Review
Glycaemic variability in diabetes: clinical and therapeutic implications

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Summary

Glycaemic variability is an integral component of glucose homoeostasis. Although it has not yet been definitively confirmed as an independent risk factor for diabetes complications, glycaemic variability can represent the presence of excess glycaemic excursions and, consequently, the risk of hyperglycaemia or hypoglycaemia. Glycaemic variability is currently defined by a large and increasing number of metrics, representing either short-term (within-day and between-day variability) or long-term glycaemic variability, which is usually based on serial measurements of HbA1c or other measures of glycaemia over a longer period of time. In this Review, we discuss recent evidence examining the association between glycaemic variability and diabetes-related complications, as well as non-pharmacological and pharmacological strategies currently available to address this challenging aspect of diabetes management.

Introduction

Strategies for the management of glycaemia in patients with diabetes should aim to address the three main components of dysglycaemia: chronic hyperglycaemia, hypoglycaemia, and glycaemic variability.1 These features contribute to the development and progression of diabetic complications.2 Long-term interventional trials comparing intensive with standard management of diabetes have clearly shown the association between prolonged poor glycaemic control and the development of microvascular and, to a lesser extent, macrovascular complications.3, 4 During the past decade, deleterious effects of both short-term glycaemic variability (within-day glucose fluctuations; peaks to nadirs), and long-term variations, as measured by changes in fasting plasma glucose (FPG) and HbA1c, have been proposed,5, 6 although definitive evidence on hard clinical outcomes remains scarce.7

Notably, the availability of glucose monitoring, especially continuous glucose monitoring (CGM) has become of considerable value in informing management decisions, whereas HbA1c used in isolation can be misleading.8 Short-term glycaemic variability is of increasing concern to health-care professionals intent on preventing excessive glucose fluctuations, posing the potential risk of precipitating episodes of hyperglycaemia or hypoglycaemia,6 negatively affecting patients' quality of life.9 Short-term and longer-term glycaemic variability also seem to be associated with increased episodes of severe hypoglycaemia, which in turn are associated with adverse cardiovascular outcomes and all-cause mortality.10, 11 However, definitive evidence for the role of glycaemic variability in the genesis and severity of adverse clinical outcomes in people with diabetes is scarce compared with the evidence for the negative effects of chronic glucose exposure, as assessed by HbA1c.2, 3, 4

In this Review, we assess the emerging evidence on the clinical and therapeutic relevance of glycaemic variability in diabetes, focusing on studies published in the past few years while also drawing on landmark earlier studies. The clinical association between glycaemic variability and diabetes complications is difficult to establish because of heterogeneity between studies, including their design and, notably, the different metrics used to assess glycaemic variability. Additionally, most antidiabetes treatments affect components of the so-called glycaemic triumvirate (ambient hyperglycaemia, glycaemic variability, and hypoglycaemia) to different degrees.1, 12, 13, 14, 15, 16 Individualising care on the basis of change in CGM and glycaemic variability could be an important aspect of precision medicine in diabetes, although such an objective might take a long time to achieve.

Section snippets

Metrics of glycaemic variability: does profusion create confusion?

Glycaemic variability is usually defined by the measurement of fluctuations of glucose or other related parameters of glucose homoeostasis over a given interval of time. This description covers two predominant categories of measurements (table): short-term glycaemic variability, represented by both within-day and between-day glycaemic variability, and long-term glycaemic variability, based on serial determinations over a longer period of time, usually involving HbA1c, but sometimes serial FPG

Glucose variability and clinical outcomes in people with and without diabetes

Before 2015, several studies had shown a positive association between glycaemic variability and diabetes complications, both macrovascular and microvascular.29 Since 2015, new evidence has also emerged in support of glycaemic variability as an independent risk factor for total mortality and death due to cardiovascular disease in both type 1 and type 2 diabetes.26, 30, 31, 32, 33, 34

Glycaemic variability increased recurrent cardiovascular events and mortality in people with diabetes following

Intervention studies

Importantly, long-term intervention studies will be necessary to provide compelling evidence for a beneficial effect of reducing short-term glycaemic variability on hard outcomes, such as the development and progression of microvascular and macrovascular diseases. In all studies aimed at attenuating the magnitude of glycaemic variability or of postprandial excursions reported so far, the tested group and its comparator group received pharmacological interventions with different treatment

Glycaemic variability and tissue damage

Findings from two in-vitro studies done almost 20 years ago (the first showing a specific damaging effect of glycaemic variability) showed that short-term (4 days) and long-term (21 days) glucose oscillation enhanced human tubule-interstitial cell growth and collagen synthesis72 and accelerated apoptosis in human umbilical vein endothelial cells73 more than exposure to a constantly high glucose concentration. Shortly afterwards, oxidative stress was shown to be the key player in producing

Glycaemic variability and hypoglycaemia

Achievement of near normoglycaemia is a key objective in the management of diabetes. This objective is well supported by observational, epidemiological, and interventional studies confirming the association between hyperglycaemia and cardiovascular events, premature death, and microvascular complications.87

Unfortunately, the maintenance of normoglycaemia over a lifetime of diabetes, while also attempting to avoid hypoglycaemia, is a major challenge for patients.88 In 2000, the investigators of

Therapeutic implications

There are several possibile methods for reducing glycaemic variability in clinical practice, using pharmacological and non-pharmacological tools.

Conclusions

Now that the improved availability of CGM has made blood glucose monitoring easier and more meaningful, glycaemic variability is emerging as an additional glycaemic target, even though doubt remains over whether both short-term or long-term glycaemic variability should be considered independent risk factors for diabetes-related complications. The potential risks associated with glycaemic variability seem likely to be related to possible vascular damage due to excessive glucose fluctuations and

Search strategy and selection criteria

We searched PubMed for articles published in English from database inception up to Jan 31, 2018, using the search terms “glycaemic variability”, “glucose variability”, “fasting glucose variability”, “HbA1c variability”, “glucose fluctuation”, and “oscillating glucose”. We reviewed and selected retrieved references on the basis of relevance. We gave priority for inclusion to relevant scientific literature published from 2015 onwards, although selected key older references are also cited.

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