Counterregulatory response to hypoglycemia during a hypoglycemic clamp in people with type 2 diabetes treated with tirzepatide.

Pieber TR, Svehlikova E, Urva S, Haupt A, Zhou C, Coskun T, Höller V, Fluhr G, Karanikas CA, Milicevic Z, Pratt EJ

Frontiers in endocrinology2 Sept 2025Cited by 2 (Europe PMC)

PMID40964167PMCIDPMC12436105DOI10.3389/fendo.2025.1627947PepBankPUB-40964167

Summary

IntroductionTo evaluate counterregulatory hormonal responses during a hypoglycemic clamp with tirzepatide.MethodsParticipants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks. The primary objective was the change in glucagon response during clamp-induced hypoglycemia from plasma glucose (PG) 100 mg/dL to nadir PG (45 mg/dL). Secondary measures were changes in responses of other counterregulatory hormones during clamp-induced hypoglycemia. Time to recovery from the nadir to 72 mg/dL and hypoglycemic symptom scores using the 7-point Edinburgh Hypoglycemia Symptom scale were also assessed.ResultsAt 12 weeks, HbA1c change from baseline was -1.5% with tirzepatide versus +0.5% with placebo. During induced hypoglycemia, mean PG levels at nadir were 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo. Increases in glucagon from PG 100 mg/dL to nadir PG and during recovery from the nadir to 72 mg/dL did not differ between treatments (p=0.756 and p=0.565, respectively). Growth hormone and adrenaline responses did not differ between treatments. Cortisol and noradrenaline responses were delayed with tirzepatide, consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007). The proportion of participants aware of hypoglycemia did not differ between treatments.DiscussionThe response of the key counterregulatory hormone glucagon to induced hypoglycemia was maintained with tirzepatide.Clinical trial registrationClinicalTrials.gov, identifier NCT04050553.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

10 results from studies that gave the peptide. 10 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the glucagon increase from plasma glucose 100 mg/dL to nadir during induced hypoglycemia did not differ between tirzepatide and placebo.
In plain wordsIn adults with type 2 diabetes, the glucagon rise during low blood sugar was similar with tirzepatide and with placebo.
Peptide
Tirzepatide
Outcome
No significant changeGlucagon increase from PG 100 mg/dL to nadir
Study
n = 42
Comparator
Placebo
Analysis
Primary
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Increases in glucagon from PG 100 mg/dL to nadir PG and during recovery from the nadir to 72 mg/dL did not differ between treatments (p=0.756 and p=0.565, respectively).
2 context sentences(design, population, supporting numbers)
Summary · context
The primary objective was the change in glucagon response during clamp-induced hypoglycemia from plasma glucose (PG) 100 mg/dL to nadir PG (45 mg/dL).
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416703
02HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the growth hormone response to induced hypoglycemia did not differ between tirzepatide and placebo.
In plain wordsIn adults with type 2 diabetes, the growth hormone response to low blood sugar was similar with tirzepatide and with placebo.
Peptide
Tirzepatide
Outcome
No significant changeGrowth hormone response to hypoglycemia
Study
n = 42
Comparator
Placebo
Analysis
Secondary
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Growth hormone and adrenaline responses did not differ between treatments.
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416705
03HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the adrenaline response to induced hypoglycemia did not differ between tirzepatide and placebo.
In plain wordsIn adults with type 2 diabetes, the adrenaline response to low blood sugar was similar with tirzepatide and with placebo.
Peptide
Tirzepatide
Outcome
No significant changeAdrenaline response to hypoglycemia
Study
n = 42
Comparator
Placebo
Analysis
Secondary
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Growth hormone and adrenaline responses did not differ between treatments.
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416706
04HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the cortisol response to induced hypoglycemia was delayed with tirzepatide compared with placebo.
In plain wordsIn adults with type 2 diabetes, the cortisol response to low blood sugar came later with tirzepatide than with placebo.
Peptide
Tirzepatide
Outcome
Not applicableCortisol response to hypoglycemia
Study
n = 42
Comparator
Placebo
Analysis
Secondary
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Cortisol and noradrenaline responses were delayed with tirzepatide, consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007).
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416707
05HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the noradrenaline response to induced hypoglycemia was delayed with tirzepatide compared with placebo.
In plain wordsIn adults with type 2 diabetes, the noradrenaline response to low blood sugar came later with tirzepatide than with placebo.
Peptide
Tirzepatide
Outcome
Not applicableNoradrenaline response to hypoglycemia
Study
n = 42
Comparator
Placebo
Analysis
Secondary
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Cortisol and noradrenaline responses were delayed with tirzepatide, consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007).
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416708
06HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, HbA1c change from baseline at 12 weeks was -1.5% with tirzepatide 15 mg versus +0.5% with placebo.
In plain wordsIn adults with type 2 diabetes, HbA1c fell with tirzepatide and rose with placebo over 12 weeks.
Peptide
Tirzepatide
Outcome
DecreaseHbA1c change from baseline at 12 weeks
Study
n = 42
Comparator
Placebo
Outcome group
Glycemic control · Metabolic and weight
Studied dose
15 mg · 12 weeksAs given in this study (human).
Measurements
HbA1c change
−1.5%
tirzepatide
HbA1c change
0.5%
placebo
Source sentences
Summary
At 12 weeks, HbA1c change from baseline was -1.5% with tirzepatide versus +0.5% with placebo.
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416701
07HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, mean plasma glucose at the clamp nadir was 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo.
In plain wordsIn adults with type 2 diabetes, blood sugar at the lowest point of the clamp was 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo.
Peptide
Tirzepatide
Outcome
Not applicablePlasma glucose at nadir of hypoglycemic clamp
Study
n = 42
Comparator
Placebo
Outcome group
Glycemic control · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Measurements
Nadir plasma glucose
44.5 mg/dL
tirzepatide
Nadir plasma glucose
47.5 mg/dL
placebo
Source sentences
Summary
During induced hypoglycemia, mean PG levels at nadir were 44.5 mg/dL with tirzepatide and 47.5 mg/dL with placebo.
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416702
08HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the glucagon increase during recovery from the nadir to 72 mg/dL did not differ between tirzepatide and placebo.
In plain wordsIn adults with type 2 diabetes, the glucagon rise during recovery from low blood sugar was similar with tirzepatide and with placebo.
Peptide
Tirzepatide
Outcome
No significant changeGlucagon increase during recovery from nadir to 72 mg/dL
Study
n = 42
Comparator
Placebo
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
Increases in glucagon from PG 100 mg/dL to nadir PG and during recovery from the nadir to 72 mg/dL did not differ between treatments (p=0.756 and p=0.565, respectively).
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416704
09HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, hypoglycemic symptom scores at nadir were lower during tirzepatide periods than during placebo (p=0.007).
In plain wordsIn adults with type 2 diabetes, symptoms of low blood sugar were milder at the lowest point with tirzepatide than with placebo.
Peptide
Tirzepatide
Outcome
DecreaseHypoglycemic symptom scores at nadir
Study
n = 42
Comparator
Placebo
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
consistent with lower hypoglycemic symptom scores at nadir observed during tirzepatide treatment periods versus placebo (p=0.007).
2 context sentences(design, population, supporting numbers)
Summary · context
Time to recovery from the nadir to 72 mg/dL and hypoglycemic symptom scores using the 7-point Edinburgh Hypoglycemia Symptom scale were also assessed.
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416709
10HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes, the proportion of participants aware of hypoglycemia did not differ between tirzepatide and placebo.
In plain wordsIn adults with type 2 diabetes, the share of people who noticed low blood sugar was similar with tirzepatide and with placebo.
Peptide
Tirzepatide
Outcome
No significant changeProportion aware of hypoglycemia
Study
n = 42
Comparator
Placebo
Outcome group
Hormone levels · Endocrine and hormones
Studied dose
15 mg · 12 weeksAs given in this study (human).
Source sentences
Summary
The proportion of participants aware of hypoglycemia did not differ between treatments.
1 context sentence(design, population, supporting numbers)
Summary · context
Participants with type 2 diabetes (N=42) were randomized to tirzepatide (15 mg) or placebo for 12 weeks in a crossover design, with a wash-out period of 8-10 weeks.
Show in the study text Report a problemFND-4096416710

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 1Results postedNCT04050553

A Study of Tirzepatide in Participants With Type 2 Diabetes Mellitus

Eli Lilly and Companyn = 4224 Feb 2020 to 25 Jan 2022

Diabetes Mellitus, Type 2 · Hypoglycemia

Trial page ClinicalTrials.govUpdated 20 May 2024

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, 12:58 UTC
Study results updated
Version 1
9 Oct 2026, 03:07 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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