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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.

DPP-4 inhibitors

The DPP-4 inhibitors (commonly called gliptins) inhibit the proteolytic cleavage of circulating GLP-1 by binding to the DPP-4 enzyme, increasing the concentration of endogenous GLP-1 approximately two- to threefold.49–51 These concentrations result in more prompt and appropriate secretion of insulin and suppression of glucagon in response to a carbohydrate-containing snack or meal, with the change in glucagon correlating linearly with improved glucose tolerance.51

DPP-4 inhibitors, which are given orally, include sitagliptin and saxagliptin (approved in the United States) and vildagliptin (not approved in the United States but used in the European Union and Latin America).8,22,33,52 Sitagliptin can be used either as monotherapy or in combination with metformin or a TZD.8,49–55 Recently, a single-tablet formulation of sitagliptin plus metformin was granted regulatory approval.8

When used alone or in combination with metformin or pioglitazone, sitagliptin has been associated with significant reductions in HbA1c (of ~0.5% to 0.6% when used alone, ~0.7% with metformin, and ~0.9% with pioglitazone [P < .001 vs placebo]), with hypoglycemia occurring in 1.3% or less of the population.54 In an 18-week study in which patients with T2DM who were inadequately controlled with metformin monotherapy were randomized to receive add-on sitagliptin (100 mg QD), rosiglitazone (8 mg QD), or placebo, sitagliptin reduced HbA1c –0.73% (P < .001 vs placebo) and reduced body weight –0.4 kg, while rosiglitazone reduced HbA1c –0.79% and increased body weight +1.5 kg.55

To evaluate the effectiveness of sitagliptin and metformin as initial therapy, a 54-week study was completed in 885 patients with T2DM and inadequate glycemic control (HbA1c 7.5–11%) on diet and exercise.56 Patients were evaluated on monotherapy with either sitagliptin (100 mg QD) or metformin (1 g or 2 g QD), or on initial therapy with the two in combination (sitagliptin 100 mg + metformin 1 mg or 2 mg QD). At week 54, in the all-patients-treated analysis, mean changes in HbA1c from baseline were –1.8% with sitagliptin plus metformin 2 g QD, –1.4% with sitagliptin plus metformin 1 g QD, –1.3% with metformin 2 g QD monotherapy, –1.0% with metformin 1 g QD monotherapy, and –0.8% with sitagliptin 100 mg QD monotherapy.

All treatments improved measures of beta-cell function (eg, homeostasis model assessment [HOMA]-beta, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1%–3%) across treatment groups. The incidence of gastrointestinal adverse experiences was evaluated with the coadministration of sitagliptin and metformin and appeared similar to that observed with use of metformin as monotherapy.56 Thus, this study suggested that an initial combination of a DPP-IV inhibitor with metformin can improve glycemic control and markers of beta-cell function in patients with T2DM.

Incretin-based therapies compared

Studies in both healthy individuals and in patients with T2DM have shown that oral DPP-4 inhibitors such as sitagliptin increase endogenous GLP-1 concentrations by about twofold compared with placebo.22,50 The pharma­cologic concentration of subcutaneously administered exenatide available for activating the GLP-1 receptor is significantly greater than the increased endogenous GLP-1 concentrations achieved with sitagliptin. In a recent clinical study comparing exenatide and sitagliptin in patients with T2DM, the mean 2-hour plasma concentration for exenatide was 64 pM compared with the mean 2-hour postprandial GLP-1 concentration of 15 pM for sitagliptin (baseline GLP-1 concentration was 7.2 pM).57 While both agents were shown to be effective, exenatide appeared to have had a greater effect than sitagliptin in increasing insulin secretion and reducing postprandial glucagon secretion, leading to significantly (P < 0.0001) greater reductions in PPG.57

Sitagliptin has been minimally associated with nausea, whereas patients who take exenatide need to be informed of the risk of usually mild to moderate, but sometimes severe, nausea and vomiting that tends to decrease over time.

For a detailed comparison of the effects of GLP-1 receptor agonists and DPP-4 inhibitors on HbA1c, weight, and hypoglycemia, see “Advances in therapy for type 2 diabetes: GLP–1 receptor agonists and DPP–4 inhibitors.”

CONCLUSION

Despite advances in diagnosis and treatment, T2DM, overweight/obesity, CVD, and their complications remain major public health burdens worldwide. The concepts that explain the pathophysiology of T2DM include the contribution of various factors beyond insulin secretion and insulin resistance, such as the role of incretin hormones in disease progression. A comprehensive approach to managing patients with T2DM requires targeting the fundamental defects of the disease and its comorbidities. Newer agents, including incretin-based therapies such as GLP-1 receptor agonists and DPP-4 inhibitors, address the fundamental defects of T2DM. The definition of treatment success in the management of T2DM will be redefined as more data become available on agents that exert beneficial effects not only on glycemia but on parameters that may influence overall CV health, such as weight, BP, and lipid profiles.

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