Differential Longitudinal Effects of Glucose-Lowering Medications on Glucagon and C-peptide Responses in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

Kahn SE, Tripputi M, Lachin JM, Balasubramanyam A, Banerji MA, Barzilay J, Cohen RM, Garvey WT, Gramzinski MR, Rasouli N, Rhee M, Seegmiller JC and 5 more

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Singh V, Sivitz WI, Steffes MW, Utzschneider K, DeFronzo RA

Diabetes care1 Feb 2026

PMID41432725PMCIDPMC12824799DOI10.2337/dc25-2186PepBankPUB-41432725

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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 the 724-participant subset with type 2 diabetes, the four glucose-lowering medications had no clear differential effects on glucagon responses.
In plain wordsIn the 724-person type 2 diabetes subgroup, the medicines showed no clear differences in glucagon responses.
Peptide
Liraglutide
Outcome
Not applicableGlucagon responses
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
There were no clear differential effects of the medications on glucagon responses.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272501
02HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, baseline fasting glucagon was not associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, baseline glucagon was not linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
No significant changeBaseline fasting glucagon association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Baseline fasting glucagon and GGI were not associated with the primary metabolic outcome (2 df; P = 0.55), whereas the β-cell measures were (2 df; P = 0.04).
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272502
03HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, baseline glucagon index was not associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, baseline glucagon index was not linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
No significant changeBaseline glucagon index association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Baseline fasting glucagon and GGI were not associated with the primary metabolic outcome (2 df; P = 0.55), whereas the β-cell measures were (2 df; P = 0.04).
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272503
04HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, baseline beta-cell measures jointly were associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, the combined baseline beta-cell measures were linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
Direction not reportedBaseline beta-cell measures association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Baseline fasting glucagon and GGI were not associated with the primary metabolic outcome (2 df; P = 0.55), whereas the β-cell measures were (2 df; P = 0.04).
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272504
05HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, treatment-associated fasting glucagon changes were not associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, treatment-related fasting-glucagon changes were not linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
No significant changeTreatment-associated fasting glucagon change association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272505
06HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, treatment-associated glucagon-index changes were not associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, treatment-related glucagon-index changes were not linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
No significant changeTreatment-associated glucagon index change association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272506
07HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, treatment-associated fasting C-peptide changes were not associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, treatment-related fasting-C-peptide changes were not linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
No significant changeTreatment-associated fasting C-peptide change association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272507
08HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, treatment-associated C-peptide-index changes were associated with the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, treatment-related C-peptide-index changes were linked to reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
Direction not reportedTreatment-associated C-peptide index association with primary metabolic outcome
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Source sentences
Summary
Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272508
09HumanNot a test of Liraglutide aloneRandomized controlled trialOther
In the 724-participant type 2 diabetes subset, a 1-SD increase in C-peptide index was associated with a 17% reduction in risk of the primary metabolic outcome of HbA1c at least 7.0%.
In plain wordsIn the 724-person type 2 diabetes subgroup, a higher C-peptide index was linked to lower risk of reaching HbA1c 7.0% or higher.
Peptide
Liraglutide
Outcome
DecreasePrimary metabolic outcome risk by C-peptide index
Study
n = 724
Outcome group
Glycemic control · Endocrine and hormones
Measurements
Risk reduction
17%
1-SD increase in C-peptide index
Source sentences
Summary
A 1-SD increase in CPI was associated with a 17% reduction in the risk of the primary metabolic outcome.
3 context sentences(design, population, supporting numbers)
Summary · context
In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin.
Summary · context
In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]).
Summary · context
Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined.
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-4143272509

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

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, 03:04 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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