Real-world effectiveness of adding newer generation GLP-1RA to SGLT2i in type 2 diabetes.

Chaiyakunapruk N, Tan X, Liang Y, Guevarra M, Xie L, Cheng AYY

Cardiovascular diabetology24 Apr 2025Cited by 22 (Europe PMC)

PMID40275332PMCIDPMC12023599DOI10.1186/s12933-025-02737-1PepBankPUB-40275332

Summary

BackgroundGuidelines recommend combination therapy with glucagonlike peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) for cardiorenal risk reduction in people with type 2 diabetes (T2D); however, there is limited real-world evidence on the long-term effects of combination therapy on cardiometabolic and renal outcomes. The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.MethodsThis retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023. The study included 100,455 people in the combination GLP-1RA and SGLT2i group and 339,540 people in the comparison SGLT2i group across 3 cohorts: T2D with atherosclerotic cardiovascular disease (ASCVD), T2D, and T2D with chronic kidney disease (CKD). Entropy balancing was used to balance patient characteristics. Time to first event of ischemic stroke, myocardial infarction (MI), 3-point major adverse cardiovascular event (MACE), and 5-point MACE in T2D with ASCVD cohort were measured. In the T2D cohort, follow-up and change in glycated hemoglobin (HbA_1c) and weight, odds of achieving HbA_1c 1c < 8%, and odds of achieving 5%, 10%, and 15% decrease in weight were also measured.ResultsThe combination and comparison groups included 34,690 and 130,220 people, respectively, in the T2D with ASCVD cohort; 8,220 and 22,891 people, respectively, in the T2D cohort; and 8,783 and 35,532 people, respectively, in the T2D with CKD cohort. Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD. Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA_1c, and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D.ConclusionsCombination of SGLT2i and GLP-1RA achieved significantly better cardiometabolic outcomes compared with SGLT2i alone; this supports the hypothesis that the cardioprotective benefits of GLP-1RA and SGLT2i may be additive.

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

Results from this study7

3 results from studies that gave the peptide. 3 results from people.

01HumanObservational studyEfficacy outcome
In US adults with type 2 diabetes receiving SGLT2i, adding once-weekly semaglutide gave the largest cardiovascular risk reductions among the individual GLP-1 receptor agonists assessed.
In plain wordsAmong GLP-1 drugs studied in adults with diabetes, adding once-weekly semaglutide to an SGLT2 inhibitor was linked to the biggest cardiovascular risk drop.
Peptide
Semaglutide
Outcome
DecreaseCardiovascular risk reduction with SGLT2i plus once-weekly semaglutide
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA_1c, and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
Show in the study text Report a problemFND-4027533205
02HumanObservational studyEfficacy outcome
In US adults with type 2 diabetes receiving SGLT2i, adding once-weekly semaglutide gave the largest HbA1c reduction among the individual GLP-1 receptor agonists assessed.
In plain wordsAmong GLP-1 drugs studied in adults with diabetes, adding once-weekly semaglutide to an SGLT2 inhibitor was linked to the biggest HbA1c drop.
Peptide
Semaglutide
Outcome
DecreaseHbA1c reduction with SGLT2i plus once-weekly semaglutide
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA_1c, and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
Show in the study text Report a problemFND-4027533206
03HumanObservational studyEfficacy outcome
In US adults with type 2 diabetes receiving SGLT2i, adding once-weekly semaglutide gave the largest weight reduction among the individual GLP-1 receptor agonists assessed.
In plain wordsAmong GLP-1 drugs studied in adults with diabetes, adding once-weekly semaglutide to an SGLT2 inhibitor was linked to the biggest weight loss.
Peptide
Semaglutide
Outcome
DecreaseWeight reduction with SGLT2i plus once-weekly semaglutide
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA_1c, and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
Show in the study text Report a problemFND-4027533207

Studies that did not test the peptide alone4

In this study, Semaglutide 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 Semaglutide.

04HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In US adults with type 2 diabetes and ASCVD, adding a pooled newer-generation GLP-1 receptor agonist class (including semaglutide) to SGLT2i was associated with 42% lower risk of ischemic stroke than SGLT2i alone.
In plain wordsIn diabetes with heart disease, adding GLP-1 drugs to an SGLT2 inhibitor was linked to 42% lower stroke risk than the inhibitor alone.
Peptide
Semaglutide
Outcome
DecreaseIschemic stroke risk
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk reduction
42%
ischemic stroke
Source sentences
Summary
Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
In this study, Semaglutide 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 Semaglutide.
Show in the study text Report a problemFND-4027533201
05HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In US adults with type 2 diabetes and ASCVD, adding a pooled newer-generation GLP-1 receptor agonist class (including semaglutide) to SGLT2i was associated with 37% lower risk of myocardial infarction than SGLT2i alone.
In plain wordsIn diabetes with heart disease, adding GLP-1 drugs to an SGLT2 inhibitor was linked to 37% lower heart attack risk than the inhibitor alone.
Peptide
Semaglutide
Outcome
DecreaseMyocardial infarction risk
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk reduction
37%
myocardial infarction
Source sentences
Summary
Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
In this study, Semaglutide 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 Semaglutide.
Show in the study text Report a problemFND-4027533202
06HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In US adults with type 2 diabetes and ASCVD, adding a pooled newer-generation GLP-1 receptor agonist class (including semaglutide) to SGLT2i was associated with 46% lower risk of 3-point MACE than SGLT2i alone.
In plain wordsIn diabetes with heart disease, adding GLP-1 drugs to an SGLT2 inhibitor was linked to 46% lower 3-point MACE risk than the inhibitor alone.
Peptide
Semaglutide
Outcome
Decrease3-point MACE risk
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk reduction
46%
3-point MACE
Source sentences
Summary
Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
In this study, Semaglutide 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 Semaglutide.
Show in the study text Report a problemFND-4027533203
07HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In US adults with type 2 diabetes and ASCVD, adding a pooled newer-generation GLP-1 receptor agonist class (including semaglutide) to SGLT2i was associated with 45% lower risk of 5-point MACE than SGLT2i alone.
In plain wordsIn diabetes with heart disease, adding GLP-1 drugs to an SGLT2 inhibitor was linked to 45% lower 5-point MACE risk than the inhibitor alone.
Peptide
Semaglutide
Outcome
Decrease5-point MACE risk
Study
n: not reported in source
Comparator
SGLT2i alone
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Risk reduction
45%
5-point MACE
Source sentences
Summary
Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD.
2 context sentences(design, population, supporting numbers)
Summary · context
The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.
Summary · context
This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023.
In this study, Semaglutide 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 Semaglutide.
Show in the study text Report a problemFND-4027533204

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
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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Real-world effectiveness of adding newer generation GLP-1RA to SGLT2i in type 2 diabetes.

Summary

Results from this study7

Studies that did not test the peptide alone4

Version history

Subjects

Publication types

MeSH terms

Keywords