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

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Despite advances in diagnosis and treatment, type 2 diabetes mellitus (T2DM), overweight/obesity, cardiovascular disease, and their sequelae are major public health burdens worldwide. The understanding of the pathophysiology of T2DM has traditionally emphasized decreased insulin secretion and increased insulin resistance, but evolving concepts now include the role of incretin hormones in disease progression. A comprehensive approach to managing patients with T2DM requires targeting both the fundamental defects of the disease and its comorbidities, including the sequelae of nonoptimal control of blood glucose, blood pressure, body weight, and lipids. Newer antidiabetes agents, such as the glucagon-like peptide–1 (GLP-1) receptor agonists and the dipeptidyl peptidase–4 (DPP-4) inhibitors, address fundamental defects related to glycemic control in T2DM and may have potential effects on other markers of cardiovascular risk. A redefinition of treatment success may be warranted as more data become available.


  • The NHANES 1999–2004 data showed that only 13.2% of patients with diagnosed diabetes achieved concurrent weight, blood pressure, and lipid level goals.
  • Among patients with T2DM, lifestyle intervention (control of weight, blood pressure, lipid levels) should be reinforced at every physician visit; glycosylated hemoglobin (HbA1c) should be monitored every 3 months until it is less than 7.0%, and then rechecked every 6 months.
  • The effects of GLP-1 agonists on HbA1c are comparable to insulin analogues, but GLP-1 agonists are associated with weight reduction, while insulin is associated with weight gain.
  • DPP-4 inhibitors have been associated with significant reductions in HbA1c when used alone or with metformin or pioglitazone.



According to the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA), glycosylated hemoglobin (HbA1c) in patients with diabetes should be maintained at 6.5% or less (AACE) or at less than 7.0% (ADA). Both organizations support an aggressive stepwise approach that includes medication and lifestyle modification, with strategies and clinical attention devoted to avoiding significant hypoglycemia.1,2 Yet, despite the introduction of new antidiabetes agents, most current management strategies are offset by limitations in achieving and maintaining glycemic targets needed to provide optimal care for patients with diabetes, more than 90% of whom have type 2 diabetes mellitus (T2DM).3,4

Nationally, glycemic control among patients with T2DM has improved but is still far from optimal. According to data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES), glycemic control (HbA1c < 7.0%) rates were 35.8% for patients with T2DM.5 In a more recent report (NHANES 1999–2004), fewer than half (48.4%) of adult patients with diagnosed diabetes achieved HbA1c levels below 7.0%.5,6 Factors contributing to these data include earlier onset and earlier detection of T2DM.7


Available treatments for patients with T2DM include secretagogues, such as sulfonylureas and “glinides” (repaglinide and nateglinide), metformin, thiazolidinediones (TZDs), and dipeptidyl peptidase–4 (DPP-4) inhibitors among oral medications, and insulin and glucagon-like peptide–1 (GLP-1) receptor agonists among parenterally administered agents. According to the latest published data on prescribing patterns for patients with T2DM, analyses of the National Disease and Therapeutic Index (1994–2007) and the National Prescription Audit (2001–2007), sulfonylurea use decreased from 67% of treatment visits in 1994 to 34% of visits in 2007.8 By 2007, metformin, used in 54% of treatment visits, and TZDs, used in 28%, were the most frequently administered antidiabetes agents. Insulin use declined from 38% of visits during which a treatment was administered in 1994 to 25% of visits in 2000, but had increased subsequently to 28% of visits in 2007.


Clinical research has suggested that focusing solely on improving glycemic control may be insufficient to reduce overall morbidity and mortality associated with diabetes. Specifically, data from recent studies, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT), emphasized that lowering HbA1c below 7% in a high-risk population of individuals with T2DM did not improve cardiovascular (CV) outcomes.9–11 The observations confirm that risk factors, including weight, blood pressure (BP), and lipid levels, are vitally important in reducing morbidity and mortality in this population. This perception is further underscored by the NHANES 1999–2004 data, which showed poor concurrent control of HbA1c, BP, and lipids; only 13.2% of patients with diagnosed diabetes achieved all three target goals simultaneously.6 Similarly, a nationwide survey in Norway showed that only 13% of patients with T2DM concurrently achieved goals for HbA1c, BP, and lipids.12

In the Danish Steno-2 Study, patients with T2DM and persistent microalbuminuria were treated with either intensive target-driven therapy using multiple drugs or conventional multifactorial treatment. Over a mean period of 13.3 years (7.8 years of treatment plus 5.5 years of follow-up), intensive multifactorial intervention to control multiple CV risk factors, including HbA1c, BP, and lipids, was associated with a lower risk of death from CV causes (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19 to 0.94; P = .04) and a lower risk of CV events (HR, 0.41; 95% CI, 0.25 to 0.67; P < .001) than was conventional therapy.13

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 203014; 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/m2 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 obese17; 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


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