DIABETES and its prevention!!!

1. DIABETES and its prevention!!! Norbert Goldfield, M.D. Executive Director Healing Across the Divides, Inc

2. Diabetes Is Associated with Serious Health Consequences • It is a major risk factor for coronary heart disease (CHD) and stroke. In fact, the vast majority of diabetic patients die of cardiovascular complications. Diabetes is also the leading cause of blindness, kidney failure, and nontraumatic amputations, resulting from microvascular complications. The economic toll of diabetes is enormous. For example, in 2002, direct medical and treatment costs and indirect costs due to diabetes-related disability and mortality in the United States exceeded $132 billion (3)

3. Are Type 2 diabetic patients offered adequate foot care?The role of physician and patient characteristics-

4. Diabetes- General Facts • 15.7 million people have diabetes: • 10.3 million diagnosed (= a sixfold increase over the past 40 years) • 5.4 million undiagnosed • ➤ 798,000 new cases diagnosed per year • ➤ 7th leading cause of death in the U.S.

5. Diabetes Disproportionately Affects Minority Populations • ➤ Native Americans • Overall prevalence of Type 2 diabetes in Native Americans is 12.2%, compared to 5.2% of the general population. In some tribes, 50% of the population has diabetes.

6. Self-Management Goals • Identify self-management tools, including the following: • an action plan that includes goals and describes behavior (e.g., increasing activity by walking 15 minutes 3 times per week) • A review of the patient’s personal barriers (e.g., too busy to exercise) • Steps to overcome barriers • The patient’s confidence level (e.g., on a scale of 1 to 10, how confident are you that you can meet your goals?) • follow-up plan

7. N Engl J Med, Vol. 344, No. 18·May 3, 2001·PREVENTION OF TYPE 2 DIABETES MELLITUS BY CHANGES IN LIFESTYLEAMONG SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE

8. The Diabetes Prevention Program (DPP)Description of lifestyle interventionTHE DIABETES PREVENTION PROGRAM (DPP) RESEARCH GROUP – D Nathan

9. Diabetes Control and Complications Trial (DCCT) Long term study showed benefits of intensive metabolic control in patients with type 1 diabetes; lowering hemoglobin A(HbA) to 7%produced significant reduction (=75%) in risk for complications (eye, kidney and nervous system)

10. Treatment Protocol Medications (eg, sulfonylure, metformin, or insulin) added sequentially to treatment regimens once failure occurred as indicated by rising levels of blood glucose (BG)

11. United Kingdom prospective Diabetes Study UKPDS Patients had initial levels of HbA of 7%, 1% difference maintained between groups (intensive therapy vs. standard therapy); in all patients, disease worsened metabolically with time (insulin resistance worsened, insulin secretion declined, and levels of HbA rose.)

12. Effect of Metabolic control on Complications • Risk for retinopathy reduced by 37% for each decrease in HbA of 1 percentage point (similar to results from DCCT)

13. Diet and Exercise • Short-term benefits of diet and exercise well established; modest reduction in weight (eg, 5-10 lb) results in dramatic decrease in level of BG, thereby reducing requirements for medication; however, high rate of recidivism; results form UKPDS – patients saw dieticians every 3 to 4 mos for entire course of study; although patients lost weight initially, they gained weight ultimately (weight gain less than in patients undergoing intensive therapy); HbA rose over time;

14. Relative Importance • Increasing activity alone not effective but important in maintaining weight loss; weight loss of 5 to 10 lb may lead to remission in short term; long-term maintenance of weight loss in population of overweight individuals difficult to attain; other interventions required if diet fails.

15. Hemoglobin A • Minor fraction of HbA that occurs normally (glycosylated Hb) and increases in patients with diabetes; glycosylation of Hb related to control of diabetes.

16. Sulfonylureas • Oldest class of medications for control of diabetes; HbA decreased by 1 to 2 percentage point; rates of primary and secondary failure substantial; mechanism –stimulate secretion of insulin by binding to specific receptor on B cell; problems – less effective in nonobese patients; may cause severe hypoglycemia and weight gain; fail over time (HbA typically returns to pretreatment level within 5 yr;

17. Study – 51 patients with HbA^7.5% Randomized to bid insulin or glibenclamide (glyburide); found that insulin lowered HbA significantly more than glibenclamide; over 2yr, B-cell function declined more in patients treated with glibenclaimide than in those treated with insulin (ie, sulfonylureas accelerate decline of B-cell function)

18. Metformin: Fear of lactic acidosis kept drug off market in United States until 1995; incidence of lactic acidosis much lower than with phenformin; most common oral treatment for diabetes worldwide; mechanism-inhibits hepatic glucose output; lowers glucose with lower levels of insulin (ie, insulin sensitizer); works in obese and nonobese patients;

19. Clinical Trials 1. Found metformin reduces HbA by 1.5 in patients who had failed diet therapy; 2. When patients who had failed therapy with sulfonylurea (glyburide) switched to metformin, no change in HbA, ie, metformin and glyburide equipotent; when metformin added to glyburide, HbA fell by =1.7%; to achieve synergistic effect in combination therapy, drugs must have different mechanisms of action;

20. Adverse Effects • 10% of patients experience gastrointestinal (GI) discomfort (diarrhea, rumbling or increased production of gas); lactic acidosis rare, but fatal in 25% to 30% of cases; hypoglycemia does not occur when metformin used as monothereapy; titrating dosage may reduce GI effects (speaker begins with 500 mg once daily, then increases to 500 mg bid, then further increases dose to 850 mg bid;

21. Comparison to Sulfonylureas Similar potencies and long-term efficacies; adverse-effect profile may determine choice; because sulfonylureas associated with hypoglycemia, weight gain, and possible cardiovascular risk, speaker prefers metformin as first-line oral therapy; primary and secondary failure occurs in 3 to 5 yr on metformin or sulfonylureas.

22. Ox-glycosidase – Weak Drugs • Generally used in combination with other therapies; acarbose reduced HbA by 0.5 to 1.0 percentage point when added to treatment regiment of diet, sulfonylurea, metformin, or insulin; mechanism – inhibits absorption of carbohydrates in small intestine ( increasing production of methane in large intestine); limiting intake of carbohydrates and titrating dosage may reduce adverse effects.

23. Thiazolidinediones (TZDs) Increase uptake of glucose in periphery and suppress release of glucose from liver by binding to specific nuclear receptors (peroxisome proliferator-activated receptor-y (PPAR-y); efficacy –poor as monotherapy (HbA actually rose in some studies), but good in combination therapy (leads to additional decrease in HbA of =1%; Study – compared pioglitazone and rosiglitizone; no differences in weight gain or effect on HbA, but pioglitazone had lipis-lowering effect (total cholesterol, low-density lipoprotein (LDL, and

24. triglycerides decreased); adverse effects – generally well tolerated, but edema and congestive heart failure (CHF) may occur: although liver dysfunction not commonly seen, monitoring of liver function still required (no long-term data available)

25. Insulin • Quantity more important than frequency or mode of delivery; prescribed dosage often subtherapeutic; no maximum dose;

26. Studies • Benefits found for intensive treatment (beginning with 90 units daily, and increasing to maintain target level of HbA); single dose of insulin suspension (NPH) at bedtime (increased every 3 or 4 days until target level of BG reached) effective at lowering HbA; 85 units required , on average; other studies show lowest effective dose 60 units, with some patients requiring up to 150 units, on average;

27. Hypoglycemia • DCCT showed 3 fold increase in frequency of hypoglycemic episodes in patients on intensive therapy, compared to those on standard therapy; incidence substantially lower in other studies (maximum of 3 episodes per 100 patient-years)

28. Monotherapy • Study compared NPH and insulin glargine; 518 patients followed for 6 mo; differences in reduction in HbA not statistically significant; hypoglycemia less severe with glargine; other studies found no differences in HbA fasting glucose, or incidence of severe hypoglycemia.

29. Combination Therapy • Most important combination includes diet, exercise, and medication (patients often neglect diet once medications started); metformin good for controlling weight gain; triple combination therapy (3 oral agents) does not achieve lower HbA than 70/30 insulin bid plus metformin; insulin therapy also has positive effects on lipid profile and costs less than therapy with 3 oral agents.

30. Conclusions • Type 2 diabetes difficult to control over time; diet most cost-effective therapy when effective behavior modification important to increase likelihood of success); substantial rate of failure with oral agents necessitates changing or adding medications; aggressive use of insulin recommended; treatment of other risk factors for cardiovascular disease also critical; individualization of treatment regimen important.

31. Diabetes Prevention Program (DPP) • Randomized clinical trial; study groups – a.lifestyle modifications (7% reduction in weight [=15 lb] plus 30 min of moderate-intensity activity [eg, walking] 5 days/wk; • metformin; troglitazone (discontinued because of concerns about safety; • patient selection criteria- impaired glucose tolerance (IGT)

32. Life style intervention • The two major goals of the Diabetes Prevention Program (DPP) lifestyle intervention were a minimum of 7% weight loss/weight maintenance and a minimum of 150 min of physical activity similar in intensity to brisk walking. Both goals were hypothesized to be feasible, safe, and effective based on previous clinical trials in other countries.

33. The methods used to achieve these lifestyle goals include the following key features: • Individual case managers or “lifestyle coaches; • Frequent contact with participants; • A structured, state-of-the-art, 16-session core-curriculum that taught behavioral self-management strategies for weight loss and physical activity; • Supervised physical activity sessions; • A more flexible maintenance intervention, combining group and individual approaches, motivational campaigns, and “restarts;” • Individualization through a “toolbox” of adherence strategies; • Tailoring of materials and strategies to address ethnic diversity; and finally • An extensive network of training, feedback, and clinical support.

34. Goal Based Behavior Intervention • The DPP lifestyle intervention was designed to be administered consistently across the 27 centers and 1,079 participants in this arm of the trial and to allow maximum flexibility, given the heterogeneity of the participants.

35. cont • There was also a range of education: 25.8% of the population had13 years of education, 48.1% had 13–16 years, and 26.1% had 17 years. To provide an intervention that would be appropriate for the diverse population, a decision was made to use a goal-based behavioral intervention, where all participants at all centers were given the same weight loss and physical activity goal, but individualization was permitted in the specific methods used to achieve these goals.

36. Results • Weight gain – patients in placebo group maintained weight; patients on metformin lost average of 2kg; patients with lifestyle modifications achieved 7% weight loss initially and and maintained=5% weight loss over course of study; development of diabetes – 11% per year in placebogrouip; 7.8% per year with metformin therapy; 4.8% per year with lifestyle modification; over course of therapy, interventions lead to 31% (with metformin) and 58% (with lifestyle changes) reduction in development of diabetes; reduction in risk maintained across age groups.

37. Wt Loss Goal • The weight loss goal for all DPP participants was to lose 7% of initial body weight and to maintain this weight loss throughout the trial. The decision to use 7% of initial body weight as the goal was based on epidemiological data and results of previous weight loss trials. The risk of developing diabetes appears to increase with increased levels of BMI; thus, any decrease in BMI might be anticipated to decrease risk of diabetes.

38. Treatment Protocol for Patients with Type 2 Diabetes • Heterogeneous disorder; insulin secretion and resistance vary among patients; begin treatment with metformin, along with diet and exercise, then initiating treatment with insulin if therapeutic goals not reached;

39. Strong epidemiologic evidence indicates that diabetes is associated with lifestyle. People who migrate to Westernized countries, with their more sedentary lifestyles and “Westernized” diets have greater risk of developing type 2 diabetes than do their counterparts, who remain in the native countries (80).

40. The preventability of diabetes has been demonstrated by several randomized trials.

41. In a Chinese trial, 577 subjects who had impaired glucose tolerance (IGT) were randomly assigned to either the control group or to three different intervention groups (diet, exercise, or diet plus exercise) (96). Participants in the diet-intervention group were prescribed a diet with a specific fat content and with individual goals for cereal, vegetables, meat, milk, and oil intake. Compared with the control group, the diet alone, exercise alone, and diet-plus exercise interventions were associated with 31%, 46%, and 42% reductions, respectively, in risk of developing diabetes.

42. Smoking • Several prospective studies have demonstrated that smoking is associated with a modestly increased risk of developing diabetes. Although earlier studies did not detect a significant positive effect, most have not focused on smoking and diabetes in their major hypotheses, and the majority have lacked the power to detect the relatively small but important effect. Although smoking cessation is associated with a modest increase in weight, it increases insulin sensitivity and improves the lipoprotein profile. Prospective studies clearly demonstrated that the beneficial effects of smoking cessation on diabetes risk outweigh the adverse effects on weight gain.

43. Amount and Types of Fat • Higher total fat intake has been hypothesized to contribute to diabetes through two major pathways. First, a high percentage of fat in the diet may promote weight gain and the development of obesity. Second, a high percentage of fat in the diet may cause insulin resistance, independent of obesity. The first hypothesis has been hotly debated within recent years (53, 148). Although in short-term studies, a modest reduction in body weight has been seen typically in individuals assigned to diets with a lower percentage of calories from fat, recently published weight loss

44. continued trials on low-carbohydrate-high-fat/protein diets suggest greater weight loss with high-fat diets than with low-fat diets (30, 112).

45. Quality and Quantity of Carbohydrates • Low-fat, high-carbohydrate diets generally produce high postprandial glucose and insulin responses. However, similar to total fat, the total percentage of energy derived from carbohydrates in the diet generally has not been found to predict diabetes risk.

46. Diets low in carbohydrates – epidemiology of obesity parallels consumption of fat, not carbohydrates; short-term data suggests diets high in fat and low in carbohydrates better for weight loss than diets high in carbohydrates and low in fat; however, no difference between groups at 1 yr;

47. Micronutrients • Magnesium is an important component of whole grains and other unprocessed foods, such as nuts and green leafy vegetables. Its intake has substantially decreased in industrialized countries owing to overprocessing of foods and adoption of western diets. Hypomagnesemia is a frequent condition in patients with type 2 diabetes (129).

48. Coffee • An inverse association between coffee consumption and the risk of type 2 diabetes has been observed in several prospective cohort studies (106, 108, 131, 134), but not in all (113). The beneficial effect of long-term coffee consumption on the development of diabetes has been attributed to caffeine, but other constituents of coffee, e.g., potassium, niacin, magnesium and antioxidant substances, may have beneficial effects on glucose metabolism and insulin resistance as well.

49. Meat • Frequent consumption of meat, in particular processed meat, has been consistently shown to increase the risk of diabetes in prospective studies (34, 116, 119, 136).

50. Study Design • Impaired glucose tolerance was defined as a plasma glucose concentration of 140 to 200 mg per deciliter (7.8 to 11.0 mmol per liter) two hours after the oral administration of 75 g of glucose in subjects whose plasma glucose concentration after an overnight fast was less than 140 mg per deciliter.