Postprandial hyperglycemia as an etiological factor in vascular failure

By: Koichi Node and Teruo Inoue
Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan

Cardiovascular Diabetology 2009, 8:23doi:10.1186/1475-2840-8-23

Abstract
Postprandial hyperglycemia is characterized by hyperglycemic spikes that induce endothelial dysfunction, inflammatory reactions and oxidative stress, which may lead to progression of atherosclerosis and occurrence of cardiovascular events. Emerging data indicate that postprandial hyperglycemia or even impaired glucose tolerance may predispose to progression of atherosclerosis and cardiovascular events. There is evidence that postprandial hyperglycemia, but not fasting hyperglycemia, independently predicts the occurrence of cardiovascular events. We proposed a concept of 'vascular failure' as a comprehensive syndrome of vascular dysfunction extending from risk factors to advanced atherosclerotic disease. Postprandial hyperglycemia is therefore one of the very important pathophysiological states contributing to vascular failure. Accordingly, controlling postprandial hyperglycemia should be the focus of future clinical investigation as a potential target for preventing vascular failure.

Therapeutic Paradigm
A number of clinical trials have demonstrated that specific pharmacological approaches can reduce the impact of postprandial glycemic excursions on overall glycemic control [69-71]. However, to date, there have been no prospective clinical trials evaluating the impact of improved postprandial hyperglycemia on long-term outcomes in patients with diabetes. Given recent data on the impact of postprandial glycemia on overall glucose control [72], it is likely that therapeutic approaches that focus on this aspect of overall glycemia will benefit patients in the long term. Traditional diabetic agents such as insulin and sulfonylureas predominantly lower fasting glucose and are less effective at reducing postprandial hyperglycemia. Although sulfonylureas target insulin secretion directly through the beta cell potassium channel, they may also have an impact on fasting and postprandial glycemia. However, the pharmacokinetics of the majority of these agents are not tailored toward acute insulin release, and therefore they do not correct abnormalities in early-phase insulin secretion [73]. On the other hand, the pharmacokinetics and mechanisms of action of several agents are directed specifically at postprandial hyperglycemia. Such agents include the meglitinide class of drugs, α-glucosidase inhibitors and thiazolidinediones.

The meglitinide analogues include repaglinide, nateglinide and mitiglinide, which are modern nonsulfonylurea secretagogues that restore the first-phase insulin response. A single dose of nateglinide has been shown to reduce postprandial endothelial dysfunction by lowering postload glycemia in patients with type 2 diabetes [74]. In a randomized trial of diabetic patients, repaglinide reduced postprandial glucose levels to a greater degree than the sulfonylurea, glyburide, whereas glyburide was more effective for lowering fasting glucose levels. Despite identical reductions in HbA1c levels in the 2 groups, repaglinide caused regression of carotid intima-media thickness in 52% of patients, compared with only 18% of patients treated with glyburide [75]. This regression in atherosclerosis was shown to be directly proportional to the reduction in postprandial hyperglycemia.

Alpha-glucosidase inhibitors block the α-glucosidase enzyme, thereby slowing the rate of carbohydrate digestion including starches and disaccharides. In diabetic or glucose-intolerant patients, α-glucosidase inhibitors lower postload glucose peaks by between 30 to 70 mg/dl and reduce HbA1c by about 0.7%, with negligible effects on fasting glucose levels [76]. Long-term acarbose therapy also reduces the levels of triglycerides and chylomicrons, possibly by improving insulin sensitivity [77]. A recent study showed that even a single mixed meal of 450 calories caused substantial and immediate deterioration in endothelial function in diet-treated patients with diabetes [76]. Pretreatment of these same subjects with a single dose of acarbose markedly reduced postprandial hyperglycemia and associated endothelial dysfunction after the ensuing meal. The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) was an international trial of 1,429 subjects with impaired glucose tolerance who were randomized to either acarbose 100 mg, 3 times daily with meals or placebo [78]. After 3.3 years, acarbose significantly reduced the primary end point of the study, the progression to new diabetes, by 25%. In this trial, acarbose treatment was associated with significant reductions of 49% for any cardiovascular event and 91% for myocardial infarction. Acarbose also slowed progression of carotid atherosclerosis and reduced the development of new hypertension by 34%, results that indicated postprandial dysmetabolism may play a role in the genesis of hypertension. A large retrospective meta-analysis of seven long-term studies of acarbose in patients with type 2 diabetes showed significant risk reductions of 35% for cardiac events and 64% for myocardial infarction [79]. We have also previously observed increases in FMD and a reduction in hsCRP and VCAM-1 levels after 3 months of treatment with acarbose (Fig. 4). This suggests attenuation of postprandial dysmetabolism induced by acarbose results in improved endothelial function and inflammatory status, possibly slowing the progression of atherosclerosis. In addition, in a recent study in patients with mild diabetes mellitus we used meal tolerance testing to compare the effects of a new α-glucosidase inhibitor, miglitol, with those of a meglitinide analogue, mitiglinide, on postprandial glucose and insulin metabolism. Other glucose metabolism-related markers, atherosclerosis-related markers and renal function were also assessed. We showed that three months of administration of both agents caused similar improvements in postprandial hyperglycemia, although different postprandial patterns of insulin secretion were observed (Fig. 5A). The changes in 1, 5-anhydroglucitol levels after 3 months were significantly higher in the miglitol group than in the mitiglinide group. Insulin resistance assessed by the homeostasis model assessment index and urinary albumin excretion decreased significantly in the miglitol group but not in the mitiglinide group. Serum cystatin C levels did not change in the miglitol group, although the levels increased in the mitiglinide group. Miglitol caused a significant decrease in hsCRP levels, whereas mitiglinide did not (Fig. 5B and Fig 6), while serum adiponectin levels were increased significantly only by miglitol therapy [80,81]. These results suggest that miglitol has anti-inflammatory and renoprotective effects, possibly associated with an improvement in insulin resistance.

The thiazolidinedione peroxisome proliferator-activated receptor-γ (PPAR-γ) activating class of drugs, such as troglitazone, rosiglitazone or pioglitazone, are insulin-sensitizing agents and are not generally considered for their effects on insulin secretion [82]. However, as demonstrated with troglitazone, this class of compounds, when used in subjects with impaired glucose tolerance, may improve glucose-coupled insulin secretion and reduce the level of postprandial hyperglycemia [83]. PPAR-γ agonism has been shown to have anti-inflammatory effects and to improve endothelial function by regulating the cellular redox state. Thiazolidinediones have also been shown to decrease inflammatory markers such as hsCRP [84] and to improve FMD of the brachial artery [85]. In a large randomized clinical trial of pioglitazone in 5238 patients with type 2 diabetes with macrovascular disease there was some evidence of a reduction in adverse cardiovascular outcomes compared to matching placebo, when the treatments were taken in combination with glucose-lowering drugs and other medications [86]. Pioglitazone was also reported to reduce the rate of progression of carotid intimal medial thickness [87] and coronary atherosclerosis assessed by intravascular ultrasound imaging [88], when compared to glimepiride.

Several new drugs with glucose-lowering actions that may offer certain clinical advantages have recently become available. These include injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion, whilst delaying gastric emptying and reducing appetite. These agents have a low risk of hypoglycaemia in combination with sustained weight loss. The DPP-4 inhibitors, sitagliptin and vildagliptin, are generally weight neutral, and have less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Vildagliptin is generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and is not associated with hypoglycemia. Co-administration of vildagliptin with either glyburide or pioglitazone in patients with type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics [89].