Clinical trial NCT03014011: Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes
Official title: Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type II
Hypoglycemia
Cognitive Change
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
Collaborators: name: University Hospital, Gentofte, Copenhagen
name: Psychiatric Centre Rigshospitalet
First posted: 2017-01-09
Enrollment: 28
Sex: ALL
Minimum age (years): 35
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Hypoglycaemia in subjects suffering from type 2 diabetes may have substantial consequences including a significant negative impact on quality of life. Further, repeated minor hypoglycaemias may result in significant productivity losses.

Here, the investigators propose to provide quantitative results on cognition during an acute mild hypoglycaemic episode (target plasma glucose 3 mmol/L) in 28 subjects with type 2 diabetes. Data will be provided on executive function, attention and memory.

Detailed description: Hypoglycaemia in subjects suffering from type 2 diabetes may have substantial consequences including a significant negative impact on quality of life. Further, repeated minor hypoglycaemias may result in significant productivity losses. In healthy subjects a number of studies show that during a hypoglycaemic episode with plasma levels of 2.2 - 2.5 mmol/L (40-45 mg/dl) brain areas responsible for cognition have an altered neuronal function when measuring cerebral blood flow. This is accompanied by severely impaired cognitive function with a reduced ability to solve simple cognitive tasks. At higher levels of glucose (above 3 mmol/L (54 mg/dl)), it remains to be settled whether cognitive functions are also affected negatively and whether this may be accompanied by changes in brain metabolism. Apart from raising the blood glucose directly or indirectly via glucagon, no treatment for hypoglycaemia exists, but since Glucagon-like peptide-1 (GLP-1) based therapies used in type 2 diabetes may affect brain glucose consumption, therapeutic interventions to prevent negative results of hypoglycaemia may eventually become clinically possible.

Here, the investigators propose to provide quantitative results on cognition during an acute mild hypoglycaemic episode (target plasma glucose 3 mmol/L). Data will be provided on executive function, attention and memory.

Eligibility criteria: Inclusion Criteria:

* Informed and written consent
* Clinically diagnosed type 2 diabetes mellitus for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO)).
* Normal haemoglobin ≥ 8.0 mmol/L (male) or ≥ 6.4 mmol/L (female)
* Male or female participants aged 35-70 years, both inclusive.
* Treated with diet or any antidiabetic medication except sulfonylureas, meglitinides or insulin.
* HbA1c ≤ 9.0 % by local laboratory analysis.
* BMI \>23 kg/m2 and \<35 kg/m2

Exclusion Criteria:

* Receipt of any investigational medicinal product within 3 months before screening in this trial.
* Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) \>2 times normal values) or history of hepatobiliary disorder.
* Nephropathy (serum creatinine levels ≥ 126 μmol/L (male) or ≥ 111 μmol/L (female)).
* Cardiac problems defined as decompensated heart failure (New York Heart Association (NYHA) class III and IV) at any time and/or angina pectoris within the last 12 months and/or acute myocardial infarction at any time.
* Active or recent malignant disease.
* Treatment with drugs that cannot be paused for 12 hours.
* Repeated resting blood pressure at screening outside the range 90-140 mmHg for systolic or 50-90 mmHg for diastolic. This exclusion criterion also pertains to subjects taking antihypertensives.
* Visual impairment or auditory impairment.
* Known abnormalities of the central nervous system or any endocrinological (with the exception of diabetes mellitus and euthyroid goiter), haematological, neurological, psychiatric diseases or other major disorders that in the opinion of the investigator precludes compliance with the protocol, evaluation of the results or represent an unacceptable risk for the participant's safety.
* Proliferative retinopathy (funduscopy performed within 3 months before the screening is acceptable) and/or severe neuropathy.
* Current treatment with systemic drugs, which may interfere with glucose metabolism.
* Significant history of alcoholism or drug/chemical abuse as per investigator's judgement.
* Current tobacco user (smoking or nicotinic product use 3 months prior to screening).
* Severe hypoglycaemic event during the past 6 months.
* Known hypoglycaemia unawareness.
* Participants with mental incapacity or language barriers precluding adequate understanding or co-operation or who, in the opinion of the investigator or their general practitioner, should not participate in the trial.
* For females only: Pregnancy, breast-feeding status or intention of becoming pregnant during the trial.
* Any chronic disorder or severe disease that in the opinion of the investigator might endanger participant's safety or compliance with the protocol.

Primary outcomes:
measure: Psychomotor Speed
timeFrame: All neurocognitive testing was assessed at each intervention when glucose levels had been stabile for 40 minutes, an average of 2 hours after clamp procedure start. The duration of neurocognitive testing was approximately 40 min.
Secondary outcomes:
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Research in Endocrinology, Bispebjerg University Hospital
Study officials:
affiliation: Department of Endocrinology, Bispebjerg University Hospital, Denmark
name: Jørgen Rungby, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nilsson M, Jensen N, Gejl M, Bergmann ML, Storgaard H, Zander M, Miskowiak K, Rungby J. Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial. Diabetologia. 2019 Oct;62(10):1948-1958. doi: 10.1007/s00125-019-4964-4. Epub 2019 Jul 31.