Presented by : mohammadreza khosravi Internist

2. Presented by : mohammadrezakhosravi Internist

3. Glycemic control and vascular complications in type 1 and 2 diabetes mellitus

4. Morbidity from diabetes is a consequence of both macrovascular disease (atherosclerosis) and microvascular disease (retinopathy, nephropathy, and neuropathy). Epidemiologic studies first showed an association between poor glycemic control and microvascular complications . This association was confirmed in the prospective Diabetes Control and Complications Trial (DCCT), which demonstrated that intensive therapy aimed at lower levels of glycemia results in decreased rates of retinopathy, nephropathy, and neuropathy in type 1 diabetes patients

5. The importance of tight glycemiccontrol for protection against macrovascular disease in diabetes has also been established in the DCCT/EDIC study for type 1 diabetes. In the EDIC follow-up study to the DCCT, intensive insulin therapy in patients with type 1 diabetes decreased fatal and nonfatal cardiovascular events.

6. PATHOGENESIS: 1- Two proposed contributing factors are advanced glycosylation end products and sorbitol; protein kinase C and other factors also may contribute . In addition to systemic factors, organ-specific factors also appear to be important. In the kidney, for example, stimulation of mesangial matrix production by hyperglycemia, activation of protein kinase C, and an increasing degree of intraglomerular hypertension may contribute to the glomerular injury.

7. 2- Genetic predisposition may be another important factor. This was illustrated in a report from the DCCT in which 372 patients and 467 first-degree was three times more frequent among the relatives of patients with retinopathy than among relatives of patients who did not have retinopathy. Familial clustering was also noted for diabetic nephropathy.

8. MICROVASCULAR DISEASE epidemiologic studies suggest that nephropathy and retinopathy are more likely to occur in patients with poorer glycemic control . The risk is highest if the hemoglobin A1C (A1C) value is above 12 percent. but is still increased at all values above the non-diabetic range

9. These associations were confirmed in the prospective Diabetes Control and Complications Trial (DCCT) • In this study, patients with type 1 diabetes were randomly assigned to receive either conventional therapy or intensive insulin therapy, consisting of multiple daily injections or continuous insulin administration using an insulin pump, and guided by frequent self-monitoring of blood glucose.

10. Patients with no retinopathy or nephropathy at baseline were evaluated in the primary prevention study, while those with established disease were evaluated in the secondary intervention study. • The mean A1C values during the nine-year study were 7.2 percent with intensive therapy as opposed to 9.1 percent with conventional therapy; the respective mean blood glucose concentrations were 155 mg/dL (8.6 mmol/L) and 235 mg/dL (12.8 mmol/L).

11. The DCCT provided conclusive evidence that strict glycemic control can both delay the onset of microvascular complications (primary prevention) and slow the rate of progression of already present complications (secondary intervention). • Following completion of the DCCT in 1993, the conventional treatment group was offered intensive treatment, and 93 % of DCCT participants (n = 1394) agreed to participate in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study.

12. 11 years of follow-up were concluded in February 2005. Differences in A1C levels between the intensive and conventional treatment groups at the end of the DCCT trial (7.4 and 9.1 %, respectively) narrowed at the end of the 11 year follow-up EDIC (7.9 and 7.8 %, respectively).

13. Retinopathy - Retinopathy has been chosen as the major end-point in many of the prospective diabetes trials because it is the most common microvascular complication and is relatively easy to quantify and follow. Standard retinal photographs are taken and scored, based upon the number of microaneurysms, hemorrhages, exudates, and other abnormalities

14. Primary prevention • at nine years, the incidence of new retinopathy was 12 % in the intensive therapy group versus 54 percent in the conventional therapy group • There was a continuous relation between the degree of glycemic control and the incidence of retinopathy (the only complication for which such data were reported): the rate of progression increased from one per 100 patient-years at a mean A1C value of 5.5 percent up to 9.5 per 100 patient-years at a mean A1C value of 10.5 percent; progressive retinopathy was uncommon at A1C values below 7 percent.

15. Established retinopathy • In addition to its efficacy in primary prevention, intensive insulin therapy also slows the rate of progression of mild to moderate retinopathy. • However, during the first two years of intensive therapy, the DCCT found that retinopathy may worsen most commonly in association with an increased number of soft exudates (due to retinal infarcts in the superficial layers). This probably represents the closure of small retinal blood vessels that were narrowed but patent. Correction of hyperglycemia lowers the plasma volume, which can put marginal vessels at risk. Increased availability of insulin-like growth factor-1 also may contribute.

16. This early worsening of retinopathy in the DCCT was transient, largely resolving after 18 to 24 months, and there was clear evidence of benefit from intensive therapy when patients with very mild to moderate nonproliferative retinopathy were followed for nine years • The incidence of worsening retinopathy in intensively treated patients was higher than in those receiving conventional therapy at one year (7.4 versus 3 percent) but much lower at nine years (25 versus 53 %).

17. At the end of the DCCT, the conventional treatment group was taught intensive therapy, and the diabetes care of all of the participants was returned to their own health care providers. During the subsequent observational follow-up of the DCCT cohort, in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the difference in the median A1C values between the original intensive and conventional therapy groups (7.2 and 9.1 percent, respectively) narrowed during follow-up (8.1 and 8.2 percent, respectively, by five years)

18. Thus, intensive insulin therapy for 6.5 years during the DCCT reduced the risk of retinopathy over at least the next 10 years compared with conventional therapy, despite an absence of a difference in A1C values during the post-DCCT trial period. This phenomenon has been called "metabolic memory”

19. Strict glycemic control is of little or no benefit in advanced retinopathy. This has been best demonstrated in patients who have undergone pancreas transplantation. In one study, for example, 22 transplanted patients (most of whom had advanced nephropathy) were compared to 16 nontransplanted patients with similar disease severity . Despite the attainment and maintenance of normoglycemia in the transplant group, there was no difference between the groups in the rates of progression of retinopathy or visual loss at two years.

20. Nephropathy Following a cohort of 20,000 individuals diagnosed with type 1 diabetes before the age of 20 years, a Finnish study reported a prevalence of end-stage renal disease of 2.2 percent at 20 years and 7.7 % at 30 years. These prevalence rates are significantly lower than previous estimates of 30 to 40 percent, and likely reflect, at least in part, the impact of improved glycemic management

21. Primary prevention : The DCCT included 1365 patients with normal albumin excretion at baseline. At follow-up of up to nine years (mean 6.5 years), intensive therapy was associated with a significantly lower rate of new onset microalbuminuria in these patients (16.4 versus 23.9 %, adjusted risk reduction 39 percent) . There was also a significant reduction in new onset macroalbuminuria in the entire study population (3.2 versus 7.2 %, adjusted risk reduction 51 %).

22. Similar to the case with retinopathy, metabolic memory applies to the primary prevention of nephropathy. At year eight of the EDIC follow-up study, significant persistent benefits were noted in those who had received intensive therapy compared with those who received conventional therapy during the DCCT.

23. Results: • New microalbuminuria was less common (7 versus 16 %) • New clinical albuminuria, also called macroalbuminuria, was less common (1.4 versus 9 %) • The prevalence of hypertension was lower (30 versus 40 %) Thus, previous intensive treatment with near-normal glycemia during the DCCT had an extended benefit in delaying the onset and progression of diabetic nephropathy.

24. Intensive insulin therapy may act in part by reversing the early glomerularhyperfiltration and hypertrophy that are thought to be important risk factors for glomerular.

25. Established microalbuminuria • Intensive insulin therapy is also effective at a somewhat later stage, after microalbuminuria has developed • In addition to preventing progression, maintenance of relative normoglycemia often diminishes the degree of protein excretion, although one to two years are usually required for this effect.

26. Established macroalbuminuria • In contrast to the benefit of aggressive therapy in patients with microalbuminuria, it has been suggested that strict glycemic control with intensive insulin therapy may not slow the rate of progressive renal injury once overt dipstick-positive proteinuria (equivalent to albuminuria >300 mg/day, called macroalbuminuria or overt proteinuria) has developed.

27. the apparent lack of substantial benefit in overt diabetic nephropathy from strict glycemic control alone suggests that other factors (such as intraglomerular hypertension and glomerular hypertrophy) may contribute to the progressive glomerular injury. At this late stage, there is often marked glomerulosclerosis. Only antihypertensive therapy (preferably with an angiotensin converting enzyme inhibitor) and perhaps dietary protein restriction have been shown to slow the rate of progressive disease or reverse established lesions.

28. Neuropathy • The first evidence that improved glycemic control has a beneficial effect on painful diabetic neuropathy came from a report of nine patients • Initiation of intensive therapy led to symptomatic improvement in all patients in association with increases in vibration sense and motor (but not sensory) nerve conduction velocity.

29. In the DCCT • The incidence of confirmed clinical neuropathy (defined as findings from the history and physical examination that were confirmed by neurologic testing) was reduced with intensive insulin therapy by 64 % (5 versus 13 %).

30. Intensive insulin therapy also reduced the incidence of abnormal nerve conduction by 44 percent (26 versus 46 %) and of autonomic dysfunction by 53 percent (4 versus 9 %). • observations indicate that an intensive insulin regimen to improve glycemic control delays or prevents clinical and physiological evidence of diabetic neuropathy.

31. The Oslo study suggested that there was a graded effect of hyperglycemia on disease progression, as each 1 percent rise in A1C values was associated with a 1.3 m/sec slowing of nerve conduction at eight years.

32. A number of other potentially modifiable risk factors appear to be associated with the risk of diabetic neuropathy, including hypertriglyceridemia, obesity, smoking, and hypertension.

33. MACROVASCULAR DISEASE • This represented a 42 % decrease in any cardiovascular event (95% CI 9-63 percent); there was also a 57 percent reduction in a serious cardiovascular event (non fatal MI, stroke, or CVD death) (95% CI 12-79 percent) comparing the original DCCT intensive therapy with the DCCT conventional treatment group.

34. Microalbuminuria and albuminuria were also independently associated with cardiovascular outcome, but differences in outcome between the two treatment groups remained after correction for these renal factors.

35. These results indicate that a sustained period of glycemic control (6.5 years in the DCCT study) has lasting benefit in reducing cardiovascular morbidity and mortality in type 1 diabetes. • The results are supported by similar findings from a cohort study of 879 individuals with type 1 diabetes followed for 20 years. In this study, individuals in the highest quartile of A1C (12 %) had increased all-cause (relative risk [RR] 2.4, 95% CI 1.5-3.8) and cardiovascular (RR 3.3, 95% CI 1.8-6.1) mortality compared with individuals in the lowest quartile (9.4 %).

36. An earlier report from the EDIC study showed that progression of carotid intima-media thickness, a measure of atherosclerosis, was significantly less in those who had received intensive therapy during the DCCT compared with those who had received conventional therapy; (progression of intima-media thickness of the common carotid artery 0.032 versus 0.046 mm)

37. GLYCEMIC GOALS • The above findings provide conclusive evidence that strict glycemic control, if achieved before irreversible end-organ damage has occurred, reduces the incidence of microvascular disease, neurologic dysfunction, and cardiovascular disease in patients with type 1 diabetes. • Additional data from the DCCT support the importance of beginning intensive therapy as early as possible after the diagnosis of type 1 diabetes:

38. Long-term observational data from the DCCT/EDIC study showed that patients with type 1 diabetes duration of 30 years, who were initially assigned to intensive versus conventional therapy, had the lowest cumulative incidences of proliferative retinopathy (21 versus 50 percent), nephropathy (9 versus 25 %), and cardiovascular disease (9 versus 14 %).Thus, intensive insulin therapy should be attempted in all appropriate patients with type 1 diabetes as early in the course of disease as is safely feasible. Both patient and physician education and support are required to perform this task safely

39. From a renal viewpoint, this regimen has demonstrated to be beneficial in all patients except those with overt proteinuria in whom strict blood pressure control with an ACE inhibitor appears to be more important.

40. In general, we aim for an A1C value of 7 percent or lower in patients in whom the benefits outweigh the risks. Specific glycemic targets should be set for individual patients, weighing benefits related to life-expectancy and existing complications against the risk of hypoglycemia. • In general A1C goals are set higher for children and adolescents, especially in children with frequent hypoglycemia or hypoglycemia unawareness.

41. Increasing the intensity of glycemic control to achieve A1C <7 % is indicated during pregnancy in type 1 and type 2 diabetic women, since the A1C level in nondiabetic women falls during pregnancy and the demonstrated benefits to the fetus and neonate drive the therapeutic goals.

42. Glycemic variability : The effect of fluctuations in glucose levels, as measured within or between days, on the risk of developing diabetic complications is uncertain. This has theoretical clinical implications, as free radicals have been implicated in endothelial damage and the formation of atherosclerotic plaques. One may therefore hypothesize that control of daily blood glucose fluctuations, in addition to management of chronic hyperglycemia (as measured by A1C) in diabetic patients, could be important in protection against micro- and macrovascular disease .

43. Analysis of data from the DCCT demonstrated that while retinopathy correlated directly with average glucose control, as measured by the A1C, fluctuations of glucose within the day (glucose variability) did not impact the development of retinopathy.

44. Microvascular complications - Improved glycemic control improves the risk of microvascular complications in patients with type 2 diabetes. Every 1 percent drop in A1C is associated with improved outcomes with no threshold effect.

45. Macrovascular complications : To date, no randomized clinical trial has convincingly demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in individuals with long-standing type 2 diabetes. In contrast, the results of the UKPDS post-trial observation study suggest that initial intensive control (A1C 7.0 %) in individuals with newly diagnosed diabetes has long-term benefit in decreasing the risk of myocardial infarction, diabetes-related death, and overall death. In the aggregate, the clinical evidence supports initiating intensive therapy with the goal of lowering A1C levels to <7.0 % as early as possible in the course of diabetes.

46. Glycemic targets - Target A1C goals in patients with type 2 diabetes should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. A reasonable goal of therapy might be an A1C value of 7.0 percent for most patients (using an assay in which the upper limit of normal is 6.0 percent). Glycemic targets are generally set somewhat higher for older patients and those with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy.

47. Multifactorial risk reduction - Vigorous cardiac risk reduction (smoking cessation, aspirin, blood pressure control, reduction in serum lipids, preferably using a statin, diet, exercise, and, in high-risk patients, an angiotensin converting enzyme inhibitor) should be a top priority for all patients with type 2 diabetes.

48. In spite of evidence that aggressive risk factor reduction lowers the risk of both micro- and macrovascular complications in patients with diabetes, the vast majority of patients do not achieve recommended goals for A1C, blood pressure control, and management of dyslipidemia.

49. Nutriton therapy in Diabet Glycemic index (GI) was first defined by Jenkins et al. as an indicator of the potential of glycemic carbohydrates in different types of food to raise blood glucose levels within 2h of ingestion.

50. Low-GI foods are classified as being digested and absorbed slowly and high-GI foods as being digested and absorbed rapidly. Thus, a food with a higher GI is asuemed to result in a higher glycemic response, Which should induce various hormonal and metabolic changes that negatively affect health conditions; foods eliciting low glycemicresponses should generally induce clinically important benefits.