 to >50 months with a median of 26 months) without pharmacologic intervention to reduce blood glucose .3
1. Andrews WJ, Vasquez B, Nagulesparan M, Klimes I, Foley J, Unger R, Reaven GM. Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33: 634642, 1984. 2. Pratipanawatr T, Cusi K, Ngo P, Pratipanawatr W, Mandarino LJ, DeFronzo RA. Normalization of plasma glucose concentration by insulin therapy improves insulin-stimulated glycogen synthesis in type 2 diabetes. Diabetes 51: 462468, 2002. 3. Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 20: 13536, 1997
Korean Study1
16-month Korean trial in 92 patients with T2DM of longer duration disease . Overall,34% of the patients went into remission that lasted an average of 14 months after 54 39 days on intensive insulin therapy using an insulin pump.
Note: The criteria for remission was sustained FPG of <108 mg/dL and PPG of <180 mg/dL .
Result : Remission rates were higher when patients started intensive insulin therapy with a shorter diabetes duration (3.3 3 years vs. 9.1 4 years for the remission and non-remission groups, respectively; p < 0.001) . With lower ppg levels and higher C-peptide responses, strongly suggesting better b-cell reserve.
1. 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 19: 124130, 2003.
Epidemiological analysis of the UKPDS data showed a continuous association between the risk of CV complications and glycemia and showed that for each 1% decrease in HbA1c there were significant reductions in major DM-related endpoints, that is, a 37% reduction in microvascular endpoints, a significant 43% reduction in amputation or death from peripheral vascular disease, a significant 14% reduction in combined fatal and non-fatal myocardial infarction.
1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405412,2000
1. University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 19(Suppl. 2):747830, 1970
1. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial: Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med 157:181188, 199
1. UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854865, 1998 2. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 317:703713, 1998 3. UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of both macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ 317:713720, 1998
Risks associated with glitazone therapy in type 2 diabetes, specifically bone fracture and MI ? Debate about appropriate glycated haemoglobin (HbA1c) targets ??? Can Lowering HbA1c to <6.0% reduce macrovascular complications in patients with type 2 diabetes ?
Pioglitazone and rosiglitazone can be employed as oral therapy in patients with type 2 diabetes and preserved endogenous insulin secretion. Potential benefits and risks of each agent should be considered. An acceptable initial target for HbA1c is 7%. Lowering HbA1c to 6.5% did not reduce macrovascular complications in patients with type 2 diabetes, but did reduce new or worsening nephropathy. Aggressive therapy aiming to lower HbA1c to <6% in patients with type 2 diabetes at especially high risk of cardiovascular disease may lead to a higher risk of mortality.
ACCORD trial
10 251 middle aged and older participants with type 2 diabetes at high risk of cardiovascular disease events were randomised into a standard therapy group aiming for HbA1c 7.0 7.9% and an intensive control group aiming for HbA1c of <6% (normoglycemia). The primary outcome was first occurrence of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death. The study incorporated parallel lipid lowering and tight blood pressure control arms, with completion planned in June 2009 to provide 4 8 years (mean 5.6 years) follow up of participants.
1. 1he ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):21133.
Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) 1
A Long Term, Randomised Study in Patients With T2DM, Comparing the Combination of Rosiglitazone and Either Metformin or SFU With Metformin Plus SFU on Cardiovascular Endpoints and Glycaemia The primary outcome, cardiovascular hospitalization or CV death, occurred in 321 and 323 participants assigned to the rosiglitazone and metformin/SFU groups, respectively (HR, 0.99; 95% CI, 0.85-1.16). MI, and stroke was not significant (HR, 0.93; 95% CI, 0.74-1.15) for rosiglitazone vs metformin/SFU.
1. Home PD, Pocock SJ, Beck-Nielsen H et al. The Lancet 2009; 373:2125-2135
1. Home PD et al.Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): A Multicentre, Randomized, Open-Label Trial. Lancet 2009
Thankyou
References : ADA 2011 Guideline. http://www.who.int Mokdad AH et al. JAMA .2001;286:1195-1200 Controversies In treating diabetes ;a clinical and research aspect by Derek LeRoith American Diabetes Association Home Page Website: www.diabetes.org/ Control and Complications in Type II Diabetes. Arch Intern Med 157:181188, 199 McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 718, 2002. Butler AE et al. Beta-cell deficit and increased betacell apoptosis in humans with type 2 diabetes. Diabetes 52: 102110, 2003. The ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):21133. Home PD et al.Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): A Multicentre, Randomized, Open-Label Trial. Lancet 2009 UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854865, 1998 National Heart, Lung and Blood Institute. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, February 6, 2008. Available at www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm [Accessed March 2008]. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial: Veterans Affairs Cooperative Study on Glycemic Look AHEAD Research Group, Wing RR. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes:oneyear results of the look AHEAD trial. Diabetes Care 2007;30:13741383 Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine, 2002. 346(6): p. 393 403 Stratton IM et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405412,2000 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:245771. www.emedicine.com
Individualizing Care
Current Best Practice Guidelines: Any patient that can achieve near-normal glycermia without significant morbidity (especially hypoglycemia and weight gain) or polypharmacy should do so All patients should receive multifactorial therapy (ASA, ACE, ARB, Statin therapy) Patients with short duration of disease, long life expectancy (>10 years), no significant CV disease, should be treated aggressively Patients of advanced age, advanced microvascular or macrovascular disease might do better with less stringent targets (HgA1c 7.5-8.0%) A Position Statement of the ADA, ACC and AHA J Am Coll Cardiol 2009:53:296-304 John Buse Endocrinology 7: 67 (February 2011)
If Type II is Notthe risk equivalent of a prior MI, should ASA even be used at all? Boyko and Meigs Diabetes Care (2011) ASA as primary preventionin lower riskpatients has shown only a modest benefit at any dose, based on a meta-analysis of 90,000 patients Bartolucci et
alAm J Cardiol March 2011