Evidence map›SGLT2 inhibitors × cardiovascular events›PMID 40105285›Full record

Trial reportJournal of the American Geriatrics Society2025

The Efficacy and Safety of Canagliflozin by Frailty Status in Participants of the CANVAS and CREDENCE Trials.

Tu N Nguyen, Jie Yu, Vlado Perkovic, Meg Jardine, Kenneth W Mahaffey, Clara K Chow, Clare Arnott, Richard I Lindley

3 registry-linked trialsAbstract readClinical Trial, Phase IIIMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Journal of the American Geriatrics Society, 2025. The graph read 8 numbers from its abstract, feeding 3 cells of the map: it supports the treatment in 1, finds no clear difference in 2. It reports registered trial NCT01032629. Cited by 4 papers.

8numbers the graph read from it
3cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the treatmentfavours the comparator →
241 · no effect
All-cause mortalitycanagliflozin vs placebo, in non-frailno clear difference · ascvd, t2dfeeds one cell of the map
HR 0.930.74 to 1.16
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×all-cause mortality
Osmotic diuresiscanagliflozin vs placebo, in frailfavours the comparator · ascvd, t2dfeeds one cell of the map
HR 1.671.22 to 2.28
Adverse events were similar among frail and non-frail participants, except for osmotic diuresis (HRs 1.67, 95% CI 1.22-2.28 in the frail vs. 3.05, 95% CI 2.13-4.35 in the non-frail, p for interaction = 0.01).
FeedsSGLT2 inhibitors×adverse events & safety
Osmotic diuresiscanagliflozin vs placebo, in non-frailfavours the comparator · ascvd, t2dfeeds one cell of the map
HR 3.052.13 to 4.35
Adverse events were similar among frail and non-frail participants, except for osmotic diuresis (HRs 1.67, 95% CI 1.22-2.28 in the frail vs. 3.05, 95% CI 2.13-4.35 in the non-frail, p for interaction = 0.01).
FeedsSGLT2 inhibitors×adverse events & safety
All-cause mortalitycanagliflozin vs placebo, in frailfavours the treatment · ascvd, t2dfeeds one cell of the map
HR 0.810.70 to 0.94
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×all-cause mortality
Cardiovascular mortalitycanagliflozin vs placebo, in non-frailno clear difference · ascvd, t2dfeeds one cell of the map
HR 0.940.70 to 1.27
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×cardiovascular events
Cardiovascular mortalitycanagliflozin vs placebo, in frailfavours the treatment · ascvd, t2dfeeds one cell of the map
HR 0.790.67 to 0.95
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×cardiovascular events
Major adverse cardiovascular events (MACE)canagliflozin vs placebo, in frailfavours the treatment · ascvd, t2dfeeds one cell of the map
HR 0.800.70 to 0.90
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×cardiovascular events
Major adverse cardiovascular events (MACE)canagliflozin vs placebo, in non-frailno clear difference · ascvd, t2dfeeds one cell of the map
HR 0.910.75 to 1.09
The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39).
FeedsSGLT2 inhibitors×cardiovascular events

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

SGLT2 inhibitors×cardiovascular events

InconclusiveOpen on the map →What to test next →

22 readable studies in this cell: 9 favour the treatment, 11 find no difference, 2 favour the comparator.

Belief with this paper
0.50contested · 9 families support, 6 contradict · against placebo
Without it
0.50This paper does not move the number.
← favours the treatmentfavours the comparator →
1 · no effect
This paper’s trial, registry resultNCT01989754 · 5,813 enrolled · 2014
HR 0.720.55 to 0.94
This paper’s trial, registry resultNCT02065791 · 4,401 enrolled · 2014
HR 0.700.59 to 0.82
This paper4,330 enrolled · 2009
HR 0.910.75 to 1.09
NCT0546531762,197 enrolled · 2022
HR 0.750.65 to 0.86
NCT0399313226,774 enrolled · 2018
HR 1.010.91 to 1.11
NCT0173053417,190 enrolled · 2013
HR 0.930.84 to 1.03
NCT0493781616,746 enrolled · 2021
HR 1.000.83 to 1.20
NCT045096746,522 enrolled · 2020
HR 0.900.76 to 1.06
NCT036192136,263 enrolled · 2018
HR 0.820.73 to 0.92
NCT030579515,988 enrolled · 2017
HR 0.790.69 to 0.90
NCT045647424,017 enrolled · 2020
Win Ratio (WR) 1.341.20 to 1.50
NCT030579773,730 enrolled · 2017
HR 0.750.65 to 0.86
NCT043636972,401 enrolled · 2020
HR 0.860.68 to 1.08
NCT04157751530 enrolled · 2020
Stratified Win Ratio 1.361.09 to 1.68
NCT03436693308 enrolled · 2018
HR 0.600.23 to 1.55

SGLT2 inhibitors×all-cause mortality

InconclusiveOpen on the map →What to test next →

13 readable studies in this cell: 6 favour the treatment, 5 find no difference, 2 favour the comparator.

Belief with this paper
0.50contested · 5 families support, 4 contradict · against placebo
Without it
0.50This paper does not move the number.
← favours the treatmentfavours the comparator →
1 · no effect
This paper’s trial, registry resultNCT01989754 · 5,813 enrolled · 2014
HR 0.720.55 to 0.94
This paper’s trial, registry resultNCT02065791 · 4,401 enrolled · 2014
HR 0.700.59 to 0.82
This paper4,330 enrolled · 2009
HR 0.810.70 to 0.94
NCT0546531762,197 enrolled · 2022
HR 0.750.65 to 0.86
NCT0399313226,774 enrolled · 2018
HR 0.990.83 to 1.18
NCT0173053417,190 enrolled · 2013
HR 0.930.84 to 1.03
NCT045096746,522 enrolled · 2020
HR 0.900.76 to 1.06
NCT036192136,263 enrolled · 2018
HR 0.820.73 to 0.92
NCT030579515,988 enrolled · 2017
HR 0.790.69 to 0.90
NCT030579773,730 enrolled · 2017
HR 0.750.65 to 0.86
NCT043636972,401 enrolled · 2020
HR 0.860.68 to 1.08
NCT04157751530 enrolled · 2020
Stratified Win Ratio 1.361.09 to 1.68
NCT03436693308 enrolled · 2018
HR 0.600.23 to 1.55

SGLT2 inhibitors×adverse events & safety

SupportsOpen on the map →What to test next →

38 readable studies in this cell: 18 favour the treatment, 18 find no difference, 2 favour the comparator.

Belief with this paper
0.00contested · 0 families support, 26 contradict · against placebo
Without it
0.00This paper does not move the number.
← favours the treatmentfavours the comparator →
1 · no effect
This paper’s trial, registry resultNCT02065791 · 4,401 enrolled · 2014
HR 0.800.67 to 0.95
This paper4,330 enrolled · 2009
HR 3.052.13 to 4.35
NCT05162014494,679 enrolled · 2021
HR 0.880.76 to 1.02
NCT02864914333,580 enrolled · 2016
IRR 2.781.77 to 4.36
NCT0546531762,197 enrolled · 2022
HR 1.370.89 to 2.10
NCT0399313226,774 enrolled · 2018
HR 1.010.91 to 1.11
NCT0173053417,190 enrolled · 2013
HR 0.830.73 to 0.95
NCT0493781616,746 enrolled · 2021
HR 1.000.83 to 1.20
NCT045096746,522 enrolled · 2020
HR 0.900.76 to 1.06
NCT036192136,263 enrolled · 2018
HR 0.820.73 to 0.92
NCT030579515,988 enrolled · 2017
HR 0.930.85 to 1.01
NCT030579773,730 enrolled · 2017
HR 0.850.75 to 0.95
The sodium-glucose cotransporter-2 inhibitor canagliflozin does not in…PMID 37161691 · 2023
HR 1.060.94 to 1.19
Effects of canagliflozin on serum potassium in people with diabetes an…PMID 34423370 · 2021
HR 0.780.64 to 0.95
4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01032629 phase3completed

A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus

Ran2009Enrolled4,330Registered outcomes13Posted comparisons33ConditionsCardiovascular Diseases, Diabetes Mellitus, Type 2, Risk FactorsArmsCanagliflozin (JNJ-28431754) 100 mg, Canagliflozin (JNJ-28431754) 300 mg, Placebo
Open the trial in the graph
NCT01989754 phase4completed

A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects With Type 2 Diabetes Mellitus

Ran2014Enrolled5,813Registered outcomes3Posted comparisons3ConditionsAlbuminuria, Diabetes Mellitus, Type 2ArmsCanagliflozin, 100 mg, Canagliflozin, 300 mg, Placebo
Open the trial in the graph
NCT02065791 phase3completed

A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 Diabetes Mellitus and Diabetic Nephropathy

Ran2014Enrolled4,401Registered outcomes8Posted comparisons8ConditionsDiabetes Mellitus, Type 2, Diabetic NephropathyArmsCanagliflozin, Placebo
Open the trial in the graph
5 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Frailty and Cardiovascular Risk.European cardiology · 2026
    Review
  3. The use of SGLT2 inhibitors in older people: What is important?Aging clinical and experimental research · 2025
    Review
  4. Frailty Matters-Why Isn't It Guiding Clinical Decisions?Journal of the American Geriatrics Society · 2025
    Article
6 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

7 · Who and what money

Authors and funding

8 authors.

Tu N NguyenWestmead Applied Research Centre, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.ORCID 0000-0002-8836-8920
Jie YuThe George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
Vlado PerkovicThe George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
Meg JardineNHMRC Clinical Trials Centre, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
Kenneth W MahaffeyStanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California, USA.
Clara K ChowWestmead Applied Research Centre, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
Clare ArnottThe George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
Richard I LindleyWestmead Applied Research Centre, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Funding

National Health and Medical Research Council (NHMRC) Program Grant APP1149987
8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

backgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve renal and cardiovascular outcomes in patients with type 2 diabetes. Limited evidence exists about the efficacy and safety of SGLT2 inhibitors in patients with frailty.

methodsThis was a post hoc pooled, participant-level data analysis of the CANVAS Program (CANVAS and CANVAS-R) and the CREDENCE trial. We examined the effect of canagliflozin on: (1) Major adverse cardiovascular events (MACE), (2) Cardiovascular mortality, (3) all-cause mortality, and (4) key safety outcomes. Frailty was defined by a Frailty Index (FI) based on a deficit accumulation approach (FI > 0.25: frail). Cox proportional-hazard models were used to estimate the efficacy and safety of canagliflozin overall and according to frailty status.

resultsThere were 14,543 participants (10,142 from the CANVAS Program, 4401 from the CREDENCE trial). Their mean age was 63.2 years; 35.3% were female. Frailty was present in 56% of the study participants. The benefits of canagliflozin were observed in both the frail and non-frail subgroups: HRs for MACE 0.80 (95% CI 0.70-0.90) in the frail versus 0.91 (95% CI 0.75-1.09) in the non-frail (p for interaction = 0.27); HRs for cardiovascular mortality 0.79 (95% CI 0.67-0.95) in the frail versus 0.94 (95% CI 0.70-1.27) in the non-frail (p for interaction = 0.38); HRs for all-cause mortality 0.81 (95% CI 0.70-0.94) in the frail versus 0.93 (95% CI 0.74-1.16) in the non-frail (p for interaction = 0.39). Adverse events were similar among frail and non-frail participants, except for osmotic diuresis (HRs 1.67, 95% CI 1.22-2.28 in the frail vs. 3.05, 95% CI 2.13-4.35 in the non-frail, p for interaction = 0.01).

conclusionsCanagliflozin improved cardiovascular and mortality endpoints in participants with type 2 diabetes irrespective of frailty status, with a similar safety profile. Our findings, in addition to those from other recent studies, provide evidence to support the introduction of SGLT2 inhibitor therapy in patients perceived to be frail.

trial registrationClinicalTrials.gov CANVAS: NCT01032629; CANVAS-R: NCT01989754; CREDENCE: NCT02065791.

Indexed as

CanagliflozinDiabetes Mellitus, Type 2FrailtySodium-Glucose Transporter 2 InhibitorsAgedCardiovascular DiseasesFemaleFrail ElderlyHumansMaleMiddle AgedTreatment OutcomeCanagliflozinSodium-Glucose Transporter 2 Inhibitorsadverse outcomescanagliflozinCANVAS trialCREDENCE trialdiabetesfrailtysafety

Identifiers

PMID40105285
PMCPMC12205298

What Socratic holds

Texttitle and abstract
LicenceCC BY
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.