What does postprandial hyperglycaemia mean?

AIMS: The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well-established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes. RESULTS: Post-prandial hyperglycaemia is a risk indicator for micro- and macrovascular complications, not only in patients with Type 2 diabetes but also in those with impaired glucose tolerance. In addition, the metabolic syndrome confers an increased risk of CVD morbidity and mortality. The debate focused on the relative contributions of postprandial hyperglycaemia, the metabolic syndrome and, in particular, raised triglyceride levels in the postprandial state, to the development of cardiovascular complications of diabetes. CONCLUSIONS: The panel recommended that in the prevention and management of microvascular complications of Type 2 diabetes, targeting both chronic and acute glucose fluctuations is necessary. Lowering the macrovascular risk also requires control of (postprandial) triglyceride levels and other components of the metabolic syndrome.     

Diabetes and cardiovascular disease: pathophysiology of a life-threatening epidemic

Diabetes is associated with the development of premature cardiovascular disease (CVD), which relates to the clustering of risk factors such as dyslipidaemia, hypertension, obesity and hyperglycaemia in the presence of insulin resistance. In addition, diabetes is associated with an inflammatory and pro-thrombotic environment, exacerbating the development of atherothrombosis. Insulin resistance and hyperglycaemia both contribute to the development of endothelial cell dysfunction and increased oxidative stress, culminating in accelerated atherosclerosis. Clot formation and function are also directly affected by insulin resistance and hyperglycaemia, with increased levels of coagulation factors and anti-fibrinolytic proteins and a fibrin network that is more resistant to lysis, coupled with increased platelet activation.It is well recognised that the intensification of glycaemic control leads to a reduction in microvascular complications in type 1 and type 2 diabetes; however, the same is less clear with macrovascular disease. Several randomised studies have attempted to address the effect of short-, medium- and long-term glycaemic control on cardiovascular outcomes, with mixed results. The overall interpretation of these trials suggests that intensive glycaemic control in patients with a relatively short duration of diabetes, without very poor control and with no CVD, might be safe and associated with fewer cardiovascular events.This review will summarise the effects of hyperglycaemia on the development of atherothrombosis and examine key cardiovascular outcome trials following intensive glucose control.     

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes‐related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA_1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon‐like peptide‐1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium‐glucose co‐transporter‐2 and dual sodium‐glucose co‐transporter‐2 and ‐1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis‐related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.     

Rationale and options for combination therapy in the treatment of Type 2 diabetes

Pharmacological therapy for Type 2 (non-insulin-dependent) diabetes mellitus aims at controlling hyperglycaemia to delay or prevent complications associated with the disease. Most patients with Type 2 diabetes present with both stimulated insulin deficiency and insulin resistance. In general, the former can manifest as postprandial hyperglycaemia and the latter as fasting hyperglycaemia, though a definitive association has not been established. Emerging data show a high failure rate of long-term monotherapy and establishes the significance of mealtime glycaemia and the role of postprandial glucose excursions in the development and progression of vascular complications. To overcome such failures of monotherapy and to address the different underlying defects of the pathology of Type 2 diabetes, a combined therapy of oral antidiabetic agents with complementary modes of action should be considered. Currently used oral antidiabetic agents such as sulphonylureas, biguanides (metformin) and the thiazolidinediones (rosiglitazone, pioglitazone) commonly target fasting hyperglycaemia and have limited additive effects on postprandial glycaemia. In contrast, alpha-glucosidase inhibitors can reduce postprandial hyperglycaemia but gastrointestinal side effects restrict their use. The development of new agents to control postprandial glucose excursions could be considered as an additional objective for the management of Type 2 diabetes. To this end new short-acting enhancers of insulin secretion such as repaglinide (benzoic acid derivative) and nateglinide (amino acid derivative) have been developed. The combination of such agents with other complementary modes of action, e.g. an insulin sensitizer, could target better major underlying defects of Type 2 diabetes and thereby provide a better approach for controlling the entire glycaemic risk.     

Persistent poor glycaemic control in adult Type 1 diabetes. A closer look at the problem.

Around 25% of the adult Type 1 diabetes population is in persistent poor glycaemic control and thus at increased risk of developing microvascular complications. We here discuss correlates of long-standing poor glycaemic control and review the efficacy of clinical strategies designed to overcome persistent poor control. Only a few studies have identified determinants and correlates of long-standing poor glycaemic control in Type 1 diabetes. There is some evidence implicating genetic factors, as well as lower economic status, and psychological factors, including lack of motivation, emotional distress, depression and eating disorders. Ways of improving glycaemic control include strategies to enable self-management, e.g. motivational strategies, coping-orientated education, psychosocial therapies, and/or intensifying insulin injection therapy plus continuous subcutaneous insulin infusion. Long-standing poor glycaemic control appears to be a heterogeneous and complex phenomenon, for which there is no simple, single solution. Comprehensive psycho-medical assessment in diabetes care may prove useful in tailoring interventions. Further research is warranted, to increase our understanding how psychosocial and biomedical factors, separately and in interaction, determine poor outcomes in Type 1 diabetes.     

Intensive insulin regimens: evidence for benefit

It is now well established that the risk of experiencing diabetic complications is dependent on the degree of glycaemic control in patients with diabetes. Clinical trials such as the Diabetes Control and Complications Trial (DCCT) and Kumamoto study have demonstrated that tight glycaemic control achieved with intensive insulin regimens can reduce the risk of developing or progressing retinopathy, nephropathy or neuropathy in patients with type I or II diabetes. The EDIC trial, a follow-up to the DCCT, has shown that the previous degree and duration of glycaemic exposure are also important determinants of risk of developing microvascular diabetic complications. It appears that beneficial outcomes with regard to microvascular risk can be achieved with the improved metabolic control associated with intensive insulin regimens; however, data examining the effect of intensive insulin regimens on macrovascular risk is inconclusive. Epidemiological data highlight the role of postprandial blood glucose in cardiovascular disease and mortality, especially in patients with type II diabetes. Consequently, it is logical to suppose that insulin regimens that control both fasting plasma glucose and postprandial glucose excursions should also achieve the best macrovascular risk outcomes and there are some data that suggest this. Intensive insulin treatment can also improve prognosis in acute clinical situations such as myocardial infarction in patients with or without diabetes. In summary, intensive insulin regimens achieve strict metabolic control in patients with diabetes and could offer the best possible outcomes with regard to microvascular and macrovascular complications.     

Thiazolidinedione insulin sensitizers and the heart: a tale of two organs?

Thiazolidinediones (TZDs) are relatively new agents for the treatment of type 2 diabetes. They act as agonists at the PPAR-γ nuclear receptor and their therapeutic effects include decreased insulin resistance and hyperglycaemia, an improved plasma lipid, inflammation and pro-coagulant profile, and amelioration of hypertension, microalbuminuria and hepatic steatosis. The most common side effects of TZDs include weight gain and oedema, with occasional reports of congestive heart failure (CHF). This review discusses the benefit–risk profile of TZDs in treating patients with type 2 diabetes, with particular reference to the heart. To provide context, we explore briefly the epidemiology and pathophysiology of heart failure in patients with type 2 diabetes, touch on the association of heart disease and cardiovascular mortality with antihyperglycaemic treatment modalities other than TZDs, and then focus on the effects of TZDs on the heart, cardiovascular risk factors and outcomes. We describe the cluster of host factors, which seems to predispose patients with type 2 diabetes to TZD-induced or TZD-exacerbated oedema and CHF and then provide an overview of the putative mechanisms of these TZD-related side effects. We also propose that certain diuretics (amiloride and spironolactone), by targeting the distal nephron that expresses PPARγ in collecting duct cells, might be of benefit in ameliorating the fluid retention and oedema associated with TZDs.     

Durability of glycemic control: a feature of the thiazolidinediones

Type 2 diabetes is a rapidly growing disorder that affects millions of Americans. It usually results from a combination of insulin resistance and a beta-cell secretory defect leading to hyperglycemia and microvascular and macrovascular complications, including cardiovascular disease. With the increasing number of options available for the treatment of type 2 diabetes, it can be difficult to determine which medication to prescribe for each patient. Ideally, an agent that effectively lowers glucose concentrations while also minimizing disease progression should be chosen. The thiazolidinediones (TZDs), a relatively newer class of antidiabetic agents, have been shown to be efficacious in lowering glucose concentrations, maintaining glycemic control, and improving other cardiovascular risk factors. These include reduction of visceral adiposity, alteration of lipoprotein concentrations with a favorable distribution of cholesterol subfractions, and decreasing markers of inflammation and endothelial dysfunction. Overall, the TZDs appear to be a promising therapeutic option for consistent control of glucose levels and may slow the progression of type 2 diabetes.     

Epidemiology of cardiovascular complications in type 2 diabetes mellitus

Type 2 diabetes is increasing in epidemic proportions worldwide, and is strongly associated with atherosclerotic cardiovascular disease (CVD). Hyperglycaemia increases risk of CVD, but glycaemic control does not substantially reduce CVD risk. There are several potential explanations for this apparent paradox, including the roles of the metabolic syndrome and post-load hyperglycaemia in the association of type 2 diabetes and CVD.     

When basal insulin therapy in type 2 diabetes mellitus is not enough—what next?

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by co-existing insulin deficiency (relative) and insulin insensitivity. Both fasting and post-prandial blood glucose are elevated, exposing the patient to acute and chronic complications due to micro- and macro-vascular angiopathy. Improving glycaemic control has been demonstrated to lower the risk of these complications. Owing to the progressive nature of the disease, an evolving treatment strategy is necessary to maintain glycaemic control. Insulin therapy is required when dietary and lifestyle modifications combined with oral hypoglycaemic agents fail to provide adequate glycaemic control. Adding an optimized dose of basal insulin to the existing oral therapy is a simple and widely used method for initiating insulin therapy. However, despite an effective control of fasting hyperglycaemia, further intervention to control post-prandial hyperglycaemia may become necessary to achieve HbA1c targets. Strategies for the addition of prandial insulin include administering short-acting (or rapid-acting) insulin analogues before each meal or twice-daily administration of pre-mixed insulin. As a single large meal often contributes to the greatest part of daytime hyperglycaemia, an alternative strategy is emerging with the addition of a single injection of prandial insulin prior to the meal that induces the largest post-prandial blood glucose excursion measured 2 h after the start of the meal. Over time, additional prandial boluses of insulin may be required to sustain daytime glycaemic control. This strategy offers a simple, stepwise approach to progress from basal insulin to a basal-bolus regimen. Studies are needed to validate this method and better define specific titration tactics.     

Different risk factors of microangiopathy in patients with Type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study

Aims/hypothesis. To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus.¶Methods. The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease ( ≤ 5 years) compared with 1062 subjects with long duration ( ≥ 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 μg/min.¶Resu1ts. The prevalence of microvascular disease was 25 % in the short duration group. In the long duration group 18 % had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels.¶Conclusion/interpretation. At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease. [Diabetologia (2000) 43: 348–355]     

The effects of thiazolidinediones on blood pressure levels - a systematic review

Insulin resistance has been proposed to be the underlying disorder of the so-called metabolic or insulin resistance syndrome, which represents the clustering in the same individual of several cardiovascular risk factors, such as type 2 diabetes mellitus, hypertension, abdominal obesity, elevated triglycerides and low high-density lipoprotein-cholesterol. As far as the connection of insulin resistance and compensatory hyperinsulinaemia with hypertension is concerned, a number of mechanisms possibly linking these disturbances have been described, such as activation of sympathetic nervous system, enhancement of renal sodium reabsorption, or impairment of endothelium-dependent vasodilatation. Thiazolidinediones (TZDs) constitute a class of oral antihyperglycaemic agents that act by decreasing insulin resistance, and apart from their action on glycaemic control, they have been also reported to exert beneficial effects on other parameters of the metabolic syndrome. In particular, during recent years a considerable number of animal and human studies have shown that the use of TZDs was associated with usually small but significant reductions of blood pressure (BP) levels. Since a possible beneficial action of these compounds on BP could be of particular value for patients with the metabolic syndrome, this review aimed to summarize and evaluate the literature data in the field, derived either from studies that just examined BP levels among other parameters or from studies that were specifically designed to determine the effect of a TZD on BP.     

Beyond HbA1c: using continuous glucose monitoring metrics to enhance interpretation of treatment effect and improve clinical decision‐making

Assessment of glycaemic outcomes in the management of Type 1 and Type 2 diabetes has been revolutionized in the past decade with the increasing availability of accurate, user‐friendly continuous glucose monitoring (CGM). This advancement has brought a need for new techniques to appropriately analyse and understand the voluminous and complex CGM data for application in research‐related goals and clinical guidance for individuals. Traditionally, HbA_1c was established using the Diabetes Control and Complications Trial (DCCT) and other trials as the ultimate measure of glycaemic control in terms of efficacy and, by default, risk of microvascular complications of diabetes. However, it is acknowledged that HbA_1c alone is inadequate at describing an individual's daily glycaemic variation and risks for hypo‐ and hyperglycaemia, and it does not provide the guidance needed to decrease those risks. CGM data provide means by which to characterize an individual's daily glycaemic excursions on a different time scale measured in minutes rather than months. As a consequence, clinical reports, such as the ambulatory glucose profile, increasingly include summary statistics related to averages (mean glucose, time in range) as well as markers related to glycaemic variability (coefficient of variation, standard deviation). However, there is a need to translate those metrics into specific risks that can be addressed in an actionable plan by individuals with diabetes and providers. This review presents several clinical scenarios of glycaemic outcomes from CGM data that can be analysed to describe glycaemic variability and its attendant risks of hyperglycaemia and hypoglycaemia, moving towards relevant interpretation of the complex CGM data streams.     

Acute and chronic effects of hyperglycaemia on glucose metabolism

Summary In normal man, several hormonal and metabolic adjustments allow the maintenance of the blood glucose concentration within narrow limits. Hyperglycaemia participates in this regulation via stimulation of glucose disposal and inhibition of glucose production. The effects are mediated, in addition to changes in insulin and glucagon secretion, by the mass-action effect of glucose. In both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, hyperglycaemia, by mass-action abnormally elevates the basal glucose utilization rate but compensates for reduced postprandial insulin-stimulated glucose disposal. When exposed to chronic hyperglycaemia, the body tissues seem to protect themselves, at least partly, against excessive glucose utilization. These protective mechanisms include both a reduction in insulin stimulated glucose disposal and insulin secretion. Chronic hyperglycaemia may also reduce non-insulin-dependent glucose utilization, at least in rats. In Type 1 diabetic patients with normal peripheral insulin concentrations, chronic hyperglycaemia per se could be a major cause of insulin resistance. In Type 2 diabetic patients, insulin resistance is often already present before the development of overt fasting hyperglycaemia. At the diabetic stage, hyperglycaemia could, however, maintain a self-perpetuating cycle, where the deleterious effects of high glucose concentrations on insulin action and secretion cause further deterioration of glycaemic control. The biochemical basis for hyperglycaemia-induced insulin resistance is still far from clear, but could involve changes in the glucose transporter number and gene expression.     

The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality

Cardiovascular morbidity and mortality in patients with type 2 diabetes are a major problem in clinical practice. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated receptor gamma which improve glycaemic control by reducing insulin resistance. TZDs also seem to have beneficial effects on various cardiovascular risk factors and consequently may have the potential to reduce the risk of cardiovascular disease (CVD). Although the first large-scale clinical trial evaluating the effect of a TZD on secondary prevention of major adverse cardiovascular outcomes supported this hypothesis, a recently published meta-analysis raised substantial uncertainty about the cardiovascular safety of rosiglitazone. This article summarises the evidence from completed and ongoing outcome trials with TZDs, as well as the recent meta-analytic data on their cardiovascular safety, aiming to provide an up-to-date and balanced view of a very important field. Data from clinical trials consistently indicate that treatment with glitazones significantly increase the risk of heart failure. Despite the fact that rosiglitazone and pioglitazone have much more similarities than differences with regards to their effects on cardiovascular risk factors, pioglitazone seems to have more favourable effects on major cardiovascular outcomes. This issue also highlights the potential hazards involved in using surrogate end-points for drug approval.     

Managing diabetes: what to do about cardiovascular disease

Type 2 diabetes increases the risk of coronary heart disease (CHD) 2-4-fold, making CHD the predominant cause of death in patients with diabetes. Currently identified risk factors include, among others, hyperglycaemia, hypertension and dyslipidaemia. Since studies show that intensive glycaemic control alone will not overcome the excess CHD risk, reducing blood pressure by any means and lipid levels by using statins and fibrates is effective in reducing CHD and associated mortality in patients with type 2 diabetes. Other interventions include aspirin therapy and the use of angiotensin-converting enzyme (ACE) inhibitors.     

Insulin resistance, diabetes and cardiovascular risk: approaches to treatment

The prevalence of diabetes is increasing worldwide. Insulin resistance and diabetes mellitus are major predictors of cardiovascular ischaemic disease. Other risk factors for cardiovascular death including hypertension, dyslipidaemia, smoking and visceral obesity are especially lethal in diabetics. C-reactive protein, plasminogen activator inhibitor-1, matrix metalloproteinases and other emerging risk factors and their roles are continually being researched and discovered. Treatment of this syndrome must be aimed at lifestyle modification, glycaemic control and management of concomitant risk factors. Diet and exercise play a vital role in the treatment of diabetes and the metabolic syndrome. Weight reduction and increased physical activity will improve insulin resistance, hyperglycaemia, hypertension and dyslipidaemia. Hypertension management has been shown to be especially important in diabetics to prevent cardiovascular events. Likewise, multiple clinical trials show that reduction of cholesterol is even more vital in diabetics than the general population for risk reduction of coronary disease. There is a great deal of evidence that tight control of glycaemia is essential to treatment of this condition. There are a variety of available pharmacological agents available including metformin, insulin secretagogues, alpha-glucosidase inhibitors, thiazolidinediones and insulin. The mechanisms and side effects of these medications are discussed. As macrovascular disease is the major cause of morbidity and mortality, an early, aggressive, multi-factorial approach to treatment of the metabolic syndrome and diabetes is vital to prevent adverse cardiac outcomes.