Diabetes Related Complications Clinical Trial
Official title:
QT Interval Abnormalities in Sulfonylurea Treated Type 2 Diabetes: Relationship to Treatment Induced Hypoglycaemia and Glycaemic Variability Determined by Simultaneous Ambulatory Monitoring
Hypoglycaemia is the most common acute complication of diabetes and can limit therapeutic
efforts to improve glycaemic control. It is a potential side effect of drugs used to treat
diabetes, particularly with the use of sulfonylurea (SU) treatment. It has been demonstrated
that hypoglycaemia causes the prolongation of corrected QT (QTc) interval, which is
associated with ventricular arrhythmias and sudden death. Hypoglycaemia in T2DM has recently
come into focus with the results of the ACCORD, ADVANCE and VADT trials.
In this study, the investigators aim to examine the association of hypoglycaemia and glucose
fluctuations on QT-interval and QT variability in patients with type 2 diabetes treated with
SU. Patients will be studied using simultaneous Continuous Glucose Monitoring (CGM) and
ambulatory ECG monitoring (Holter).
Study participants will be recruited from the Diabetes Centre, RPAH or from specialist
consulting rooms. They will be required to attend the Diabetes Centre on two occasions.
At the first visit, blood will be collected and CGM and Holter monitoring commenced. At Visit
2, i.e. two days later, the patient will return to the Diabetes Centre to have the equipment
removed. The data obtained from the CGM and Holter monitor will then be downloaded for review
and analysis.
Background/Scientific Basis:
Hypoglycaemia is the most common acute complication of diabetes and can limit therapeutic
efforts to improve glycaemic control. It is a potential side effect of the drugs used to
treat diabetes, particularly with the use of exogenous insulin or insulin secretagogues, such
as sulfonylurea (SU) treatment. As many people are prescribed these agents, hypoglycaemia is
frequent in clinical practice, particularly as treatment targets have become more stringent.
Several studies have demonstrated that insulin-induced hypoglycaemia causes prolongation of
corrected QT (QTc) interal (Chugh et al), which is associated with ventricular arrhythmias
and sudden death, perhaps as a result of hypokalaemia and an increase in serum
catecholamines. Cardiac effects of hypoglycaemia are usually associated with type 1 diabetes
and insulin therapy. Hypoglycaemia in type 2 diabetes (T2DM) on oral agents has not, until
recently, been considered to be as serious. Recently, hypoglycaemia in T2Dm has come in into
focus since the salutary results of the ACCORD, ADVANCE and VADT trails, each of which
implicated hypoglycaemia as a cause for increased death. The majority of excess deaths in the
intensive treatment group of ACCORD were classified as sudden cardiac death. There is now a
growing body of evidence that hypoglycaemia is a pro-arrhythmic event via QT prolongation and
particularly in the context of myocardial ischemia which reduces the tolerance of myocardial
tissue for the further pro-arrhythmic action of hypoglycaemia.
It is notable that hypoglycaemia occurs commonly in those using SU. For example in the UK
Hypoglycaemia Study (UK Hypoglycaemia Study Group) , 7% of individuals treated with SUs had
at least one episode of severe (requiring external assistance) hypoglycaemia and the
proportion reporting at least one mild (symptomatic, self-treated) episode was 39%, a rate
comparable to insulin treatment. Furthermore, the SU receptor functions as the regulatory
subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. KATP channels
are widely expressed in the heart and vascular smooth muscle cells. There have been long-held
concerns that SU effects on these channels may affect ischaemic preconditioning (Cleveland et
al), a protective mechanism in the myocardium. This may represent an additive deleterious
impact specific to SUs in a hypoglycaemic setting.
Despite these theoretical concerns associated with SU treatment the pro-arrhythmic effects of
SU induced hypoglycaemia have not previously been easy to study in ambulatory patients. Now
the dual ambulatory technologies of CGMS (Maia et al) and ambulatory ECG (Holter) monitoring
provide an opportunity to examine this potential association under real life conditions. Even
in the absence of absolute QT prolongation, there is evidence that beat-to-beat QT
variability is also a risk marker for sudden death and ventricular arrhythmia (Piccirillo et
al). Additionally, glucose variability may also have an impact on cardiac tissue. Habituation
to chronic hyperglycaemia could lead to a situation where a sudden decrease to plasma glucose
leads to changes in QT interval, even when the glucose falls within the normal range
("relative hypoglycaemia").
A pilot study in our institution of 14 individuals on insulin (3 with T1DM and 11 with T2DM)
showed statistically significant prolongation of QTc during periods of hypoglycaemia. The
mean difference in QTc during hypos was 7.8ms (p<0.05). An inverse relationship between the
magnitude of increase in QTs during hypoglycaemia and baseline QTc was found. The limitations
of the pilot study are that it was restricted to those subjects treated with insulin and that
relative hypoglycaemia and QT variability were not analysed.
Hypothesis:
Sulfonylurea induced hypoglycaemia and/or fluctuations in glucose are pro-arrhythmic by
prolonging the QTc interval and/or increasing beat-to-beat QTc variability. It is expected
that the QT interval will be significantly longer during the hypoglycemic periods compared to
the non-hypoglycemic periods in patients in T2DM treated with SU.
Aims:
To examine the association of hypoglycaemia and glucose fluctuations on QT-interval and QT
variability in patients with type 2 diabetes treated with SU. Patients will be studied using
simultaneous Continuous Glucose Monitoring (CGM) and ambulatory ECG monitoring (Holter).
Potential Significance:
The information gained from this study has the potential to improve our understanding of the
relationship between hypoglycaemia and cardiac arrhythmia in patients with diabetes.
Recruitment Process:
Patients with type 2 diabetes attending the Diabetes Centre, Royal Prince Alfred Hospital who
fulfils the entry criteria will be approached to participate in this study. They will be
approached either when they attend the Diabetes Centre for treatment, or by means of a
telephone call. The requirements of the study will be discussed with each potential
participant and they will be given a copy of the Participant Information Sheet and Consent
Form to take home and read. The proposed number of participants for this study is
approximately 30 individuals.
Research Interventions:
1. Blood Collection
2. Continuous Glucose Monitoring
3. Home Blood Glucose Monitoring
4. Holter Monitor
Risk and Side Effects:
We do not anticipate any adverse events associated with study participation. However, there
may be some mild discomfort and/or bruising at the site of blood collection, or insertion of
the glucose sensor for CGM, or skin irritation from the ECG adhesive tapes required for
Holter monitoring.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT05787990 -
Time-In-Range Based Risk Stratification of Type 2 Diabetes Microvascular Complications
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