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Therapeutics Letter, issue 23, January - February - March 1998

MANAGEMENT OF TYPE 2 DIABETES

Diabetes mellitus is a common disease affecting approximately 5 % of the population. (1) Type 2 diabetes (non-insulin-dependent diabetes mellitus) accounts for 85-90 % of patients with diabetes mellitus. (2) Patients with diabetes have an approximately threefold risk for all cardiovascular diseases (3),(4) and their relative risk of death from all causes is increased by 75%. (5),(6)

What is the evidence that improved glucose control leads to a decrease in complications of type 2 diabetes?

As yet there is no conclusive evidence that improved glucose control with oral agents leads to a decrease in the complications of type 2 diabetes. There is some evidence that improved glucose control delays the onset of complications in type 2 diabetes. In a cohort study of 114 patients followed for 5 years, the incidence of progression of retinopathy increased linearly as a function of the HbA1C level: 2% in those with HbA1C less than 0.070 and 62% in those with HbA1C greater than 0.090. (7) In a randomised secondary prevention intervention trial of diabetic patients (majority type 2 diabetes) who had suffered an MI, those who had intensive insulin treatment had an absolute reduction of mortality of 11% (44% vs 33%) compared to the regular therapy group after 3.4 years of follow-up. (8) In a randomised trial of 110 patients with type 2 diabetes, those who received multiple insulin injections had an absolute reduction in the progression of retinopathy of 24%, and of nephropathy of 20%, after 6 years of follow-up, when compared with a conventional therapy group. (9) Preliminary results of a large prospective randomised trial, that is examining the relationship of glucose control to complications of diabetes in type 2 diabetics, show an improvement in HbA1C levels in patients who received treatment, whether with sulfonylurea, metformin or insulin. (10)

In contrast, there is strong evidence that near-normalisation of blood glucose levels with insulin can delay the development and progression of retinopathy, nephropathy, and neuropathy of patients with type 1 diabetes mellitus (IDDM). (11)

What are the new criteria for the diagnosis of diabetes mellitus?

• Fasting glucose*7.0 mmol / L.*

and/or

• 2 hour post 75 g glucose load*11.1 mmol / L.*

and/or

• Symptoms of diabetes plus a single random glucose *11.1 mmol / L.

* In the absence of symptoms, a second test should be done to confirm the diagnosis.

The development of diabetic retinopathy and nephropathy mainly occurs when the fasting glucose is 7.8 mmol/L or greater. (12),(13) However, fasting glucose levels of greater than 6.0 mmol/ L are associated with a higher incidence of cardiovascular disease. (12),(13) This information led the Canadian and American Diabetes Associations to develop new, lower criteria for the diagnosis of diabetes. (14),(15)

What are the risk factors for diabetes?

The risk factors for diabetes are age (>45 years), family history (first degree relative with diabetes), high-risk ethnic group (aboriginal, Asian, Pacific Islander, Hispanic, African), obesity (BMI > 27 kg/m2), history of gestational diabetes or macrosomic infant (>4.5 kg), hypertension, coronary artery disease.

What is the evidence for non-drug therapies?

There is good evidence that diet and exercise can delay the onset of type 2 diabetes in persons at risk. In one intervention trial 577 subjects with impaired glucose tolerance (a lesser degree of hyperglycemia) were randomized to control, diet, and exercise groups. Over a 6-year period, 67% of the control group but only 41 to 43% of the intervention groups developed type 2 diabetes, an absolute risk reduction of approximately 25%. (16) In several well designed, large scale cohort studies, with follow-up of 6 to 14 years, there was a relative decrease of 30 to 50% in the development of type 2 diabetes among those who exercised regularly compared to those who were sedentary. (17),(18),(19) This result was found in both men and women, and obese and non-obese subjects.

Weight loss, restricted diets, and exercise have all been advocated for the treatment of type 2 diabetes. Exercise, as an adjunct to diet, leads to increased weight loss and prevention of weight gain among patients with type 2 diabetes. There is some inconsistency, but most studies have demonstrated the effectiveness and feasibility of exercise over the long term in treating type 2 diabetes. (20),(21)

There is evidence that a variety of dietary interventions and weight loss work in the short term in the treatment of type 2 diabetes. However, the evidence of longer-term intervention trials suggests that diet alone does not improve glucose control or reduce morbidity in type 2 diabetes. (22)

What drug therapies have been shown to lower blood glucose?

A controlled trial of 2520 patients comparing diet alone with diet plus chlorpropamide, glyburide, insulin, or metformin found all the drugs equally good at lowering glucose and better than diet alone. (23) In this study, patients had significant weight gain on sulfonylurea or insulin therapy (a mean of 5 kg and 7 kg, respectively) but not on metformin therapy (1 kg weight gain). Hypoglycemic reactions over a 6-year period were 17 and 27 % for sulfonylurea and insulin respectively, but only 5 % for metformin. In this study glucose control deteriorated steadily over time in patients on all types of therapy, whether diet, sulfonylurea, metformin, or insulin because of decreasing B-cell function. After 4 to 5 years of therapy, HbA1C levels returned to higher values than existed before therapy was initiated. (22) Sulfonylureas, metformin, and insulin all reduce mean levels of HbA1C by between 0.7% and 0.8% over diet alone. (22) Troglitazone reduces HbA1C by 0.5% compared to diet alone. (24) Acarbose reduces HbA1C by 0.55% to 0.9%. (25),(26).

Modes of action:

Sulfonylureas increase insulin secretion and potentiate insulin action on the liver and peripheral tissues.

Metformin decreases hepatic glucose production, increases glucose uptake and possibly decreases appetite.

Alpha glucosidase inhibitors slow the absorption of carbohydrates.

Troglitazone decreases insulin resistance.

Conclusions

• Exercise and diet are effective in preventing type 2 diabetes.
• Exercise and weight loss are effective in treating type 2 diabetes, but weight loss is difficult to maintain.
• Sulfonylureas, metformin, and insulin are equally efficacious in improving glucose control in type 2 diabetes.
• The effectiveness of intensive insulin treatment in delaying the onset of complications of diabetes has been established for type 1 and to lesser extent for type 2 diabetes.

Table 1: Oral Drug Therapies

* Average price in BC (1997 Pharmacare data) || ** Not yet available in Canada || *** Estimate based on current US price.

Table 2: Choice of Oral Medication

*adjust dose based on creatinine clearance

References:

1. World Health Organization. Diabetes mellitus: report of a WHO study group. Geneva, World Health Organization,1995.(tech.rep.ser.no.727)
2. National Diabetes Data Group. Diabetes in America. Bethesda , Md: National Institute of Diabetes and Digestive and Kidney Diseases. National Institutes of Health; 1985: ii – 2.
3. Garcia MJ, McNamara PM, Gordon T, Kannell WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes. 1974;23:105-11.
4. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993:16:434-44.
5. Panzram G. Mortality and survival in type 2 diabetes (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987;30:123-31.
6. Walters DP, Gatling W, Houston AC, Mullee MA, Julious SA, Hill RD. Mortality in diabetic subjects: an eleven-year follow-up of a community-based population. Diabet Med. 1994;11:968-73.
7. Morisaki N, Watanabe S, Kobayashi J, et al. Diabetic control and progression of retinopathy in elderly patients: 5 year follow-up study. J Am Geriatric Soc. 1994;42:142-5.
8. Malmberg K et al. Prospective randomised study of intensive insulin treatment on long term survival after myocardial infarction in patients with diabetes mellitus. Br Med J. 1997;314:1512-5.
9. Ohkubo Y, Kishikawa H, Arake E, et al. 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 and Clin Practice. 1995;28:103-17.
10. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study 24: a 6-year randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Int Med. 1998;128:165-75.
11. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86.
12. Jarrett RJ, Keen H. Hyperglycaemia and diabetes mellitus. Lancet. 1976;2:1009-12.
13. Pettitt DJ, Knowler WC, Lisse JR, Bennett PH. Development of retinopathy and proteinuria in relation to plasma glucose concentration in Pima Indians. Lancet. 1980;2:1050-2.
14. Canadian Diabetes Association Expert Committee. Clinical practice guidelines for the management of diabetes mellitus. Draft 9. October 10, 1997.
15. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20(7):1183-97.
16. Pan X, Li G, Hu Y, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Diabetes Care. 1997;20(4):537-44.
17. Helmrich SP, Ragland DR, Leung RW, Pfaffenbarger RS. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med.1991;325:147-52.
18. Manson JE, Rimm EB, Stampfer MJ, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet. 1991;338:774-78.
19. Burchfiel CM, Sharp DS, Curb JD et al. Physical activity and incidence of diabetes: The Honolulu Heart Program. Am J Epidemiol. 1995;41:360-68.
20. Skarfors ET, Wegener TA, Lithell H, Selinus I. Physical training as treatment for type 2 diabetes (non-insulin-dependent) diabetes mellitus in elderly men. A feasibility study over 2 years. Diabetologia. 1987;30:930-33.
21. Schneider SH, Khachadurian AK, Amoroso LF, Clemow L, Ruderman N. Ten year experience with an exercise based outpatient lifestyle modification program in the treatment of diabetes mellitus. Diabetes Care. 1992;15(suppl):1800-10.
22. Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trail of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Int Med. 1996;124(1 pt 2):136-45.
23. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study(UKPDS) 13: relative efficacy of randomly allocated diet, sulfonylurea, insulin or metformin in patients with newly diagnosed non-insulin dependent diabetes mellitus followed for three years. Br Med J. 1995;310:83-8.
24. Iwamoto Y, Kosaka K, Kuyuza T, et al. Effects of troglitazone, a new hypoglycemic agent, in patients with NIDDM poorly controlled by diet therapy. Diabetes Care. 1996;19:151-6.
25. Chiasson J-L, Josse RG, Hunt JA, et al. The efficacy of acarbose in the treatment of non-insulin-dependent diabetes mellitus. Ann Int Med. 1994;121:928-35.
26. Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter placebo-controlled trial comparing acarbose with placebo, tolbutamide and tolbutamide plus acarbose in NIDDM. Am J Med. 1995;98:443-45.
27. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatric Soc. 1996;44:751-5.

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