Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial.

Luchsinger JA, Rosin SP, Kazemi EJ, Younes N, Suratt CE, Fattaleh BN, Florez HJ, Gonzalez JS, Hollander P, Hox SH, Kuo S, Lee MS and 5 more

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Martens T, Pop-Busui R, Seaquist ER, Waltje AH, Barzilay JI

JAMA internal medicine1 Jul 2025Cited by 6 (Europe PMC)

PMID40388190PMCIDPMC12090067DOI10.1001/jamainternmed.2025.1189PepBankPUB-40388190

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Summary

The text of this summary is not shown here, because the article license does not allow reuse. Read it at the source (opens in a new tab)

Text rights: Publisher copyright. Results still quote short attributed sentences.

Results from this study9

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone9

In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Liraglutide.

01HumanNot a test of Liraglutide aloneRandomized controlled trialEfficacy outcome
In metformin-treated T2D participants with baseline/follow-up cognitive data, DSST scores showed no statistically significant difference across randomized drug groups including liraglutide; no native-specific contrast was reported.
In plain wordsIn T2D participants on metformin, DSST scores showed no significant differences across randomized drug groups including liraglutide.
Peptide
Liraglutide
Outcome
No significant changeDigit Symbol Substitution Test score at follow-up
Study
n = 3,721
Comparator
Randomized liraglutide, insulin glargine, glimepiride and sitagliptin groups
Analysis
Primary
Outcome group
Cognition and memory · Nervous system and cognition
Source sentences
Summary
There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up.
3 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819001
02HumanNot a test of Liraglutide aloneRandomized controlled trialEfficacy outcome
In metformin-treated T2D participants with cognitive data, immediate spanish english verbal learning test recall showed no statistically significant difference across randomized drug groups including liraglutide; no native-specific contrast was reported.
In plain wordsIn T2D participants on metformin, immediate verbal recall showed no significant differences across randomized drug groups including liraglutide.
Peptide
Liraglutide
Outcome
No significant changeImmediate Spanish English Verbal Learning Test recall at follow-up
Study
n = 3,721
Comparator
Randomized liraglutide, insulin glargine, glimepiride and sitagliptin groups
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Source sentences
Summary
There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up.
3 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819003
03HumanNot a test of Liraglutide aloneRandomized controlled trialEfficacy outcome
In metformin-treated T2D participants with cognitive data, delayed spanish english verbal learning test recall showed no statistically significant difference across randomized drug groups including liraglutide; no native-specific contrast was reported.
In plain wordsIn T2D participants on metformin, delayed verbal recall showed no significant differences across randomized drug groups including liraglutide.
Peptide
Liraglutide
Outcome
No significant changeDelayed Spanish English Verbal Learning Test recall at follow-up
Study
n = 3,721
Comparator
Randomized liraglutide, insulin glargine, glimepiride and sitagliptin groups
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Source sentences
Summary
There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up.
3 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819004
04HumanNot a test of Liraglutide aloneRandomized controlled trialEfficacy outcome
In metformin-treated T2D participants with cognitive data, letter fluency score showed no statistically significant difference across randomized drug groups including liraglutide; no native-specific contrast was reported.
In plain wordsIn T2D participants on metformin, letter fluency showed no significant differences across randomized drug groups including liraglutide.
Peptide
Liraglutide
Outcome
No significant changeLetter fluency score at follow-up
Study
n = 3,721
Comparator
Randomized liraglutide, insulin glargine, glimepiride and sitagliptin groups
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Source sentences
Summary
There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up.
3 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819005
05HumanNot a test of Liraglutide aloneRandomized controlled trialEfficacy outcome
In metformin-treated T2D participants with cognitive data, category fluency score showed no statistically significant difference across randomized drug groups including liraglutide; no native-specific contrast was reported.
In plain wordsIn T2D participants on metformin, category fluency showed no significant differences across randomized drug groups including liraglutide.
Peptide
Liraglutide
Outcome
No significant changeCategory fluency score at follow-up
Study
n = 3,721
Comparator
Randomized liraglutide, insulin glargine, glimepiride and sitagliptin groups
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Source sentences
Summary
There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up.
3 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819006
06HumanNot a test of Liraglutide aloneRandomized controlled trialSafety outcome
In metformin-treated T2D participants with cognitive data, severe hypoglycemia requiring assistance occurred in 34 participants (0.9%) across all four randomized drug groups; no native-specific rate was reported.
In plain wordsIn T2D participants on metformin, severe hypoglycemia was reported in 0.9% across four drug groups; no liraglutide-specific rate was reported.
Peptide
Liraglutide
Outcome
Not applicableSevere hypoglycemia requiring assistance
Study
n = 3,721
Outcome group
Adverse events · Metabolic and weight
Measurements
Participants with severe hypoglycemia
34 participants
all four randomized drug groups
Severe-hypoglycemia proportion
0.9%
all four groups; not native-specific
Source sentences
Summary
Severe hypoglycemia requiring assistance was uncommon in all 4 groups (34 participants [0.9%]).
2 context sentences(design, population, supporting numbers)
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819002
07HumanNot a test of Liraglutide aloneObservational studyOther
In pooled metformin-treated T2D cohorts including liraglutide, a 1-unit higher time-weighted HbA1c was associated with lower digit symbol substitution test score (-0.94 points,95% CI -1.30 to -0.57) over mean 4.1 years (SD 0.1); no native-drug effect was reported.
In plain wordsIn pooled T2D cohorts including liraglutide, higher time-weighted HbA1c was linked to lower DSST score; the exact continuous reference was unstated.
Peptide
Liraglutide
Outcome
DecreaseDigit Symbol Substitution Test score association with time-weighted HbA1c
Study
n = 3,721
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Measurements
Reported score difference per1-unit HbA1c increase
−0.94 points
pooled randomized-treatment cohorts; exact continuous reference unstated
95% CI
−1.3 to −0.57 points
HbA1c-associated score difference
Mean follow-up
4.1 years
cohort follow-up, not drug exposure
Follow-up SD
0.1 years
cohort follow-up
Source sentences
Summary
However, a 1-unit increase in time-weighted hemoglobin A1c levels was associated with modestly lower Digit Symbol Substitution Test scores (-0.94 points; 95% CI, -1.30 to -0.57)
5 context sentences(design, population, supporting numbers)
Summary · context
However, a 1-unit increase in time-weighted hemoglobin A1c levels
Summary · context
over the mean (SD) of 4.1 (0.1) years of follow-up.
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The secondary objective assessed time-weighted hemoglobin A1c levels over the follow-up period.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819007
08HumanNot a test of Liraglutide aloneObservational studyOther
In pooled metformin-treated T2D cohorts including liraglutide, a 1-unit higher time-weighted HbA1c was associated with lower immediate spanish english verbal learning test recall (-0.27 points,95% CI -0.49 to -0.06) over mean 4.1 years (SD 0.1); no native-drug effect was reported.
In plain wordsIn pooled T2D cohorts including liraglutide, higher time-weighted HbA1c was linked to lower immediate verbal recall; the exact continuous reference was unstated.
Peptide
Liraglutide
Outcome
DecreaseImmediate Spanish English Verbal Learning Test recall association with time-weighted HbA1c
Study
n = 3,721
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Measurements
Reported score difference per1-unit HbA1c increase
−0.27 points
pooled randomized-treatment cohorts; exact continuous reference unstated
95% CI
−0.49 to −0.06 points
HbA1c-associated score difference
Mean follow-up
4.1 years
cohort follow-up, not drug exposure
Follow-up SD
0.1 years
cohort follow-up
Source sentences
Summary
Spanish English Verbal Learning Test scores (immediate recall, -0.27 points; 95% CI, -0.49 to -0.06)
5 context sentences(design, population, supporting numbers)
Summary · context
However, a 1-unit increase in time-weighted hemoglobin A1c levels
Summary · context
over the mean (SD) of 4.1 (0.1) years of follow-up.
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The secondary objective assessed time-weighted hemoglobin A1c levels over the follow-up period.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819008
09HumanNot a test of Liraglutide aloneObservational studyOther
In pooled metformin-treated T2D cohorts including liraglutide, a 1-unit higher time-weighted HbA1c was associated with lower category animal fluency score (-0.28 points,95% CI -0.47 to -0.09) over mean 4.1 years (SD 0.1); no native-drug effect was reported.
In plain wordsIn pooled T2D cohorts including liraglutide, higher time-weighted HbA1c was linked to lower category fluency; the exact continuous reference was unstated.
Peptide
Liraglutide
Outcome
DecreaseCategory animal fluency score association with time-weighted HbA1c
Study
n = 3,721
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Measurements
Reported score difference per1-unit HbA1c increase
−0.28 points
pooled randomized-treatment cohorts; exact continuous reference unstated
95% CI
−0.47 to −0.09 points
HbA1c-associated score difference
Mean follow-up
4.1 years
cohort follow-up, not drug exposure
Follow-up SD
0.1 years
cohort follow-up
Source sentences
Summary
and category fluency test scores (animal fluency, -0.28 points; 95% CI, -0.47 to -0.09)
5 context sentences(design, population, supporting numbers)
Summary · context
However, a 1-unit increase in time-weighted hemoglobin A1c levels
Summary · context
over the mean (SD) of 4.1 (0.1) years of follow-up.
Summary · context
This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data.
Summary · context
For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin).
Summary · context
The secondary objective assessed time-weighted hemoglobin A1c levels over the follow-up period.
In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.
Report a problemFND-4038819009

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT01794143

A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes

GRADE Study Groupn = 7,850May 2013 to 30 Apr 2021

Type 2 Diabetes · Comparative Effectiveness of Glycemia-lowering Medications

Trial page ClinicalTrials.govUpdated 10 Feb 2026

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
12 Oct 2026, 11:11 UTC
Study results updated
Version 1
9 Oct 2026, 03:05 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

Publication types

MeSH terms

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