Controversies in type 2 diabetes mellitus

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Diabetes mellitus

Diabetes mellitus

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  • In this vast field of medicine there has always been controversies and debates regarding different topics , ….regarding the ethical issues ..regarding topics like euthanasia ,organ transplantation ,cloning n gene therapy ,pregnancy related issues,regadring the cohices of drugs and its adverse effects,and in the field of medical management n so on…and the best part is that these controversies drives the clincians the medical reseachers to carry out different trials and experiments and the resultss n the outcomes makes the treatment more evedence based giving the practitioners the best treatment options to the patients.
  • Who jan 2011 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 low- and 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. As dm and its complications are related to almost all organ system of the body so there occurs a vast numbers of topics to be discussed and among them I have listed here few for the discussion.
  • Obesity is defined as an excess of body adiposity. as adiposity is not easy to measure in routine examinations For practical reasons, body weight has been used as a relationship for adiposity .EARLEIR obesity was defined by reference to an “ideal body weight,” since the 1980s, the ideal body weight approach was replaced by BMI, and the commonly used cutoffs for overweight (BMI 25–30) and obesity (BMI >30), for both men and women.
  • Obesity is defined as an excess of body adiposity. For practical reasons,, as adiposity is not easy to measure in routine examinations. body weight has been used as a relationship for adiposity Until the 1970s, obesity was defined by reference to an “ideal body weight,” since the 1980s, the ideal body weight approach was replaced by BMI, and the commonly used cutoffs for overweight (BMI 25–30) and obesity (BMI >30), for both men and women.
  •   In 1995, there were an estimated 200 million obese adults worldwide. As of 2000, the number of obese adults has increased to over 300 million. Contrary to conventional wisdom, the obesity epidemic is not restricted to industrialized societies; in developing countries, it is estimated that over 115 million people suffer from obesity-related problems. It is well accepted that obesity and a sedentary lifestyle are related to the development of type 2 diabetes. The epidemic rates of obesity have heightened interest in efforts to prevent obesity through interventions in young children and public health approaches, such as development of walking paths and taxation of junk foods. Although such efforts are important, they is a part of belief that once a person becomes overweight, there is no chance of recovery. The purpose of this topic slides is to present evidence to the contrary—showing that successful weight loss is indeed possible and that lifestyle intervention can play an important role in the prevention and treatment of diabetes. In addition, I have added specific issues of debate, 1. related to the type of diet and 2. the level of physical activity that should be prescribed for weight loss, 3. whether weight loss programs have adverse effects. Greater weight means a higher risk of insulin resistance, because fat interferes with the body's ability to use insulin.
  • as slide shows that as there is increasing prevalence of obesity in the period interval of 10 years,there is also increasing prevalence of dm .so this clearly mentions the Rfelationship between dm and obesity. Number of datas clearly show that obesity is indeed the most common risk facotr for dm. in given in terms of prevalence of dm with mean weight of the population from the year 1990 to 2000.and it shows that there is simultaneously increasing in prevalence of dm with mean weight and year.
  • Mokdad et al did a survey study on 195005 peoples. with Objective To estimate the prevalence of obesity and diabetes among US adults in 2001. Results In 2001 the prevalence of obesity (BMI ≥30) was 20.9% vs 19.8% in 2000, an increase of 5.6%. The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%. The prevalence of BMI of 40 or higher in 2001 was 2.3%. Overweight and obesity were significantly associated with diabetes, high blood pressure and high cholesterol. Compared with adults with normal weight, adults with a BMI of 40 or higher had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels 95percednt ci: 95 percent confidence that those having bmi above 40 percent has chance to get diabetes in between 6.39-8.50 Odd ratio : those who have bmi 40 or higher 7 times more getting dm than normal So this slide shows strong association of dm with obesity.
  • Behavioral weight-loss interventions that focus on diet and/or exercise are considered the most effective treatments for obesity. Such programs have also been proven effective in treating and reducing the risk of developing type 2 diabetes.  Probably the strongest evidence for the benefits of lifestyle intervention come from diabetes prevention program studies. Of particular note is the Diabetes Prevention Program (1) conducted in 27 clinical centers in the USA. This study involved 3234 overweight individuals (BMI > 24 kg/m2; BMI >22 kg/m2 in Asian Americans) with impaired glucose tolerance. And the average age was 51 years both men and women: 68% were women and 45% were members of minority groups. These participants were randomly assigned to receive either intensive lifestyle intervention or standard lifestyle intervention combined with Metformin (850 mg twice daily) or placebo. The intensive lifestyle intervention involved 16 individual sessions over 24 weeks followed by a contact at least every 2 months (typically once a month)throughout the trial. The goals of the lifestyle intervention were to lose 7% of initial body weight, maintain this weight loss, and achieve at least 150 min/week of physical activity using activities that were similar in intensity to brisk walking. The lifestyle intervention used in DPP was effective in producing weight loss and increased physical activity, both short and long term. Fifty percent of lifestyle participants achieved the 7% weight loss goal at week 24, and 38% achieved this goal at study end. Using self-reported diary data, 74% met the physical activity goal at 24 weeks and 58% at the final visit. The intervention was extremely effective in reducing the risk of diabetes.The crude incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100-person year for placebo, metformin, and lifestyle, respectively. Thus, lifestyle intervention reduced the risk of diabetes by 58% compared with placebo, and metformin reduced the risk by 31%. Moreover, lifestyle intervention was effective in all age, gender, and ethnic subgroups.
  • Behavioral Weight-Loss Programs  The behaviors targeted in behavioral weight-loss programs are primarily diet and exercise, which are altered through behavioral modification techniques. A "state-of-the-art" weight-loss program typically consists of 16–24 treatment sessions delivered over a 6-month period. 5  A group treatment format is typically used, with 10–20 participants and a multidisciplinary team of therapists (nutritionists, behavior therapists, and exercise physiologists). Participants are given calorie goals of approximately 1,200–1,500 calories per day. These calorie goals are selected to produce an energy deficit of 500–1,000 calories per day and consequently a 1–2 pound-per-week weight loss. Fat gram goals are typically equal to a 20–25% fat diet. Participants are encouraged to expend a minimum of 1,000 calories per week through moderate physical activity (e.g., brisk walking for 30 minutes, 5 days per week). 6
  • Fifty percent of lifestyle participants achieved the 7% weight loss goal at week 24, and 38% achieved this goal at study end. The intervention was extremely effective in reducing the risk of diabetes.The crude incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100-person year for placebo, metformin, and lifestyle, respectively. Thus, lifestyle intervention reduced the risk of diabetes by 58% compared with placebo, and metformin reduced the risk by 31%.
  • Look AHEAD(Action for Health in Diabetes) is a large clinical trial designed to determine whether long-term weight loss will improve glycemia and prevent cardiovascular events in subjects with type 2 diabetes. One-year results of the intensive lifestyle intervention in this trial show an average 8.6% weight loss, significant reduction of A1C, and reduction in several CVD risk factors (134), with benefits sustained at 4 years (135). Major Independent Risk Factors: Cigarette smoking  Elevated blood pressure ,Elevated serum total (and LDL) cholesterol ,Low serum HDL cholesterol  Diabetes mellitus ,Advancing age Other Risk Factors: Abdominal obesity ,Physical inactivity ,Family history of premature coronary heart disease  Elevated serum triglycerides  Elevated serum homocysteine  Prothrombotic factors (eg, fibrinogen)  Inflammatory markers (eg, C-reactive protein)
  • But is there Successful long term Weight Loss in Individuals with Diabetes Some studies added some newer facts. In one study, 12 diabetic patients and their non-diabetic spouses were enrolled together in a behavioral weight loss program. Although patients and spouses were of similarage and weight, those with diabetes lost only 7.5 kg over 20 weeks, whereas their non-diabetic spouses lost 13.4 kg (36) . In another comparison of 20 women with type 2 diabetes and 23 non-diabetic women treated together in a 16-week behavioral weight loss program, initial weight losses were comparable (7.4 and 6.4 kg for diabetic and non-diabetic subjects, respectively), but at 1-year follow-up, those with diabetes maintained a weight loss of 2 kg, whereas the non-diabetics retained a weight loss of 5.4 kg (37) . The same phenomenon has been observed in studies with weight loss medications. In both within and between study comparisons, individuals with diabetes have smaller weight losses than those without diabetes, and this difference occurs in participants treated with the weight loss medication and in those on placebo (38,39) . This shows that despite extensive behavioral weightloss program diabetes pt lost lesser weight than the non diabetes in the short term and also in the long term period.
  • There are several reasons why individuals with diabetes may be less successful at weight loss. As glycemic control improves with weight loss, individuals with diabetes may have decreased excretion of calories in their urine, thereby reducing their weight loss. As diabetics in poor glycemic control have more elevated energy expenditure, this too may normalize with weight loss and improved glycemic control. Physical problems associated with diabetes, including neuropathy, may limit physical activity. There may also be psychological reasons for poorer weight loss, including a longer history of failure to lose weight, and perhaps more frequent occurrence of depressive symptomatology. Finally, many of the medications used to improve glycemic control, including sulfonylureas, thiazolidinediones, and insulin, enhance anabolism and promote weight gain. As all of these factors may make weight loss more difficult, more intensive approaches may be needed to produce weight loss in individuals with diabetes. However, even individuals with diabetes can indeed lose weight successfully.
  • How exercise help Exercise helps increase insulin sensitivity (pancreas doesn’t need to secrete as much insulin) Exercise promotes the utilization and breakdown of blood glucose, thus lowering it’s circulatory levels During post-workout, glycogen depletion prompts glucose uptake (thus lowering blood glucose); minimal insulin is required for this mechanism to occur Developing muscles (particularly from resistance exercise) store greater quantities of glycogen, which increases glucose clearance from blood Various fats contain different proportions of saturated and  unsaturated fat . Examples of foods containing a high proportion of saturated fat include animal fats such as  cream ,  cheese ,  butter , and  ghee ;  suet ,  tallow ,  lard , and fatty  meats ; as well as certain vegetable products such as  coconut oil , cottonseed oil ,  palm kernel oil ,  chocolate , and many prepared foods. [1 If adult with dm chhose to use alcohol ,daily intake should be limited to a moderate amount ie 1 drink /d or less for adult women and 2 drink per day or less for adult men. Low fat vs low calories studies did not find significant difference. Weight loss 5 to 7 % of body weight.
  • Regarding the long-term consequences of hyperglycemia,in particular the onset and progression of vascular (micro- and macrovascular) complications, insulin therapy is increasingly seen as a key intervention in type 2 diabetes mellitus (T2DM). Major advances in insulin therapy include changes in the different formulations of insulin available and in how insulin can be delivered. The advent of long-acting insulin analogues for early basal replacement and rapid-acting insulin analogue for progressive prandial replacement can have a major impact in the management. Basal insulin provision is intended to inhibit hepatic glucose production in an attempt to normalize fasting blood glucose. When normalization is achieved, but the HbA1c remains above the defined HbA1c target of 7%,attention should then be focused on assessing and correcting the postprandial glucose excursions. This approach is very simple to understand its like, to “fix fasting first,” and then an escalation of therapy to include prandial insulin as required when the HbA1c exceeds 7%. The current treatment debate in T2DM is not about insulin, but when and how to introduce simple insulin regimens, to achieve long-term near normoglycemia with minimal effort,.
  • Traditionally, the requirement for insulin is seen as a “last resort,” once maximal combination oral agent therapy has failed and usually more than 10 years after the diagnosis of T2DM (7). Earlier insulin replacement may have further benefit and result in sustain long-term benefits by achieving good glycemic control thereby reducing progression of vascular complications, which remain the ultimate objectives in the management of patients with T2DM.
  • Why there is a need for early insulin replacement in t2dm Worldwide, the number of cases of diabetes is expected to increase exponentially,with current estimates suggesting an increase from around 170 million in 2000 to approximately 370 million persons by 2030 Given that T2DM accounts for most cases (>90%), a reevaluation of the approach taken to effectively manage T2DM, including a reassessment of the role of insulin in reaching and sustaining glycemic targets to prevent long-term complications of T2DM, is essential.
  • When should insulin be started in T2DM depends on two critical scenarios that will require solid evidence regarding the potential benefits of early insulin initiation: Can early insulin therapy “rest” the b cell and preserve its function and integrity? 2. Is early insulin therapy needed to reach glycemic targets for cardioprotection? Not needed Preliminary evidence suggests that early insulin therapy reduces strain on the b cell by correcting “glucotoxicity” and “lipotoxicity.” This b-cell “rest” may preserve function and structural integrity, which in turn can facilitate durability of glycemic control (17). Epidemiological data suggest the need to fully normalize glucose control as CV risk is already increased even in the upper normal range of the HbA1c levels or in the pre-diabetes state (18–20). If the ongoing interventional glucose control outcome studies demonstrate a reduction in CV events with even lower HbA1c levels, achievable only with early insulin supplementation in combination with other glucose-lowering agents, the use of insulin will play an increasing role in T2DM management (6). Currently, initiation of insulin therapy is generally considered only if the HbA1c level remains >7% despite maximized oral combination therapy. However, the decision-making process for insulin initiation may turn out to be even lower at >6.5% or perhaps >6% if the CV outcomes of the interventional studies are positive, which will necessitate insulin therapy in most patients with T2DM.
  • Early Insulin Therapy and and b-Cell Preservation b -Cell Dysfunction and b -Cell Loss: Key Defects in Type 2 Diabetes There is strong evidence that b-cell dysfunction is a fundamental underlying genetic abnormality in the pathogenesis of T2DM that cannot develop solely because of insulin resistance. Early b-Cell dysfunction is the key for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and finally to T2DM (21) . There is evidence that suggest As insulin fails to suppress lipolysis, the increased concentrations of free fatty acids (FFAs) combined with progressive hyperglycemia act negatively on pancreatic b cells and insulin-sensitive tissues to further inhibit both insulin secretion and peripheral action (23) .
  • Recent evidence has suggested that the progressive insulin deficiency in T2DM is not only a functional defect of the b cell but a decrease in b-cell mass (Ref) because of increased apoptosis. 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 (24) . 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. 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.
  • It appears that b-cell loss is an early feature of the pathogenesis of T2DM. The implications for treating T2DM from this perspective of b-cell dysfunction and progressive b-cell loss are that strategies that limit glucotoxicity and lipotoxicity can potentially reduce the increased rate of b-cell apoptosis, and therefore, at least partial restoration of b-cell mass may be possible as islet neogenesis remains intact resulting in increased functional b-cell mass. 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 b-cell integrity .
  • Preliminary support for the hypothesis of insulin-mediated “b-cell rest” is provided by the several studies, as briefly reviewed here , in which newly diagnosed patients with severe hyperglycemia treated only with shortterm intensive insulin therapy were subsequently able to maintain nearnormoglycemic control without any pharmacologic intervention for prolonged periods of time. The rationale for such an approach in T2DM came originally from short-term intensive insulin therapy studies performed over the period of 20 years that demonstrated improved insulin action and increased endogenous insulin secretion probably induced by reversing glucotoxicity and lipotoxicity ( 27 – 31 ). Further preliminary support for this “b-cell rest” hypothesis is provided by a small uncontrolled Israeli study in newly diagnosed hyperglycemic patients with T2DM subjected to a short, 2-week period of intensive insulin therapy, resulting in near-normoglycemia.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 (32) .  
  • A similar principle was applied in a larger, but still uncontrolled 16-month Korean trial in 92 patients with T2DM of longer duration disease (33) . 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. The criteria for remission was sustained FPG of <108 mg/dL (6.0 mmol/L) and postprandial glucose (PPG) of <180 mg/dL (10.0 mmol/L). It is important to note that 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) and with lower postprandial blood glucose levels and higher C-peptide responses, strongly suggesting better b-cell reserve. These intriguing findings, albeit with relatively few patients, suggest that the earlier introduction of insulin treatment in T2DM might halt disease progression and the increased endogenous insulin secretion may permit the use of simpler insulin-replacement regimens alone or in combination with oral agents for long-term maintenance of near-normoglycemic control and impact on the prevention of costly complications.
  • Early Insulin Therapy and Cardioprotection Sustained near-normoglycemia is the primary treatment goal in the prevention of diabetes-related complications. 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, and a significant 14% reduction in combined fatal and non-fatal myocardial infarction (5) .
  • intervention at the time of diagnosis with metformin in combination with lifestyle changes and continuing timely augmentation of therapy with additional agents (including early initiation of insulin therapy) as a means of achieving and maintaining recommended levels of glycemic control (i.e., A1C 7% for most patients). As A1C targets are not achieved,treatment intensification is based on the addition of another agent from a different class. The overall objective is to achieve and maintain glycemic control and to change interventions when therapeutic goals are not being met.
  • An association between the complications of diabetes and elevated blood glucose levels was postulated in the early part of this century. However, only in the last 3 decades has a substantial body of animal experimental studies and human observational studies and clinical trials directly linked hyperglycemia with the development of diabetic complications ( 1 ). Some of these studies have also demonstrated that treatment that lowers blood glucose reduces the risks of diabetic retinopathy, nephropathy, and neuropathy.
  • Many of the observational studies also support a correlation between glycemic control and diabetic complications in patients with type 2 diabetes, but until now, there have been only three randomized controlled trials attempting to test the benefit of lowering blood glucose on the incidence of complications. The first of these studies was the University Group Diabetes Program (UGDP), which showed no benefit of glycemic control in new-onset type 2 diabetic patients ( 4 ). However, in the UGDP, there were only 200 subjects in each treatment group, HbA 1c  was not available as a reliable method for measuring chronic glycemia, and the difference in glucose control between the most intensively treated group and the other treatment groups was only a fasting plasma glucose of ∼30 mg/dl (1.7 mmol/l). Of note, a major concern emanating from the UGDP was the observation that the sulfonylurea agent (tolbutamide) and a biguanide (phenformin) used to reduce hyperglycemia were associated with increased cardiovascular mortality. The suspicion that glucose lowering with oral agents in patients with type 2 diabetes may actually be harmful has persisted since publication of the UGDP data in 1970.
  • The second controlled trial in type 2 diabetes was only recently reported ( 5 ). This small study conducted in 110 lean Japanese subjects showed that multiple insulin injections resulting in better glycemic control (HbA 1c  = 7.1%) compared with conventional treatment (HbA 1c  = 9.4%) significantly reduced the microvascular complications of diabetes. The extent of the risk reduction in this Japanese study was similar to that in the DCCT, thereby supporting the hypothesis that glycemic control is important in both types of diabetes.
  • A pilot study that randomized 153 men to intensive or conventional therapy . Despite a 2% absolute HbA 1c  difference in glycemic control between the two groups, the trial reported no significant difference in cardiovascular events in a follow-up period of only 27 months.
  • With this background, we now have the results of the largest and longest study on type 2 diabetic patients that has ever been performed ( 7 , 8 , 9 , 10 ). The United Kingdom Prospective Diabetes Study (UKPDS) recruited 5,102 patients with newly diagnosed type 2 diabetes in 23 centers within the U.K. between 1977 and 1991. Patients were followed for an average of 10 years to determine  1 ) whether intensive use of pharmacological therapy to lower blood glucose levels would result in clinical benefits (i.e., reduced cardiovascular and microvascular complications) and  2 ) whether the use of various sulfonylurea drugs, the biguanide drug metformin, or insulin have specific therapeutic advantages or disadvantages. In addition, patients with type 2 diabetes who were also hypertensive were randomized to “tight” or “less tight” blood pressure control to ascertain the benefits of lowering blood pressure and to ascertain whether the use of an ACE inhibitor (captopril) or β-blocker (atenolol) offered particular therapeutic advantages or disadvantages.
  • The UKPDS results establish that retinopathy, nephropathy, and possibly neuropathy are benefited by lowering blood glucose levels in type 2 diabetes with intensive therapy, which achieved a median HbA 1c  of 7.0% compared with conventional therapy with a median HbA 1c  of 7.9%. The overall microvascular complication rate was decreased by 25%. These results materially increase the evidence that hyperglycemia causes, or is the major contributor, to these complications. Epidemiological analysis of the UKPDS data showed a continuous relationship between the risks of microvascular complications and glycemia, such that for every percentage point decrease in HbA lc  (e.g., 9 to 8%), there was a 35% reduction in the risk of complications. Epidemiological analysis showed a continuous association between the risk of cardiovascular complications and glycemia, such that for every percentage point decrease in HbA lc  (e.g., 9 to 8%), there was a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction.  
  • Epidemiological analysis showed a continuous association between the risk of cardiovascular complications and glycemia, such that for every percentage point decrease in HbA lc  (e.g., 9 to 8%), there was a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction.   The study showed that lowering blood pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-related deaths, heart failure, microvascular complications, and visual loss.
  • About 90% of hemoglobin is hemoglobin A (the "A" stands for adult type). approximately 8% of hemoglobin A is made up of minor components that are chemically slightly different. These minor components include hemoglobin A1c, A1b, A1a1, and A1a2. Hemoglobin A1c (HbA1c) is a minor component of hemoglobin to which glucose is bound. so HbA1c also is sometimes referred to as glycosylated or glycosylated hemoglobin or glycohemoglobin.HbA1c levels depend on the blood glucose concentration. That is, the higher the glucose concentration in blood, the higher the level of HbA1c. Levels of HbA1c are not influenced by daily fluctuations in the blood glucose concentration but reflect the average glucose levels over the prior 8-12 weeks becoz Due to the fact that red blood cells survive for 8-12 weeks Therefore, HbA1c is a useful indicator of how well the blood glucose level has been controlled in the recent past (over two to three months) and may be used to monitor the effects of diet, exercise, and drug therapy on blood glucose in people with diabetes. In healthy non diabetic people the HbA1c level is less than 6% of total hemoglobin. ADA guideline of 2008 for the care of adults with diabetes include an evidence based statement that ‘lowering HbA1c to an average of ~7% has clearly been shown to reduce microvascular and neuropathic complications of diabetes and, possibly, macrovascular disease’. In the same guidelines, a second recommendation was made on the basis of epidemiologic studies which suggested an incremental benefit (albeit small in absolute terms) to lowering HbA1c from 7% into the normal range of <6%. So the topic of controversy is will a greater reduction in HBA1c will result greater reduction in cardiovascular events in diabetes.?
  • The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial sought to test the hypothesis that a therapeutic strategy that targets an HbA1c level of <6% would lead to a greater reduction in the rate of cardiovascular events than a strategy that targets an HbA1c level of 7.0–7.9%. In this North American study, 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). Intensive control was to be achieved with at least two or more agents from a formulary including glimepiride, repaglinide, metformin, rosiglitazone, acarbose and insulin. 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. However, on 6 February 2008, the primary sponsor of the trial, the US National Heart, Lung, and Blood Institute (NHLBI) announced the termination of the intensive control arm of the study.17
  • Higher mortality in intensive control arm of ACCORD In the glycaemic control element of the ACCORD trial, median HbA1c achieved in the intensive treatment group was 6.4% compared with 7.5% in the standard treatment group.17 A higher rate of mortality was noted in the intensive arm, with 257 deaths (14/1000/ year) compared with 203 deaths (11/1000/year) in the standard arm. However, both rates were lower than previously reported for individuals with type 2 diabetes at high risk of heart disease (~50/1000/year). There was no identifiable link with rosiglitazone. The NHLBI concluded that in patients with type 2 diabetes at especially high risk for heart disease, very intensive glucose lowering treatments aimed at normalising blood glucose to an HbA1c of <6% may be detrimental. All participants in the intensive control arm of ACCORD have been switched to standard glycaemic control, while the lipid lowering and blood pressure control arms of ACCORD are ongoing. However, these findings would be applicable only to individuals similar to the ACCORD participants, namely with type 2 diabetes for an average of 10 years and with known heart disease or at least two risk factors in addition to diabetes (including high blood pressure, high cholesterol levels, obesity and smoking). The ACCORD study did not address this issue with regard to younger people with diabetes, those earlier in the course of the disease, and those without established cardiovascular disease.
  • Perform the A1C test at least two times a year in patients who have stable glycemic control. Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. Reasonable A1c goal is below or around 7 Percent.
  • Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR(peroxisome proliferator-activated receptors) receptors in fat cells and making the cells more responsive to insulin. its adverse effects are :MI ,Stroke, Bone fractures, macular edema ,hepatotoxicity.
  • Rosiglitazone and risk of myocardial infarction Two recent independent meta-analyses – one including 42 trials involving 27 847 participants10 and one including four trials involving 14 291 patients with at least 12 months of follow up11 – found an increase in the risk of myocardial infarction associated with rosiglitazone. In both meta-analyses, participants given rosiglitazone for treatment or prevention of type 2 diabetes had an increase in the risk of myocardial infarction in the order of a 40% excess over controls.10,11 There is ongoing debate as to the applicability of these findings to patients with type 2 diabetes in general, with some criticism of the meta-analysis by Nissen and Wolski on methodological grounds.10 The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial using rosiglitazone in patients with type 2 diabetes is still underway and may provide clarification of this risk.12 However, until further information is available, the possible increased risk of myocardial infarction with rosiglitazone must be considered when selecting a glitazone for use in patients with type 2 diabetes.13 This risk appears to be specific for rosiglitazone. 10. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. 11. Singh S, Loke YK and Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95. 12. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis. N Engl J Med 2007;357:28–38. 13. Therapeutic Goods Administration. Avandia (rosiglitazone maleate) product information. Issue no. 13 (M). Date of TGA approval: 8 November 2007.
  • A Long Term, Randomised Study in Patients With Type 2 Diabetes, Comparing the Combination of Rosiglitazone and Either Metformin or Sulfonylurea With Metformin Plus Sulfonylurea on Cardiovascular Endpoints and Glycaemia” This study is a phase 3b, multicentre, randomised. A 4-week run-in period will be followed by a median of 6 years of treatment with study medication in addition to continuation of background glucose lowering therapy. Patients with type 2 diabetes on monotherapy with either metformin or sulfonylurea and with hemoglobin A1c > 7% but ≤ 9% were randomly assigned to the addition of rosiglitazone (n = 1103) or metformin (if already on sulfonylurea, n = 1122) or to rosiglitazone (n = 1117) and sulfonylurea (if already on metformin, n = 1105). Patients were followed for a median of 6 years for the primary endpoint of time to first cardiovascular hospitalization or cardiovascular death. The study was designed to test noninferiority of rosiglitazone, thus requiring an upper limit of the confidence interval of the hazard ratio (HR) to be less than 1.20. The primary outcome, cardiovascular hospitalization or cardiovascular death, occurred in 321 and 323 participants assigned to the rosiglitazone and metformin/sulfonylurea groups, respectively (HR, 0.99; 95% confidence interval [CI], 0.85-1.16). A sensitivity analysis that excluded patients after transfer from dual therapy yielded similar results for the primary outcome. A predefined composite secondary endpoint of cardiovascular death, myocardial infarction, and stroke was also not significant (HR, 0.93; 95% CI, 0.74-1.15) for rosiglitazone vs metformin/sulfonylurea. Individually, HRs for myocardial infarction were elevated (HR, 1.14; 95% CI, 0.80-1.63) and depressed for stroke (HR, 0.72; 95% CI, 0.49-1.06), but were not significantly different.  
  • Record study summary: The RECORD study suggests that rosiglitazone is probably safe and effective in carefully selected patients. As with all therapies, one must ask whether the risks are worth the benefits, and whether another available option might be the wiser choice . In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended from the European market. However, patients currently taking rosiglitazone are advised to discuss alternative options during their next physician appointment.[6] In the UK, Diabetes UK announced, "People currently taking all forms of the recently suspended drug Avandia (Rosiglitazone) have until 21 October to be reviewed and transferred onto an alternative treatment". FDA Food and Drug Administration panel has not recommended rosiglitazone to be taken off the market and it remains on the market in the U.S., subject to significant restrictions.[4] From November 18, 2011 the federal government will not allow Avandia to be sold without a prescription from certified doctors.

Transcript

  • 1. Controversies in Type 2 Diabetes Mellitus Pratap Sagar Tiwari , Resident, Internal Medicine ,NGMC
  • 2. 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 low- and 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
  • 3.
    • Weight Loss in Type 2 DM : Is it worth the effort ?
  • 4. WHO standard classification of obesity 1 1. Source: The Global Challenge of Obesity and the International Obesity Task Force http://www.iuns.org/features/obesity/tabfig.htm#Table 1 For Asian Population BMI Risk of co-morbidities Normal BMI 18.5-24.9 average Overweight:     Pre-obese 25.0-29.9 increased Obesity class I 30.0-34.9 moderate Obesity class II 35.0-39.9 severe Obesity class III    40 very severe
  • 5. Global Burden of Obesity 1
    •   In 1995, there were an estimated 200 million obese adults worldwide.
    • As of 2000, the number of obese adults has increased to over 300 million.
    • In developing countries, it is estimated that over 115 million people suffer from obesity-related problems..
    1. Source: http://www.who.int .
  • 6. Growing epidemic of T2DM in relation to Obesity 1,2,3 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
  • 7. Obesity : Risk factor for DM 1
    • Objective :To estimate the prevalence of obesity and diabetes among US adults in 2001.
    • Results In 2001 the prevalence of obesity (BMI ≥30) was 20.9% vs 19.8% in 2000, an increase of 5.6%.
    • The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%.
    • Overweight and obesity were significantly associated with diabetes, high blood pressure and high cholesterol.
    • Compared with adults with normal weight, adults with a BMI of ≥40 had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels
    1. Mokdad A, Ford E, Bowman B, Dietz W, Vinicor F, Bales V,Marks J. Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors. JAMA. 2003;289(1):76-79. doi: 10.1001/jama.289.1.76
  • 8.
    • Can preventing or treating obesity decrease the incidence of T2 Diabetes ?
  • 9. Diabetes Prevention program :a study 1
    • Included 3234 overweight individuals (BMI > 24 kg/m2) with IGT.
    • Average age : 51 yrs old
    • Method: . These participants were randomly assigned to receive either intensive lifestyle intervention or therapy with Metformin (850 mg twice daily) or placebo.
    • The intensive lifestyle intervention involved 16 individual sessions over 24 weeks
    • The goals of the lifestyle intervention were to lose 7% of initial body weight, maintain this weight loss, and achieve at least 150 min/week of physical activity using activities that were similar in intensity to brisk walking.
    1. 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
  • 10. Behavioral Weight-Loss Program
    • 16–24 treatment sessions over 6 months 1
    • Group format of 10–20 members
    • Team of professionals (dietitians, exercise physiologists, behaviorists)
    • Daily self-monitoring of calories, fat, and activity (minutes or calories)
    • Calorie goal of 1,200–1,500 calories per day
    • Fat gram goal of 20% of calories coming from fat
    • Exercise goal of 1,000 cal per week (or 150 minutes) of moderate activity 2
    1. Wing RR: Behavioral approaches to the treatment of obesity. In Handbook of Obesity. Bray G, Bouchard C, James PT, Eds. New York, Marcel Dekker, 1998, p. 855-73. 2. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, Buchner D, Ettinger W, Heath GW, King AC: Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine: ACSM's guidelines for exercise testing and prescription. JAMA 273:402-407, 1995.
  • 11. Diabetes Prevention program :a study
    • 50 % of lifestyle participants achieved the 7% wt loss goal at wk 24, and 38% achieved this goal at study end.
    • The intervention was extremely effective in reducing the risk of diabetes. The crude incidence of DM was 11.0, 7.8, and 4.8 cases per 100-person year for placebo, metformin, and lifestyle , respectively.
    • Thus, lifestyle intervention reduced the risk of diabetes by 58% compared with placebo, and metformin reduced the risk by 31%.
  • 12. Look AHEAD Trials
    • Look AHEAD(Action for Health in Diabetes) is a large clinical trial designed to determine whether long-term weight loss will improve glycemia and prevent CV events in T2DM.
    • One-year results of the intensive lifestyle intervention in this trial show
    • an average 8.6% weight loss,
    • significant reduction of A1C, and
    • reduction in several CVD risk factors 1
    • with benefits sustained at 4 years 2
    1. Look AHEAD Research Group, Wing RR. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes:one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–1383 2. Look AHEAD Research Group, Wing RR: Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med 2010;170:1566–1575
  • 13. Successful Weight Loss in Individuals with DM ?
    • In one study, 12 DM pt and their non-DM spouses were enrolled together in a behavioral weight loss program. Although patients and spouses were of similar age and wt, those with DM lost only 7.5 kg over 20 weeks, whereas their non-DM lost 13.4 kg . 1
    • In another comparison of 20 wn with T2DM and 23 non-DM wn treated together in a 16-wk behavioral weight loss program, initial wt losses were comparable (7.4 and 6.4 kg for diabetic and non-diabetic subjects, respectively), but at 1-year FU, those with DM maintained a wt loss of 2 kg, whereas the non-DM retained a wt loss of 5.4 kg . 2
    1. Wing, R.R., M.D. Marcus, L.H. Epstein, and R. Salata, Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care, 1987. 10: p. 563–566. 2. Guare, J.C., R.R. Wing, and A. Grant, Comparison of obese NIDDM and nondiabetic women; short- and long-term weight loss. Obesity Research, 1995. 3(4): p. 329–335
  • 14. Why diabetes may be less successful ?
    • As glycemic control improves with weight loss, individuals with diabetes may have decreased excretion of calories in their urine, thereby reducing their weight loss.
    • As diabetics in poor glycemic control have more elevated energy expenditure , this too may normalize with weight loss and improved glycemic control.
    • Physical problems associated with diabetes, including neuropathy, may limit physical activity .
    • Finally, many of the medications used to improve glycemic control, including SFU, TZD, and insulin, enhance anabolism and promote weight gain .
  • 15. ADA 2011 :Recommendations
    • People with DM should be advised to perform at least 150 min/wk of moderate intensity aerobic physical activity.
    • In the absence of contraindications ,people with T2DM should be encouraged to perform resistance training 3 times/week.
    • Saturated fat intake < 7 % of total calories.
    • Alcohol :1 drink /d for women and 2 drink /d for men
    • Routine supplement with antioxidants is not recommended.
    • Bariatric surgery may be considered in diabetes with BMI >35 Kg/m2 if difficult to control with lifestyle and pharmacological therapy.
    Source : American Diabetes Association Home Page Website: www. diabetes .org/
  • 16. Treatment in T2 DM using Insulin
    • When to use ???..
  • 17.
    • 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 131–154.
  • 18. Why The need for earlier insulin replacement in T2 DM ?
    • Worldwide, the number of cases of diabetes is expected to increase exponentially, with current estimates suggesting an increase from around 170 million in 2000 to approximately 370 million persons by 2030 . 1,2,3
    1. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21: 1414–1431, 1998. 2. Green A, Hirsch NC, Pramming SK. The changing world demography of type 2 diabetes. Diabetes Metab Res Rev 19: 3–7, 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: 1047–1053, 2004.
  • 19. When should insulin be started ?
    • When should insulin be started in T2DM depends on two critical scenarios :
    • Can early insulin therapy “rest” the b cell and preserve its function and integrity?
    • Is early insulin therapy needed to reach glycemic targets for cardioprotection?
  • 20. Early Insulin Therapy and B cell preservation ???
    • Evidence :
    • B-cell dysfunction is a fundamental underlying genetic abnormality in the pathogenesis of T2DM that cannot develop solely because of insulin resistance. Early b-Cell dysfunction is the key for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and finally to T2DM . 1
    • As insulin fails to suppress lipolysis, the increased concentrations of free fatty acids (FFAs) combined with progressive hyperglycemia act negatively on pancreatic b cells and insulin-sensitive tissues to further inhibit both insulin secretion and peripheral action . 2
    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: 787–794, 1999. 2. McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18, 2002.
  • 21.
    • 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
    • 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.
    • 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: 102–110, 2003.
  • 22.
    • 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 b-cell integrity.
  • 23. Hypothesis :Early insulin replacement -resting the B cell Short-term intensive insulin therapy studies performed over the period of 20 years that demonstrated improved insulin action and increased endogenous insulin secretion probably induced by reversing glucotoxicity and lipotoxicity . 1 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 . 2 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: 462–468, 2002. 22 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: 1353–6, 1997
  • 24. Korean Study 1
    • 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) ..
    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: 124–130, 2003.
  • 25. Early Insulin Therapy and Cardioprotection 1
    • 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: 405–412,2000
  • 26. ADA 2011 Current Recommendation: 1
    • Currently, initiation of insulin therapy is generally considered only if the HbA1c level remains >7% despite maximized oral combination therapy.
    1. Source : American Diabetes Association Home Page Website: www. diabetes .org/
  • 27. Diabetes and Complications
    • An association between the complications of diabetes and elevated blood glucose levels was postulated in the early part of this century.
    • Some of these studies have also demonstrated that treatment that lowers blood glucose reduces the risks of diabetic retinopathy, nephropathy, and neuropathy..
  • 28. University Group Diabetes Program (UGDP) study 1
    • Result : showed no benefit of glycemic control in new-onset type 2 diabetic patients .
    • However, in the UGDP, there were only 200 subjects in each treatment group.
    • HbA 1c  was not available as a reliable method for measuring chronic glycemia, and
    • The difference in glucose control between the most intensively treated group and the other treatment groups was only a fasting plasma glucose of ∼30 mg/dl (1.7 mmol/l).
    • Of note, a major concern emanating from the UGDP was the observation that the sulfonylurea agent (tolbutamide) and a biguanide (phenformin) used to reduce hyperglycemia were associated with increased cardiovascular mortality .
    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) :747–830, 1970
  • 29. Kumamoto Study 1
    • Subjects: 110 lean Japanese
    • Results :multiple insulin injections resulting in better glycemic control (HbA 1c  = 7.1%) compared with conventional treatment (HbA 1c  = 9.4%) significantly reduced the microvascular complications of diabetes.
    1. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract  28 :103–117, 199
  • 30. Veterans Affairs Diabetes Feasibility Trial 1
    • Study randomized 153 men to intensive or conventional therapy .
    • Despite a 2% absolute HbA 1c  difference in glycemic control between the two groups, the trial reported no significant difference in cardiovascular events in a follow-up period of only 27 months.
    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 :181–188, 199
  • 31. The United Kingdom Prospective Diabetes Study (UKPDS) 1,2,3
    • Subjects : 5,102 patients with newly diagnosed type 2 diabetes in 23 centers within the U.K. between 1977 and 1991.
    • Patients were followed for an average of 10 years to determine 
    • whether intensive use of pharmacological therapy to lower blood glucose levels would result in clinical benefits
    • whether the use of various sulfonylurea drugs, the biguanide drug metformin, or insulin have specific therapeutic advantages or disadvantages.
    • In addition, patients with type 2 diabetes who were also hypertensive were randomized to “tight” or “less tight” blood pressure control to ascertain the benefits of lowering blood pressure.
    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 352:854–865, 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 317:703–713, 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 317:713–720, 1998
  • 32. Summary of the main results and conclusion of UKPDS
    • Retinopathy, nephropathy, and possibly neuropathy are benefited by lowering blood glucose levels in T2DM with intensive therapy , which achieved a median HbA 1c  of 7.0% compared with conventional therapy with a median HbA 1c  of 7.9%. The overall microvascular complication rate was decreased by 25%.
    • These results materially increase the evidence that hyperglycemia causes, or is the major contributor , to these complications.
  • 33. Summary of the main results and conclusion of UKPDS
    • Epidemiological analysis of the UKPDS data showed a continuous relationship between the risks of microvascular complications and glycemia , such that for every percentage decrease in HbA lc  (e.g., 9 to 8%), there was a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction.
    • The study showed that lowering blood pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-related deaths, heart failure, microvascular complications, and visual loss.
  • 34.
    • Targets for HbA1c in patients with type 2 diabetes ???
  • 35. ACCORD (Action to control Cardiovascular Risk in Diabetes) trial 1
    • 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.
    1. 1he ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):211–33.
  • 36. Higher mortality in intensive control arm of ACCORD
    • Median HbA1c achieved in the intensive treatment group was 6.4% compared with 7.5% in the standard treatment group. 1
    • A higher rate of mortality was noted in the intensive arm, with 257 deaths compared with 203 deaths in the standard arm.
    • The NHLBI concluded that in patients with type 2 diabetes at especially high risk for heart disease, very intensive glucose lowering treatments aimed at normalising blood glucose to an HbA1c of <6% may be detrimental.
    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].
  • 37. ADA 2011 recommendation 1
    • Perform the A1C test
    • at least 2 X Yr in patients who have stable glycemic control.
    • quarterly in patients whose therapy has changed or who are not meeting glycemic goals.
    • A1C goal : < 7 %
    1. Source : American Diabetes Association Home Page Website: www. diabetes .org/
  • 38. 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 157:181–188, 199
    • McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18, 2002.
    • Butler AE et al. Beta-cell deficit and increased betacell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–110, 2003.
    • The ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):211–33.
    • 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 352:854–865, 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:one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–1383
    • 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
    • www.emedicine.com
    Special thanks to Dr Pradeep ,Resident ,Pediatrics for statistical help
  • 39.
    • Rosiglitazone and risk of myocardial infarction
    • ???
  • 40. Rosiglitazone and its risk
    • Two recent independent meta-analyses –
    • 1 st : including 42 trials involving 27 847 participants 1
    • 2 nd : including four trials involving 14 291 patients with at least 12 months of follow up 2 – found an increase in the risk of myocardial infarction associated with rosiglitazone.
    • In both meta-analyses, participants given rosiglitazone for treatment or prevention of type 2 diabetes had an increase in the risk of myocardial infarction in the order of a 40% excess over controls . 1,2
    1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. 2. Singh S, Loke YK and Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95.
  • 41. 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
  • 42. RECORD Study :summary 1
    • The RECORD study suggests that rosiglitazone is probably safe and effective in carefully selected patients.
    • As with all therapies, one must ask whether the risks are worth the benefits, and whether another available option might be the wiser choice .
    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