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

December 1, 2009|Cleveland Clinic Journal of Medicine
William T. Cefalu, MD;Robert J. Richards, MD;Lydia Y. Melendez-Ramirez, MD
Author and Disclosure Information

William T. Cefalu, MD
Joint Program on Diabetes, Endocrinology and Metabolism, Louisiana State University Health Science Center and Pennington Biomedical Research Center, New Orleans and Baton Rouge, LA

Robert J. Richards, MD
Joint Program on Diabetes, Endocrinology and Metabolism, Louisiana State University Health Science Center and Pennington Biomedical Research Center, New Orleans and Baton Rouge, LA

Lydia Y. Melendez-Ramirez, MD
Joint Program on Diabetes, Endocrinology and Metabolism, Louisiana State University Health Science Center and Pennington Biomedical Research Center, New Orleans and Baton Rouge, LA

Correspondence: William T. Cefalu, MD, 6400 Perkins Road, Baton Rouge, LA 70808; cefaluwt@pbrc.edu

Dr. Cefalu reported that he has received research and grant support from Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Hollis-Eden Pharmaceuticals, Johnson & Johnson, and Merck & Co., Inc.; consulting/advisory fees from Amylin Pharmaceuticals, Inc., Eli Lilly and Company, Halozyme Therapeutics, Johnson & Johnson, and Merck & Co., Inc.; and honoraria from Amylin Pharmaceuticals, Inc., Eli Lilly and Company, and Merck & Co., Inc. Drs. Melendez-Ramirez and Richards reported that they have no financial interests or relationships that pose a potential conflict of interest with this article. Drs. Cefalu, Melendez-Ramirez, and Richards reported that they received no honoraria for writing this article.

Dr. Cefalu and his coauthors reported that they wrote this article and received no assistance with content development from unnamed contributors. They reported that BlueSpark Healthcare Communications, a medical communications company, assisted with preliminary literature searches, reference verification, proofing for grammar and style, and table and figure rendering based on author instructions.

ABSTRACT

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.

KEY POINTS

  • 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.

BRIDGING THE GAP FROM PATHOPHYSIOLOGY TO UNMET NEEDS

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.

CLINICAL GUIDELINES AND CV RISK FACTOR MANAGEMENT

The best strategy for managing T2DM is a comprehensive approach that addresses the fundamental core defects plus associated factors that contribute to increased CV risk. Several specialty groups have suggested guidelines and algorithms for the management of T2DM and its comorbidities. These guidelines, including the ADA standards of medical care, the AACE standards in tandem with the American College of Endocrinology guidelines, and the recent joint statement from the ADA and the European Association for the Study of Diabetes (EASD), acknowledge that the core defects of T2DM and the associated CV risk factors (eg, weight gain, obesity, hypertension, dyslipidemia) are important in developing optimal treatment strategies.1–3 Medical nutrition guidelines advocate weight loss as a key initial step in managing T2DM and the comorbidities that lead to elevated CV risk.25,26 The National Institutes of Health and the US Department of Health and Human Services/US Department of Agriculture advocate regular physical activity, dietary assessment, and periodic comorbidity and weight assessment for all people, not just those with T2DM or CVD.26,27

Weight reduction

Evidence in support of effective lifestyle intervention was demonstrated in the Action for Health in Diabetes (Look AHEAD) study. After 1 year, patients with T2DM treated with intensive lifestyle intervention lost an average of 8.6% of their initial weight compared with 0.7% in patients treated only with diabetes support and education (P < 0.001). The intensive-intervention patients also had a significant drop in HbA1c (from 7.3% to 6.6%; P < 0.001) and were able to reduce their antidiabetes, antihypertensive, and lipid-lowering medications.28 More recent data from the Look AHEAD study reported that overweight patients with T2DM enrolled in a weight management program experienced significant weight loss, improved physical fitness, reduced physical symptoms, and overall improvement in health-related quality of life.29 Thus, weight reduction appears to be a key component in reducing CV risk and improving quality of life in most patients with T2DM.28–30

Hypertension

Hypertension is a major risk factor for microvascular complications and CVD, and may be associated with, or be the underlying result of, nephropathy.2 BP control is clearly important in reducing the morbidity and mortality associated with T2DM. The recommended BP goal in patients with T2DM is less than 130/80 mm Hg.1,2

Hyperlipidemia

According to the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]), diabetes is considered a CHD risk equivalent because it confers a high risk of new CHD developing within 10 years.31 In addition to the NCEP–ATP III guidelines, the ADA and the AACE have set target levels for lipids in patients with diabetes, including T2DM.1,2,31 All three organizations have defined 100 mg/dL as the target level for low-density lipoprotein.

HbA1c and lifestyle intervention

Figure 1. Suggested algorithm for the metabolic management of patients with type 2 diabetes mellitus. Clinicians should reinforce lifestyle interventions at every visit and check glycosylated hemoglobin (HbA1c) every 3 months until it is less than 7.0%, and then check it at least every 6 months. The interventions should be adjusted if HbA1c is 7.0% or greater.
The American Heart Association and the ADA initiated a call to action for global risk assessment for CVD and diabetes.32 According to their joint scientific statement, lifestyle intervention should be reinforced at every physician visit, and HbA1c should be monitored every 3 months until it is less than 7.0% and then rechecked every 6 months. Adjustments in intervention should be made if the HbA1c level is 7.0% or higher.3 A recent joint statement from the ADA and the EASD revised an earlier treatment algorithm for the initiation of therapy in patients with T2DM; the revision includes incretin therapies (ie, GLP-1 receptor agonists) as a tier 2 option, especially in patients in whom hypoglycemia and weight gain are concerns (Figure 1).3

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