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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.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

Postprandial glucose (PPG) is emerging as an important new target in the optimal management of type 2 diabetes, as it is increasingly recognized that PPG is better correlated to cardiovascular (CV) risk than either fasting glucose or HbA1c. It is well established that up to 80% of patients with diabetes die of vascular causes. As discussed by Dr. Lawrence Leiter, Professor of Medicine and Nutritional Sciences, University of Toronto, Ontario, PPG makes a major contribution to the overall glycemic load in patients with diabetes, especially as HbA1c approaches normal values. In fact, PPG contributes to as much as 70% of the overall glycemic load when HbA1c levels are <7.3%.

Corroborative Study Findings

Many epidemiologic studies have demonstrated a relationship between PPG and the risk of coronary artery disease (CAD) in patients without known diabetes, Dr. Leiter observed. The largest study supporting this relationship was DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe), a meta-analysis of 13 prospective trials in which investigators found that PPG was really the cause behind increasing CV risk, and not fasting glucose levels (DECODE Study Group, Diabetes Care 2003;26(3):688-96). Investigators also calculated that every single millimole increase in two-hour plasma glucose carries the same magnitude of CAD risk as a 7-mm Hg increase in systolic blood pressure, Dr. Leiter told delegates.

The Framingham Offspring Study also showed that for every 2.1-mmol/L increase in two-hour glucose levels at baseline, the risk of CAD, stroke or peripheral vascular disease increased by between 12% and 42% (Wilson et al. Arch Intern Med 1999;159(10):1104-9). Results from the Funagata Diabetes Study found that the presence of impaired glucose tolerance (IGT) doubled the risk of CV death compared with normal glucose tolerance (Tominaga et al. Diabetes Care 1999;22(6):920-4). Conversely, fasting hyperglycemia had no effect on CV mortality in the same cohort. Other trials have recently shown that the best predictor of vascular disease in patients with diabetes were post-lunch glucose levels, which approximately doubled the risk of vascular disease in men and increased the risk by 5.5 in women.

As Dr. Leiter indicated, evidence suggests that oxidative stress is central to the pathology of both type 2 diabetes and CV disease. Oxidative stress contributes to endothelial dysfunction, for example—the first step in the development of atherosclerosis. Acute hyperglycemia also induces endothelial dysfunction, Dr. Leiter also pointed out, and this is mediated by oxidative stress. It has also been shown that in patients with IGT or diabetes, “there is a worsening of endothelial function as we eat, measures of oxidative stress go up, and there is a very nice correlation between plasma glucose levels and flow-mediated dilatation, patients with the highest PPG levels having the most abnormalities in brachial artery dilation,” he explained.

Conversely, studies indicate that there is less oxidative stress with better PPG control following a meal, Dr. Leiter reported. More importantly, there is emerging evidence that lowering PPG actually reduces CV risk. In the STOP-NIDDM (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus), for example (Chiasson et al. Diabetes Care 1998;21(10):1720-5), only one patient in the acarbose treatment group experienced a myocardial infarction (MI) vs. 12 of placebo controls—“small numbers,” he acknowledged, “but a very significant reduction in risk in this group of patients with IGT receiving acarbose.” In a meta-analysis of studies in which patients with diabetes were again treated with acarbose, active therapy was associated with a 50% reduction in the risk of MI and there was reduced progression in carotid artery intima media thickness (IMT) than in placebo controls. A >0.02-mm regression in carotid artery IMT was seen in over half of patients with diabetes receiving repaglinide, a rapid-acting insulin secretagogue that targets PPG, vs. 18% of those receiving glyburide even though improvements in HbA1c were similar, Dr. Leiter noted.

Furthermore, the Kumamoto study in which multiple daily insulin injections were used to control both fasting and PPG also suggested that both reduced PPG and reduced fasting plasma glucose are significantly associated with reductions in both retinopathy and nephropathy as well (Shichiri et al. Diabetes Care 2000;23(Suppl 2):B21-B29).

Targeting PPG

Global guidelines are beginning to reflect the need to target not just HbA1c and fasting glucose but PPG as well, as reflected in the Canadian Diabetes Association guidelines. Strategies to lower PPG may include both non-pharmacologic (low glycemic index foods) and a variety of pharmacologic agents, including rapid-acting insulin secretagogues and rapid-acting insulin analogues. In addition, a number of new classes of agents are emerging for the management of PPG, among which are incretin-based therapies. As Dr. Leiter explained, studies indicate that there is a greater increase in insulin in response to an oral glucose load than the exact same dose of glucose given intravenously.

The difference in insulin response to oral glucose and glucose infusion is called the “incretin effect” and it occurs as a result of altered gut hormones in patients with diabetes, GLP-1 (glucagon-like peptide-1) and gastric inhibitor polypeptide (GiP) among them. Current GLP-1 analogues are only available as injectable formulations and they may cause some nausea, Dr. Leiter noted, although they do lower glucose levels and their use has been associated with weight loss in some patients.

The other way to harness the beneficial action of GLP-1 and GiP is through the use of dipeptidyl peptidase-4 (DPP)-4 inhibitors such as sitagliptin and vildagliptin. This class of agents enhances the actions of both gut hormones by preventing their degradation, thus making them available for longer periods of time and improving sensitivity to insulin.

In studies presented at the American Diabetes Association conference earlier this year, investigators reported that the combination of sitagliptin and metformin significantly improved glycemic control in 748 patients with type 2 diabetes. Prior to study entry, patients had an average HbA1c of 8.7%. In an analysis involving all patients treated, the mean HbA1c decreased by between 0.8% and 1.4% by week 54, depending on the dosage and combination used. At the same assessment point, 67% of patients on sitagliptin 100 mg and metformin 2000 mg had achieved an HbA1c of <7%, as did 48% of those on the same dose of sitagliptin plus metformin 1000 mg. Some 44% of patients receiving metformin 2000 mg monotherapy also achieved the same HbA1c target, while smaller proportions of patients were at the same level on lower doses of metformin or on sitagliptin monotherapy. Treatment was well tolerated, investigators also noted.

At the same conference, another group of researchers also reported that sitagliptin was well tolerated when given as monotherapy, as initial combination therapy with metformin or as an add-on to oral antihyperglycemic therapy across classes. Among 5141 patients who completed phase IIb and III sitagliptin studies, the overall incidence of adverse events, serious adverse events and discontinuations due to adverse events was similar among patients who were exposed to the DPP-4 and those who were not.

“The rationale is that if we can use these hormones to improve the incretin effect, we can improve insulin secretion and thereby improve glucose levels,” Dr. Leiter told CCC delegates.

Recommendations from the International Diabetes Federation include targets for PPG and were summarized here as follows:

• Two-hour PPG should not exceed 7.8 mmol/L as long as hypoglycemia is avoided.

• Self-monitoring of blood glucose should be considered because it is currently the most practical method for monitoring PPG.

• Efficacy of treatment regimens should be monitored as frequently as needed to guide therapy towards achieving PPG targets.

Based on the CCS/CCC-sanctioned session:

“Managing Cardiometabolic Complexities: Will New Treatment Strategies Improve Health Outcomes?” Sunday, October 21, 10:00-12:00, Room 200A, Level 2.

This symposium is accredited and co-developed as an Accredited Group Learning Activity under Section 1 of the framework of Continuing Professional Development options as defined by the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).