Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 46th Annual Meeting of the European Association for the Study of Diabetes

Stockholm, Sweden / September 20-24, 2010

Comprehensive glycemic control requires a concerted effort to reduce daily variations in glucose levels. Patients who have similar glycosylated hemoglobin (HbA_1c) values or glucose concentrations at a given point in time can have markedly different glucose profiles over the course of a day, observed Dr. Antonio Ceriello, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, here at the EASD. These glucose peaks and valleys have implications for patients and clinicians.

“Glucose peaks and valleys may contribute to symptoms, complications and impaired quality of life,” stated Dr. Ceriello. “Post-prandial glucose (PPG) peaks pose a risk of microvascular and macrovascular damage, and they can play a role in fatigue, itching, thirst and other symptoms that adversely affect a diabetic patient’s quality of life. Glucose valleys or troughs can lead to symptoms of hypoglycemia, such as sweating, dizziness or shakiness.” This can lead patients toward a defensive snacking behaviour to prevent hypoglycemic episodes and a potential for weight gain without affecting the symptoms.

Targeting the Glucose Triad

Increasingly, comprehensive glucose control has revolved around the “glucose triad” of fasting plasma glucose (FPG), PPG and HbA_1c, remarked Dr. Ceriello. The triad concept has gone a step further with the development of the concept of the “trilogy of 7,” referring to 3 key treatment targets of HbA_1c <7%, PPG <7 mmol/L and FPG <7 mmol/L. “Targeting both PPG and FPG is an important strategy for achieving optimal glycemic control,” Dr. Ceriello told delegates. “Control of FPG is necessary but usually insufficient for achieving an HbA_1c <7%. Control of PPG is essential for achieving HbA_1c goals. Current clinical guidelines recommend targeting both PPG and FPG.”

Rationale for DPP-4 Inhibition

The emphasis on comprehensive glycemic control offers a sound clinical rationale for considering DPP-4 inhibitors in the management of type 2 diabetes (T2DM), according to Dr. Jens Juul Holst, University of Copenhagen, Denmark. The agents achieve clinically meaningful reductions in both FPG and PPG levels, and they have sustained efficacy, as demonstrated in 2-year data for patients treated with the agents.

Use of DPP-4 inhibitors in combination therapy also has implications for an increased emphasis of HbA1c as a measure of diabetes control. The combination of a DPP-4 inhibitor and metformin has been shown to maintain HbA_1c levels <7% for as long as 2 years, explained Dr. Holst.

Incretin-based therapy with a DPP-4 inhibitor also addresses concerns about PPG peaks. Co-administration of a DPP-4 inhibitor plus metformin increases post-prandial GLP-1 levels, which are maintained for 4 hours or longer, noted Dr. Holst.

GLP-1 has been shown to affect cardiovascular (CV) health and function in at least 4 ways, explained Dr. Holst: by improving myocardial function in nonischemic heart failure, myocardial survival in ischemic heart disease, endothelial dysfunction in T2DM and decreasing levels of markers associated with CV risk in T2DM.

“DPP-4 inhibitors produce clinically meaningful reductions in blood glucose and have sustained efficacy over the long term,” observed Dr. Holst. “The agents have predictable additive effects with other agents, especially metformin. The class has a neutral effect on weight and has a side-effect profile similar to placebo.”

Consistency of Clinical Experience

The role GLP-1 plays in regulating insulin release and glucose control has given rise to several approaches to enhance the hormone’s activity. Incretin mimetics mimic some of the activities of endogenous incretins, including glucose-dependent enhancement of insulin secretion. Some members of the class have bioengineered resistance to degradation by DPP-4.

As reported here at the EASD, data on two newer members of the incretin mimetic class provided additional support to the concept of targeting GLP-1 as a therapeutic strategy for T2DM. A multinational study involving 361 patients with T2DM showed that once-daily lixisenatide monotherapy significantly improved glycemic control and achieved a significant post-prandial effect with an overall decrease in body weight. Several studies involving liraglutide showed the agent achieved better glucose control compared with some older diabetes therapies, induced weight loss in a substantial proportion of patients, and had a favourable effect on hypertension independent of weight loss.

Clinical experience with saxagliptin has been consistent with the evolution of multifaceted clinical strategies for management of T2DM, noted Dr. Stephan Jacob, University of Tübingen, Germany. Multiple studies have shown that it has additive efficacy when used in combination with other diabetes drugs. “Saxagliptin, when added to metformin, sulfonylureas or thiazolidinediones, provides comprehensive glycemic control through consistent, clinically meaningful and significant reductions in glycosylated hemoglobin, PPG and FPG,” he told delegates.

The agent is associated with low rates of hypoglycemia, consistent with the view that steady glycemic control and avoidance of glucose peaks and valleys improve overall diabetes control. The cumulative data show that it is similar to placebo with respect to the risk of hypoglycemia. Weight changes, a concern for the vast majority of T2DM patients, also are similar between it and placebo.

The chronic nature of diabetes has created a mandate for long-term safety and efficacy in agents used to treat the disease. Studies of saxagliptin as add-on therapy to metformin have shown consistent reductions in HbA_1c and maintenance of those reductions during follow-up beyond 2 years.

According to Dr. Jacob, the DPP-4 inhibitor has emerged as an ideal add-on therapy to metformin. In a randomized clinical trial, 858 T2DM patients received the DPP-4 inhibitor or a sulfonylurea as add-on therapy to an existing metformin regimen (Int J Clin Pract 2010;epub ahead of print). Follow-up continued for 52 weeks after initiation of add-on therapy.

The 2 arms of the trial had similar diabetes control. However, patients in the DPP-4 inhibitor arm had a 3% incidence of hypoglycemia compared with 36% for patients who received the sulfonylurea. The DPP-4 inhibitor arm had an overall reduction in weight from baseline, whereas the sulfonylurea group had a net weight gain. “Saxagliptin was well tolerated in all clinical trials over 24 weeks and as add-on to metformin up to 102 weeks,” Dr. Jacob told delegates. “[It] was not associated with changes in lipid parameters, blood pressure or heart rate. No safety signals were observed relative to the pancreas, liver, skin or kidneys. Rates of infection-related adverse events have been similar to placebo.”

Data reported here at the EASD congress added to the evidence of saxagliptin’s safety and efficacy in T2DM. A pooled analysis of randomized, placebo-controlled clinical trials involving more than 1200 patients examined two key issues in clinical management, i.e. the relationship between baseline HbA1c and its response to treatment, and the proportion of patients who achieved the HbA_1c target of <7% without hypoglycemia.

The analysis showed that saxagliptin add-on therapy led to greater reductions in HbA_1c compared with placebo across the range of baseline HbA1c values, reported clinical researcher Dr. Pierre Maheux, Zaventem, Belgium. The magnitude of the difference from placebo ranged from -0.42% for patients with baseline HbA_1c levels <7.5% to -1.00% for patients with baseline HbA_1c levels of 8.5 to <9.0%.

The analysis also showed that more patients given saxagliptin as add-on therapy reached the HbA_1c goal of <7% without hypoglycemia compared with placebo, irrespective of baseline value.

Summary

DPP-4 inhibitors facilitate comprehensive glycemic control in T2DM patients by addressing multiple parameters of glucose control, notably the clinical triad of FPG, PPG and HbA_1c. Studies of DPP-4 inhibition have demonstrated durable effects during follow-up to 2 years and beyond. As add-on therapy to metformin, saxagliptin has achieved HbA1c targets across the spectrum of baseline HbA_1c values. This wide-ranging efficacy has occurred without weight gain and with a reduced risk of hypoglycemia.