De-Intensification of Antidiabetic Treatment Using Canagliflozin in Patients with Heart Failure and Type 2 Diabetes: Cana-Switch-HF Study

Round 1

Reviewer 1 Report

The manuscript entitled "De-intensification of antidiabetic treatment using Canagliflozin in patients with heart failure and type 2 diabetes: Cana-Switch-HF Study" submitted by Luis M Pérez-Belmonte and colleagues is focused on the role of the SLGT2 inhibitor Canagliflozin in heart failure protection in T2DM patients. The authors show that the administration of this drug does improves not only Diabetes but also the emergency calls and hospitalizations for heart failure. SGLT2 inhibitors are considered new antidiabetic treatments with high potential, and here the authors show another positive effect of their use. Despite the study limitations already commented by the authors in the discussion section and the minor issues indicated below, I consider that the manuscript has enough quality for publication in Journal of Clinical Medicine.

1. An introduction to the topic is missed in the Abstract
2. The weakest point that I found in the manuscript is, although the emergency calls and hospitalizations for heart failure significantly decreased, the percentage was still high. I would suggest including some data in the Discussion section about the average rate in the whole population to compare the numbers.
3. Are there differences according to gender and age? It would be interesting to include or mention some of these data, although it is not part of the study's aim.

 

Author Response

Annie Chen

Assitant Editor

Journal of Clinical Medicine

 

April 27, 2021

 

Dear Assistant Editor Annie Chen:

 

Thank you for reviewing and considering our manuscript, “De-intensification of antidiabetic treatment using Canagliflozin in patients with heart failure and type 2 diabetes: Cana-Switch-HF Study” for possible publication in the Journal of Clinical Medicine. We greatly appreciate the comments provided to us by the reviewers.

 

We have made revisions to our manuscript, according the recommendations of the reviewers, and are now resubmitting it to you for your consideration. The reviewers’ comments and our corresponding responses are listed below.

 

Thank you very much for your kind attention on this matter.

 

Sincerely

 

Corresponding authors on behalf of all co-authors.

Luis M. Pérez-Belmonte, MD, PhD

Sergio Jansen-Chaparro, MD, PhD.

 

 

 

 

 

 

 

 

 

 

 

 

 

Responses to Reviewers’ Comments:

 

Reviewer #1:

 

The manuscript entitled "De-intensification of antidiabetic treatment using Canagliflozin in patients with heart failure and type 2 diabetes: Cana-Switch-HF Study" submitted by Luis M Pérez-Belmonte and colleagues is focused on the role of the SLGT2 inhibitor Canagliflozin in heart failure protection in T2DM patients. The authors show that the administration of this drug does improves not only Diabetes but also the emergency calls and hospitalizations for heart failure. SGLT2 inhibitors are considered new antidiabetic treatments with high potential, and here the authors show another positive effect of their use. Despite the study limitations already commented by the authors in the discussion section and the minor issues indicated below, I consider that the manuscript has enough quality for publication in Journal of Clinical Medicine.

 

1. An introduction to the topic is missed in the Abstract

Authors’ reply: We have included a short introduction in the Abstract as follows: “Canagliflozin is a sodium-glucose co-transporter 2 inhibitor that reduces glycemia as well as the risk of cardiovascular events.”

 

2. The weakest point that I found in the manuscript is, although the emergency calls and hospitalizations for heart failure significantly decreased, the percentage was still high. I would suggest including some data in the Discussion section about the average rate in the whole population to compare the numbers.

Authors’ reply: We have included some data in the Discussion section about the percentages of emergency department visits and hospitalizations due to HF at 12 months after the switch obtained in our study as follows: “Despite these reductions, the percentages of emergency department visits and hospitalizations due to HF at 12 months after initiation of canagliflozin were still high (39.1% and 27.0%, respectively).”

 

3. Are there differences according to gender and age? It would be interesting to include or mention some of these data, although it is not part of the study's aim.

Authors’ reply: Although age and sex differences were not part of the study’s aim, we have mentioned that there were no differences according to age or sex in the Results as follows:

“Similar results were observed in the study outcomes when patients were grouped according to mean age (<65 vs ≥65 years old) and sex (male vs female).”

 

Author Response File: Author Response.docx

Reviewer 2 Report

The author's Pérez-Belmonte et al. describes the de-intensification and measuring the glycemic effects of substituting antidiabetic medicines with canagliflozin in the participants with type 2 diabetes and heart disease. Few major concerns need to be addressed.

 

1. Methods sections need to be elaborated on with participants' age range, gender, and other details.  
2. In the result section Table, 1 shows the ejection fraction (EF). It is essential to provide fractional shortening (FS) to see the correlation with EF.  
3. Table 1 and Table 2, heart failure medication section, the percentage of Diuretic (90.1%) is not correct. The correct result is 90.9%. Please make the changes.
4. Statistical analysis in Table 2 is not appropriately performed. Bodyweight data shows only significant with 12 months compared to baseline. The rest of the groups are not showing significant as claimed by the authors. Similarly, BMI, waist circumference, and KCCQ total symptom score did not show significant with 3 months. The author redoes the statistical analysis and modifies Table 2.

Author Response

Annie Chen

Assitant Editor

Journal of Clinical Medicine

 

April 27, 2021

 

Dear Assistant Editor Annie Chen:

 

Thank you for reviewing and considering our manuscript, “De-intensification of antidiabetic treatment using Canagliflozin in patients with heart failure and type 2 diabetes: Cana-Switch-HF Study” for possible publication in the Journal of Clinical Medicine. We greatly appreciate the comments provided to us by the reviewers.

 

We have made revisions to our manuscript, according the recommendations of the reviewers, and are now resubmitting it to you for your consideration. The reviewers’ comments and our corresponding responses are listed below.

 

Thank you very much for your kind attention on this matter.

 

Sincerely

 

Corresponding authors on behalf of all co-authors.

Luis M. Pérez-Belmonte, MD, PhD

Sergio Jansen-Chaparro, MD, PhD.

 

 

 

 

 

 

 

 

 

 

 

 

 

Responses to Reviewers’ Comments:

 

Reviewer #2:

 

The author's Pérez-Belmonte et al. describes the de-intensification and measuring the glycemic effects of substituting antidiabetic medicines with canagliflozin in the participants with type 2 diabetes and heart disease. Few major concerns need to be addressed.

 

1. Methods sections need to be elaborated on with participants' age range, gender, and other details.  

Authors’ reply: We have included in the Methods section information about age range, gender, and other details as follows:

“We carried out an observational, retrospective, real-world study on 121 outpatients with HF and T2D with poor glycemic control at the HF Unit of the Internal Medicine Department at the Hospital Regional Universitario de Málaga in Málaga, Spain, and the Hospital Helicopteros Sanitarios in Marbella, Spain.

The mean age was 64.7 ± 11.9 years (range: 44.0-84.0) and the percentage of male was 68.9%. All patients included had history of HF and T2D, HbA1c levels between 7.0% and 9.5%, and unmodified antidiabetic treatment with metformin in combination with ≥2 non-insulin antidiabetic agents or metformin in combination with basal insulin plus ≥1 non-insulin antidiabetic agent for at least three months. Patients treated with SGLT2 inhibitors and other insulin regimens were excluded. Non-insulin antidiabetic agents (excluding metformin) were replaced with canagliflozin 100 mg/day, which could be increased up to 300 mg/day during follow-up if HbA1c remained >7% or the healthcare providers considered it appropriate according to their clinical judgment. All patients received general recommendations during follow-up for following a healthy diet and doing physical activity according to their functional class. Antihypertensive treatment, diuretics, and lipid-lowering agents were modified if required as per the healthcare providers’ judgment.

Patients were followed-up on at 3, 6, and 12 months after starting canagliflozin. A wide range of sociodemographic, anthropometric (body weight, body mass index (BMI), and waist circumference), clinical (T2D duration and therapy, HF duration, principal cause, left ventricular ejection fraction, fractional shortening and medication, and previous medical history including history of smoking, history of alcohol abuse, hypertension, dyslipidemia, chronic kidney disease stage ≥3, cerebrovascular disease, chronic obstructive pulmonary disease and atrial fibrilacion), therapeutic (any reduction in doses or number of HF medications), and laboratory variables (basal fasting blood glucose; serum creatinine; estimated glomerular filtration rate measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula; uric acid; hematocrit; LDL, HDL, and total cholesterol; triglycerides; N-terminal pro-brain natriuretic peptide (NT-proBNP); and urinary albumin/creatinine ratio) was recorded at each evaluation. Other variables gathered after switching were HF health status, estimated using the total symptom score on the Spanish version of the Kansas City Cardiomyopathy Questionnaire (KCCQ) [10]; vascular risk, estimated using the Framingham equation adapted for the Spanish population (Registre Gironí del COR (Girona Heart Registry)), the REGICOR Study [11]); fatty liver disease, estimated using the Fatty Liver Index (FLI) [12]; adverse drug reactions; hypoglycemic episodes, as defined by the American Diabetes Association criteria [13]; need for canagliflozin discontinuation due to adverse events; 3-point major adverse cardiovascular events (3P-MACE) (composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death); emergency department visit due to HF; hospitalizations (all-cause and for HF); and mortality (for cardiovascular and noncardiovascular causes).”

 

2. In the result section Table, 1 shows the ejection fraction (EF). It is essential to provide fractional shortening (FS) to see the correlation with EF.  

Authors’ reply: We have added the fractional shortening in Table 1. See Table 1 below.  

 

3. Table 1 and Table 2, heart failure medication section, the percentage of Diuretic (90.1%) is not correct. The correct result is 90.9%. Please make the changes.

Authors’ reply: Thank you very much for providing this correction. We have corrected the result in both tables. See Table 1 and Table 2 below.

 

4. Statistical analysis in Table 2 is not appropriately performed. Bodyweight data shows only significant with 12 months compared to baseline. The rest of the groups are not showing significant as claimed by the authors. Similarly, BMI, waist circumference, and KCCQ total symptom score did not show significant with 3 months. The author redoes the statistical analysis and modifies Table 2.

Authors’ reply: Thank you very much for providing this correction. We have corrected the result in Table 2.

 

Table 1. Baseline sociodemographic and clinical-therapeutic characteristics.

 

Variables	n=121
Sociodemographic characteristics
Age (years)	64.7 ± 11.9
Male	83 (68.9%)
Diabetes characteristics
Diabetes duration (years)	13.5 ± 4.8
Diabetes therapy   Metformin   Sulfonylurea   Meglitinide   Thiazolidinediones   DPP4 inhibitor   GLP-1 receptor agonist   Basal insulin	108 (89.3%) 45 (37.2%) 15 (12.4%) 0 110 (90.9%) 11 (9.1%) 58 (47.9%)
Statins	109 (90.1%)
Heart failure characteristics
Heart failure duration (years)	4.5 ± 2.1
Principal cause of heart failure   Ischemic   Nonischemic   Unknown	70 (57.9%) 42 (34.7%) 9 (7.4%)
Left ventricular ejection fraction (%)	44.1 ± 10.1
Left ventricular ejection fraction <40%	58 (47.9%)
Fractional shortening (%)	21.9 ± 7.8
Heart failure medication   Diuretic   ACE inhibitor   ARB   Sacubitril-valsartan   Beta-blocker   Mineralocorticoid receptor antagonist   Digitalis	110 (90.9%) 51 (42.1%) 30 (24.8%) 40 (33.1%) 101 (83.5%) 68 (56.2%) 12 (9.9%)
Previous medical history
History of smoking	63 (52.1%)
History of alcohol abuse	31 (25.6%)
Hypertension	108 (89.3%)
Dyslipidemia	102 (84.3%)
Chronic kidney disease stage ≥3	31 (25.6%)
Cerebrovascular disease	13 (10.7%)
Chronic obstructive pulmonary disease	48 (39.7%)
Atrial fibrillation	39 (32.2%)

 

Table 2. Treatment de-intensification, glycemic control, anthropometric characteristics, heart failure health status, vascular risk, fatty liver disease, laboratory variables, adverse drug reactions, and major complications.

Variables	Baseline (n=121)	3 months’ follow-up (n=119)	6 months’ follow-up (n=116)	12 months’ follow-up (n=115)
Treatment de-intensification
Number of antidiabetic agents	3.1 ± 1.0	2.1 ± 0.9*	2.1 ± 0.9*	2.1 ± 0.8*
GLP-1 receptor agonist	11 (9.1%)	12 (10.1%)	12 (10.3%)	12 (10.4%)
Basal insulin dose (Units/day)	20.1 ± 9.8	16.6 ± 8.8*	12.8 ± 7.1†	10.1 ± 6.5†
Basal insulin	58 (47.9%)	57 (47.9%)	42 (36.2%)†	36 (31.3%)†
Diuretic	110 (90.9%)	105 (88.2%)	95 (81.9%)*	93 (80.9%)*
Glycemic control
Fasting blood glucose (mg/dL)	157.8 ± 41.3	141.8 ± 62.8†	122.8 ± 47.4‡	118.7 ± 40.1‡
HbA1c (%)	8.1 ± 0.8	7.6 ± 1.2*	7.1 ± 1.3†	6.9 ± 1.2†
Patients with HbA1c <7%	-	20 (16.8%)*	58 (50%)‡	73 (63.5%)‡
Anthropometric characteristics
Body weight (kg)	88.7 ± 14.3	86.8 ± 13.0	84.7 ± 12.4*	83.4 ± 11.2†
Body Mass Index (kg/m2)	32.4 ± 5.6	31.5 ± 4.5	30.2 ± 4.0*	29.2 ± 3.7†
Body Mass Index ≥30	51 (42.1%)	46 (38.7%)	40 (34.5%)*	34 (29.6%)†
Waist circumference (cm)	112.1 ± 15.4	109.0 ± 12.1	105.2 ± 11.4†	103.1 ± 10.1†
SBP (mmHg)	141.1 ± 17.6	138.5 ± 12.9	135.4 ± 10.9	133.5 ± 10.5
DBP (mmHg)	73.9 ± 9.2	71.2 ± 8.2	69.4 ± 7.9	68.5 ± 7.5
Heart rate (bpm)	69.6 ± 7.4	70.0 ± 7.9	65.3 ± 6.8	68.6 ± 7.2
HF health status
KCCQ total symptom score	62.2 ± 24.8	69.1 ± 25.3	72.2 ± 26.8*	75.9 ± 28.0†
NYHA functional class   I   II   III	0 75 (62.0%) 46 (38.0%)	5 (4.2%) 84 (70.6%)* 30 (25.2%)*	6 (5.2%) 86 (74.1%)† 24 (20.7%)†	6 (5.2%) 91 (79.1%)† 18 (15.7%)†
Vascular risk	18.9 ± 12.4	12.9 ± 6.9*	10.3 ± 5.8*	8.5 ± 5.1†
Fatty liver index	79.9 ± 22.1	70.2 ± 16.7*	68.8 ± 15.1*	63.0 ± 13.2†
Laboratory variables
Creatinine (mg/dL)	0.93 ± 0.41	0.82 ± 0.44	0.85 ± 0.43	0.83 ± 0.43
EGFR (ml/min/1.73 m2)	75.8 ± 16.2	71.3 ± 19.1	73.2 ± 18.1	76.9 ±18.7
Uric acid (mg/dL)	6.4 ± 1.6	6.0 ± 2.0	6.0 ± 1.3	5.5 ± 1.2*
Hematocrit (%)	30.0 ± 5.8	31.1 ± 5.9	32.2 ± 6.1	33.8 ± 7.0*
LDL cholesterol (mg/dL)	84.5 ± 28.5	68.5 ± 21.4†	68.2 ± 21.0†	66.7 ± 20.1†
HDL cholesterol (mg/dL)	37.0 ± 11.5	38.3 ± 10.4	40.4 ± 10.2	43.4 ± 11.2*
Total cholesterol (mg/dL)	159.0 ± 33.2	145.0 ± 29.3*	144.1 ± 30.0*	129.3 ± 26.7†
Triglycerides (mg/dL)	187.7 ± 49.9	183.0 ± 42.5	175.8 ± 38.3*	158.8 ± 31.5†
NT-proBNP (pg/mL)	1175.5 ± 423.1	636.0 ± 452.3†	645.2 ± 432.1†	610.0 ± 398.2†
Urinary albumin/creatinine ratio (mg/g)	59.8 ± 19.3	32.5 ± 10.0†	24.7 ± 9.7†	14.3 ± 6.2†
Safety variablesa
Adverse drug reaction of interest	-	8 (6.6%)	12 (8.3%)	15 (12.4%)
Urinary tract infections	-	3	5	7
Genital mycotic infections	-	5	7	8
Discontinuation of canagliflozin	-	2 (1.7%)	5 (4.1%)	6 (5.0%)
Major complicationa
3P-MACE	-	0	3 (2.5%)	4 (3.3%)
Emergency department visit due to HF	61 (50.4%)	12 (10.1%)	24 (20.7%)	45 (39.1%)*
Hospitalization   Due to HF   All-cause	48 (39.7%) 10 (8.3%)	11 (9.2%) 0	17 (14.7%) 0	31 (27.0%)* 2 (1.7%)*
Mortality   Cardiovascular cause   Noncardiovascular cause	-	0 0	3 (2.5%) 0	4 (3.3%) 1 (0.8%)
HF hospitalization and cardiovascular mortality	-	11 (9.2%)	20 (17.2%)	35 (30.4%)

 

 

 

Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript by Belmonete et al is informative and well written. It covers the use of canagliflozin as an alternative to metformin, the most commonly used antidiabetic drug. As per provided results, it seems that canagliflozin has some benefits and can be safely used in patients with diabetes and heart failure. The study has some pitfalls, but these are addressed in the last section of the paper. I recommend this manuscript. 

Author Response

Annie Chen

Assitant Editor

Journal of Clinical Medicine

 

April 27, 2021

 

Dear Assistant Editor Annie Chen:

 

Thank you for reviewing and considering our manuscript, “De-intensification of antidiabetic treatment using Canagliflozin in patients with heart failure and type 2 diabetes: Cana-Switch-HF Study” for possible publication in the Journal of Clinical Medicine. We greatly appreciate the comments provided to us by the reviewers.

 

We have made revisions to our manuscript, according the recommendations of the reviewers, and are now resubmitting it to you for your consideration. The reviewers’ comments and our corresponding responses are listed below.

 

Thank you very much for your kind attention on this matter.

 

Sincerely

 

Corresponding authors on behalf of all co-authors.

Luis M. Pérez-Belmonte, MD, PhD

Sergio Jansen-Chaparro, MD, PhD.

 

 

 

 

 

 

 

 

 

 

 

 

 

Responses to Reviewers’ Comments:

 

Reviewer #3:

 

The manuscript by Belmonte et al is informative and well written. It covers the use of canagliflozin as an alternative to metformin, the most commonly used antidiabetic drug. As per provided results, it seems that canagliflozin has some benefits and can be safely used in patients with diabetes and heart failure. The study has some pitfalls, but these are addressed in the last section of the paper. I recommend this manuscript. 

Authors’ reply: Thank you for reviewing our manuscript.

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The article may be accepted.