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Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin

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Type 2 diabetes mellitus is a chronic metabolic disorder associated with high morbidity and mortality from long-term microvascular and macrovascular complications. Evidence from randomized controlled trials indicates that aggressive treatment directed at improving glycemic control reduces the incidence of diabetes-related microvascular complications. Traditionally, oral monotherapy for type 2 diabetes is initiated when diet and exercise do not control hyperglycemia, followed by the sequential, stepwise addition of oral agents as glycemic control deterio-rates. Insulin is the last therapeutic option used, generally reserved for advanced stages of the disease when multiple oral combination treatment fails. Despite a better understanding of the pathophysiologic disease mechanisms in the past decade, the expanded armamentarium of targeted oral antidiabetic drugs, and the conclusive evidence of the benefits of stringent glycemic control, actual treatment outcomes in clinical practice remain suboptimal relative to established treatment goals (glycosylated hemoglobin A1c level >7%). Earlier detection and aggressive treatment are critical to address the natural progression of diabetes because multiple defects (insulin resistance, insulin insufficiency, glucotoxicity, and lipotoxicity) and vascular complications may be present at the time of diagnosis. Acknowledging the inadequacy of traditional strategies and underscoring the importance of insulin as an integral part of the therapeutic armamentarium, clinical trends are moving toward earlier use of insulin combined with 1 or more oral agents. Such strategies can address the multiple abnormalities present early in the disease course and may restore optimal control. A new treatment paradigm for patients with type 2 diabetes to achieve and maintain near-normal glycemic control is warranted.

Section snippets

PATHOPHYSIOLOGY AND NATURAL HISTORY OF TYPE 2 DIABETES MELLITUS

Type 2 diabetes is characterized by 2 major pathophysiologic defects: insulin resistance, which results in increased hepatic glucose production (HGP) and decreased glucose disposal, and impaired β-cell secretory function (both basal and glucose stimulated).11 Loss of the acute insulin response to a carbohydrate load, a prototypical defect that occurs early in the natural course of the disease, generally when fasting plasma glucose levels reach 115 mg/dL,12 leads to postprandial hyperglycemia.

TREATMENT OF TYPE 2 DIABETES MELLITUS

Type 2 diabetes has traditionally been treated in a stepwise manner, starting with lifestyle modifications (medical nutrition therapy and exercise), proceeding to the use of 1 oral antidiabetic agent, followed by a combination of 2 or more oral agents before insulin is considered.3

PRACTICAL APPROACHES TO THERAPY

Although the benefits of improved glycemic control have been well established, most patients with type 2 diabetes do not achieve optimal glycemic control.59 The current stepwise approach in the treatment of type 2 diabetes does not address the underlying pathophysiology in which defects of both insulin secretion and action occur early in the course of the disease. Treatment is often conservative and allows an oral agent to fail before another one is added and generally delays institution of

CONCLUSIONS

Hyperglycemia is an independent risk factor for both microvascular and macrovascular complications associated with diabetes, and improvement in metabolic control reduces the risk of the development or progression of these complications. Hence, the goal of treatment of patients with diabetes should be to achieve and maintain near-normal glycemic control, without increasing the risk of hypoglycemia. Medical nutrition therapy and exercise form the cornerstone of therapy for type 2 diabetes

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  • Cited by (0)

    This study was supported by an unrestricted educational grant from Aventis Pharmaceuticals Inc.

    1

    Dr Abrahamson is on the speaker's bureau for Aventis Pharmaceuticals Inc, Bristol-Myers Squibb, Glaxo-SmithKline, Eli Lilly and Co, Novo Nordisk, Novartis, and Pfizer Inc.

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