Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes

• Sponsor: Bispebjerg Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03014011
• Collaborator: University Hospital, Gentofte, Copenhagen (Other), Psychiatric Centre Rigshospitalet (Other)
• Enrollment: 28
• Location: 1
• Arms: 2
• Actual Duration (Months): 13.3
• Patients Per Site Per Month: 2.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type II; Hypoglycemia; Cognitive Change	Other: Hypoglycaemic clamp; Other: Euglycaemic clamp	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes
• Actual Study Start Date: Jun 13, 2017
• Actual Primary Completion Date: Jul 23, 2018
• Actual Study Completion Date: Jul 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Hypoglycaemic clamp first, then euglyceamic clamp First intervention with a hypoglycaemic clamp (one examination day of approximately 5 hours), there after a wash out period of 21-42 days, then second and final intervention day with an euglycaemic clamp (approximately 5 hours).	Other: Hypoglycaemic clamp; The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to lower and keep plasma blood glucose levels at 3 mmol/L for outcome measurements.; Other: Euglycaemic clamp; The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to keep plasma blood glucose levels at 6 mmol/L for outcome measurements.
Other: Euglycaemic clamp first, then hypoglycaemic clamp First intervention with an euglycaemic clamp (one examination day of approximately 5 hours), there after a wash out period of 21-42 days, then second and final intervention day with a hypoglycaemic clamp (approximately 5 hours).	Other: Hypoglycaemic clamp; The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to lower and keep plasma blood glucose levels at 3 mmol/L for outcome measurements.; Other: Euglycaemic clamp; The clamp is performed by insulin and adjustable 20% glucose infusions, with the aim to keep plasma blood glucose levels at 6 mmol/L for outcome measurements.

Outcome Measures

Primary Outcome Measures

1. Psychomotor Speed [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.]

   Symbol Digit Modalities Test was used as a measurement of psychomotor speed. For the Symbol Digit Modalities Test, participants were required to use a coded key to match nine abstract symbols paired with numerical digits. The final score is the correct number of substitutions in 120 s, and scores range between 0 and 110. Higher values represent a better outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Research in Endocrinology, Bispebjerg University Hospital	Copenhagen		Denmark

Sponsors and Collaborators

• Bispebjerg Hospital
• University Hospital, Gentofte, Copenhagen
• Psychiatric Centre Rigshospitalet

Investigators

• Principal Investigator: Jørgen Rungby, Professor, Department of Endocrinology, Bispebjerg University Hospital, Denmark

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 15, 2016

More Information

Publications

None provided.

• Responsible Party: Malin Nilsson, MD, Bispebjerg Hospital
• ClinicalTrials.gov Identifier: NCT03014011
• Other Study ID Numbers: MISP
• First Posted: Jan 9, 2017
• Last Update Posted: Jan 28, 2020
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Hypoglycemia; Diabetes Mellitus, Type 2; Hypoglycemic Agents

Study Results

Participant Flow

Recruitment Details	37 participants were screened between May 2017 and July 2018 at the Department of Endocrinology, Bispebjerg University Hospital, Denmark.
Pre-assignment Detail	Of the 37 screened participants, 28 met inclusion criteria and were randomised. 25 completed both intervention visits. Three participants (one man, two women) withdrew from the study after randomisation for reasons not related to the intervention. Baseline characteristics are based on the 25 participants that completed the study.

Arm/Group Title	Hypoglycaemic Clamp Followed by Euglycaemic Clamp	Euglycaemic Clamp Followed by Hypoglycaemic Clamp
Arm/Group Description	Participants completed a hypoglycaemic clamp on a first intervention visit. After a washout period of at least 2 weeks (maximum of 6 weeks), a euglycaemic clamp was performed on the second intervention visit.	Participants completed a euglycaemic clamp on a first intervention visit. After a washout periodof at least 2 weeks (maximum of 6 weeks), a hypoglycaemic clamp was performed on the second intervention visit.
Period Title: First Intervention
STARTED	14	13
COMPLETED	13	13
NOT COMPLETED	1	0
Period Title: First Intervention
STARTED	13	13
COMPLETED	12	13
NOT COMPLETED	1	0
Period Title: First Intervention
STARTED	12	13
COMPLETED	12	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Randomised, double-blinded, crossover study design
Overall Participants	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.2 (7.3)
Sex: Female, Male (Count of Participants)
Female	10 40%
Male	15 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	25 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Denmark	25 100%

Outcome Measures

1. Primary Outcome

Title	Psychomotor Speed
Description	Symbol Digit Modalities Test was used as a measurement of psychomotor speed. For the Symbol Digit Modalities Test, participants were required to use a coded key to match nine abstract symbols paired with numerical digits. The final score is the correct number of substitutions in 120 s, and scores range between 0 and 110. Higher values represent a better outcome.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The two interventions were hypoglycaemia (aiming for a plasma glucose target of 3.0 ± 0.2 mmol/l) and euglycaemia (plasma glucose clamp target 6.0 ± 0.2 mmol/l).

Arm/Group Title	Hypoglycaemia	Euglycaemia
Arm/Group Description	low glucose level	normal glucose level
Measure Participants	25	25
Mean (Standard Deviation) [score on a scale]	48.7 (9.8)	56.6 (12)

Adverse Events

Time Frame	For each participant, adverse event data was collected from the day they were included, until the day after their second (and final) intervention visit, an average of 2 months.
Arm/Group Title	Hypoglycaemic Clamp		Euglycaemic Clamp
Arm/Group Description	Mean plasma glucose concentration during the neurocognitive testing was 3.13 mmol/l for the hypoglycaemic clamp.		Mean plasma glucose concentration during the neurocognitive testing was 5.83 mmol/l for the euglycaemic clamp.
All Cause Mortality
	Hypoglycaemic Clamp		Euglycaemic Clamp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Serious Adverse Events
	Hypoglycaemic Clamp		Euglycaemic Clamp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Hypoglycaemic Clamp		Euglycaemic Clamp
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.