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Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes

Primary Purpose

Diabetes Mellitus, Type II, Hypoglycemia, Cognitive Change

Status

Completed

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Hypoglycaemic clamp

Euglycaemic clamp

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type II

Eligibility Criteria

35 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Department of Research in Endocrinology, Bispebjerg University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Hypoglycaemic clamp first, then euglyceamic clamp

Euglycaemic clamp first, then hypoglycaemic clamp

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Psychomotor Speed

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT03014011

First Posted

December 21, 2016

Last Updated

January 14, 2020

Sponsor

Bispebjerg Hospital

Collaborators

University Hospital, Gentofte, Copenhagen, Psychiatric Centre Rigshospitalet

1. Study Identification

Unique Protocol Identification Number

NCT03014011

Brief Title

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

2. Study Status

Record Verification Date

December 2019

Overall Recruitment Status

Completed

Study Start Date

June 13, 2017 (Actual)

Primary Completion Date

July 23, 2018 (Actual)

Study Completion Date

July 24, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Bispebjerg Hospital

Collaborators

University Hospital, Gentofte, Copenhagen, Psychiatric Centre Rigshospitalet

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type II, Hypoglycemia, Cognitive Change

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantOutcomes Assessor

Allocation

Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hypoglycaemic clamp first, then euglyceamic clamp

Arm Type

Other

Arm Description

Arm Title

Euglycaemic clamp first, then hypoglycaemic clamp

Arm Type

Other

Arm Description

Intervention Type

Other

Intervention Name(s)

Hypoglycaemic clamp

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Euglycaemic clamp

Intervention Description

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.

Primary Outcome Measure Information:

Title

Psychomotor Speed

Description

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

35 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jørgen Rungby, Professor

Organizational Affiliation

Department of Endocrinology, Bispebjerg University Hospital, Denmark

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Research in Endocrinology, Bispebjerg University Hospital

City

Copenhagen

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31367958

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.

Results Reference

derived

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Effects of Mild Hypoglycaemia on Cognitive Function in Type 2 Diabetes

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