Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects

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This article clarifies the redefinition of treatment success in patients with T2DM based on targeting the underlying physiologic defects of the disease.


The incidence and prevalence of T2DM, overweight/obesity, and CV disease (CVD) are increasing worldwide. It is estimated that the worldwide prevalence of diabetes will increase from 171 million in 2000 to 366 million by 2030 14; T2DM increases the risk of morbidity and mortality from microvascular (eg, neuropathic, retinopathic, nephropathic) and macrovascular (eg, coronary, peripheral vascular disease) complications. 15 According to a Michigan health maintenance organization study (N = 1,364), the median annual direct cost of medical care for Caucasian patients with T2DM who were diet controlled, had a body mass index (BMI) of 30 kg/m 2 or higher, and had no vascular complications was estimated to be $1,700 for men and $2,100 for women. 16 The actual cost of care for patients with T2DM may be much higher, since most patients present with multiple CV risk factors in addition to being overweight.

NHANES data show that approximately two-thirds of Americans are either overweight or obese 17; overweight/obesity affects about 80% of adults diagnosed with T2DM. 18 Overweight or obesity can increase the risk for developing T2DM by more than 90-fold and, in women, it can increase the risk for developing coronary heart disease (CHD) by sixfold. 19 The close link between T2DM and CVD is underscored further with recent data from the Framingham Heart Study, which showed a high lifetime risk of CVD in patients with diabetes, heightened further by obesity. During the 30-year study period, the lifetime risk of CVD in normal-weight people with diabetes was 78.6% in men and 54.8% in women; the risk increased to 86.9% in obese men with diabetes and to 78.8% in obese women with diabetes. 20 The NHANES data also showed that the prevalence of T2DM increased in the past decade and that patients are being diagnosed at a younger age, from a mean age of 52 years in 1988–1994 to 46 years in 1999–2000. 7


The paradigm behind the pathophysiology of T2DM has shifted from its perception as a simple “dual-defect” disease (ie, deficiency in insulin secretion and peripheral tissue insulin resistance) to a multidimensional disorder. 1,21 This new model includes overweight/obesity, insulin resistance, qualitative and quantitative defects in insulin secretion, and dysregulation in the secretion of other hormones, including the beta-cell hormone amylin, the alpha-cell hormone glucagon, and the gastrointestinal incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide. 21–23

The major target of antidiabetes agents is glycemic control, assessed by a reduction in HbA1c, but their effects on other metabolic factors and their adverse effects differ with each agent ( Table 1 ).3 Whereas metformin and alpha-glucosidase inhibitors may help normalize glycemia with weight-neutral effects, many other agents, including insulin and its analogues, the “glinides,” first- and second-generation sulfonylureas, and TZDs, are associated with weight gain. 23,24 In addition, the propensity to induce hypoglycemia differs among agents and clearly reflects the mechanism of action of each drug. The observed limitations of older therapies treating a progressive disease that is associated with a number of comorbid conditions supports the need for continued development of new antidiabetes agents.


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Author and subject indexes: 2009

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