Range of adiposity and cardiorenal syndrome

Table 1 Classification of cardiorenal syndromes

Type	Primary and secondary organs and processes affected in the syndromes
	Primary	Secondary
Type 1	Cardiac impairment, acute	Renal impairment
Type 2	Cardiac impairment, chronic	Renal impairment
Type 3	Renal impairment, acute	Cardiac impairment
Type 4	Renal impairment, chronic	Cardiac impairment
Type 5	Systemic condition	Cardiac and renal impairment

Table 2 The range of adiposity - classifications and thresholds for white individuals

General adiposity (SAT and VAT) BMI, kg/m2	Thresholds and classification
< 24.9	Normal
25-29.9	Overweight
30-34.9	Class I
35-39.9	Class II
≥ 40	Class III
Central adiposity (VA)	Thresholds
WC	M: ≥ 94 cm, W: ≥ 80 cm
	Thresholds depend on BMI and ethnicity
Waist-to-height ratio (index of central obesity)	> 50 yr: ≥ 0.6, < 40 yr: ≥ 0.5
Waist-to-hip ratio	M: ≥ 0.9, W: ≥ 0.85
Neck circumference	M: ≥ 40.5 cm W: ≥ 34.2 cm
Sagittal abdominal diameter	> 30 cm correlates with CV risk
Visceral adiposity index[189]	The formula for M and W depends on WC,BMI, TG and HDL-cholesterol
Ectopic and parenchymal adiposity
Liver, epicardial and renal fat tissue	Continuous variable, MRI or TC

BMI: Body mass index; CV: Cardiovascular; M: Male; SAT: Subcutaneous adipose tissue; TG: Triglycerides; VAT: Visceral adipose tissue; W: Women; WC: Waist circumference; HDL: High-density lipoprotein; VA: Visceral adiposity.

Table 3 Major studies on the effect of bariatric surgery in heart failure outcomes

	Year, country	ParticipantsSurgical/Control	Follow-up Surgical procedures	HF type	HF and LV outcomes
Alpert et al[190]	1985, United States	62 vs none	4.3 ± 0.3 mo	NA	A decrease in LV dimensions
			Surgical gastric restriction.	(↑ LVS, ↑ LVpW)	Lower mean blood pressure
Ramani et al[131]	2008, United States	12 vs 10	1 yr	HFrEF (treated)	Lower hospital readmission
			Mostly LRYGB		LVEF improved
					NYHA improved
Miranda et al[130]	2013, United States	13 vs 6	4.3 yr	HFrEF 77%	Better Quality of life
			Mostly RYGB	HFpEF 23%	Better functional capacity
					Less leg edema
Vest et al[127]	2016, United States	38 vs 2588 non surgical obese	2.6 yr	HFrEF	Improvement in LVEF; 28% improved; LVEF > 10% vs < 1% control
			RYGB, AGB, SG
Shimada et al[126]	2016, United States	524 vs none	2 yr	NA	Lower rate of HF exacerbations (ED visits), 1 to 2 yr after surgery
					Lower rate of hospitalizations
Berger et al[191]	2018, Switzerland	676 (meta-analysis of surgery vs conventional treatment)	NA	NA	HR for the incidence of HF in MO without pre-existing HF 0.44 (0.36, 0.55) vs conventional treatment
					Reduced ED visits and readmission
					Increase left ventricular ejection
					Improve the quality of life and symptoms

AGB: Adjusted gastric banding; ED: Emergency department; HR: Hazard ratio; HF: Heart failure; L: Laparoscopic; LRYGB: Laparoscopic RYGB; LVEF: Left ventricular ejection fraction; LVpW: Left ventricular posterior wall; LVS: Left ventricular septum; NA: Not available; RYGB: Roux-en-Y gastric bypass; SG: Sleeve gastroplasty.

Table 4 Major studies onf the effect of bariatric surgery on renal outcomes

Authors	Year, countryFollow up	PatientsSurgical/control	Surgical procedure	Diabetes, CVD, RD	Outcomes
Serra et al[192]	2015, Spain (76 ± 42 mo)	92 vs none	GB	D2: 14%	No WRF
			Renal biopsy	Glomerulopathy 75%	A decrease in creatinine and albuminuria
					No progression (not related to glomerular lesions)
Neff et al[142]	201, France (1 and 5 yr)	190 vs 271	RYGB vs	D2: 39%. CVD:	Improvement in eGFR in both procedures
			LAGB	28%. CKD: 4%
					RYGB better in remission of hypertension
					RYGB better in diabetes
Nehus et al[143]	2017, United States	242 vs none	3 yr	D2: 12.6%	eGFR increased by 3.9 mL/min per 1.73 m2 for each 10-unit loss of BMI.
			RYGB 66.5%	Albuminuria: 17%
			SG: 27.7%		A decrease in ACR
			AGB: 5.8%
Wakamatsu[141]	2018, Japan	254	LSG 24	D2: 51%	Improvement of eGFRcys in mild CKD (eGFRcys ≥ 60 mL/min per 1.73 m2)
			LSG-DJB 94
			LRYGB 26
			LAGB 10
					NS: eGFRcys in moderate CKD (< 60 mL/min per 1.73 m2)
Solini et al[138]	2019, Italy	25 vs none	1 yr	No D2. No HTA	Improvement in mGFR
			RYGB		Improvement in a renal resistive index and correlates with mGFR
					Lowers carotid intima-media thickness
Inge et al[144]	2019, United States	Adoles vs adults	5 yr	D2: 14% vs 31%	HTA and D2 remissions are higher in adolescents than in adults. Rate of death (NS)
		161 vs 396	RYGB	HTA: 30% vs 61%

ACR: Albumin-creatinine ratio; AGB: Adjusted gastric banding; D2: Diabetes mellitus type 2; GB: Gastric bypass; L: Laparoscopic; LSG-DJB: Laparoscopic sleeve gastrectomy with duodenojejunal bypass; RYGB: Roux-en-Y gastric bypass; SG: Sleeve gastrectomy; mGFR: Medium glomerular filtration rate; CKD: Chronic kidney disease; CVD: Coronary artery disease, peripheral arterial, myocardial infarction, ischemic stroke, endarterectomy carotid; NS: Not significant.

Table 5 Recent major clinical trials of MRA in cardiorenal syndrome and their relationship with adiposity

Trial	n (follow-up)	BMI > 30 %	eGFR % < 60 mL/min	CVD(%) vs HF(%)	DM2	CV and RO (HR, significant)
EMPHASIS-HF[159] (eplerenone vs PBO)	2737 (21 mo)	27%	33%	70% (IHD)	31%	CVO1,2,3,4,5
				HFrEF (NYHAII)		RO: NS
						High WC: Greater benefit of eplerenone[163]
TOPCAT[96] (spironolactone vs PBO)	3445 (3.3 yr)	50%	39%	59%(IHD)	32%	CVO4
				HFpEF (NYHAII-IV)
TOPCAT post hoc[193] (BMI&NP categories)	997 (3.3 yr)	NR	NR	NR	NR	High BMI/high NP1,4,5
						High NP5
TOPCAT post hoc[166] (eGFR categories)	1767 (3.3 yr)	70%	53.4%	MI (20.3%)	44.5%	AE increased with declining eGFR eGFR ≥ 60 vs eGFR ≤ 451,2,4,5
FIDELIO-DKD[170] (finerenone vs PBO)	5734 (< 48 mo)	58%	87%	45.9% & 7.5 (HFpEF)	100%	Outcomes expected in 2020 (composite RO and secondary endpoints CV )
FIGARO-DKD[171] (finerenone vs PBO)	7437 (< 53 mo)	60%	38%	44.3% & 7.6% (HFpEF)	100%	Outcomes expected in 2021 (composite RO and secondary endpoints CV )
AMBER[167] (patiromer vs PBO)	295 (3 mo)	NR	100%	19.3% (MI) & 45% (HF)	49.1%	Les hyperkaliemia
						Less Spironolactone withdrawal

CVD: Coronary artery disease, peripheral arterial, myocardial infarction, ischemic stroke, endarterectomy carotid; BMI: Body mass index; HF: Heart failure; PBO: Placebo; CVO: Cardiovascular outcomes; eGFR: Estimated glomerular filtration rate; IHD: Ischemic heart disease; MI: Myocardial infarction; NP: Natriuretic peptide; RO: Renal outcomes; WC: Waist circumference; O: Outcomes; DM2: Diabetes mellitus type 2; NR: Not reported.

¹Primary outcome (composite^1,2,3).

²Mortality CV.

³Aborted cardiac arrest.

⁴Hospitalization for heart failure.

⁵Death from any cause.

Table 6 Major sodium-glucose cotransporter 2 inhibitors clinical trials and cardiorenal outcomes

Trial	n (follow-up)	BMI > 30	eGFR < 60 mL/min per 1.73 m2	CVD and HF	Diabetes	CVO and RO (HR; significant)
EMPA-REG[175] (empagliflozin vs PBO)	7020 (3.1 yr)	51%	25.9%	99.2% and 10.1%	About 100%	CVO1,2,3,4 RO6,7,8,9,10
CANVAS[172] (canagliflozin vs PBO)	10142 (2.4 yr)	59%	20,1%	65.6% and 14.4%	About 100%	CVO1,3 RO6,7,8,9
DECLARE-TIMI[174] (dapagliflozin vs PBO)	17160 (4.2 yr)	60%	7.4%	40.6% and 10%	About 100%	CVO1,3 RO6,7
CREDENCE[173] (canaglifozin vs PBO)	4401 (2.6 yr)	54.4%	60%	50.4% and 15%	52%	RO6,7,8,9 CVO1,2,3,4
DAPA-HF[176] (dapagliflozin vs PBO)	2373 (18.2 mo)	35%	26.1%	55.5% (IHD) and 100% (HFrEF)	41%	CVO1,2,3 RO: NS HFrEF: Better dapagliflozin
DAPA-CKD[194] (dapagliflozina vs PBO)	4304 (NA)	NA	About 90%	NA	Non-DM: ≥ 30%	Outcomes expected in 2020 (composite renal and secondary CV endpoints)
EMPEROR-Preserved[195] (empagliflozin vs PBO)	5988 (NA)	NA	NA (eGFR ≥ 20)	HFpEF (100%)	NA	Outcomes expected late in 2020 (composite CV, HF and secondary R endpoints)
EMPEROR-Reduced[196] (empaglifozin vs PBO)	3730 (NA)	NA	NA (eGFR ≥ 20)	HFrEF (100%)	NA	Outcomes expected late in 2020 (composite CV, HF and secondary RO)

¹Composite of worsening heart failure or cardiovascular death.

²Cardiovascular death.

³Heart failure hospitalization.

⁴Major adverse cardiovascular events (MACE) (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). ⁵Extended MACE.

⁶Composite renal outcomes (doubling of serum creatinine, ≥ 40% (or 50%) decrease in estimated glomerular filtration rate (eGFR), new end-stage renal disease (ESRD), or death from renal or cardiovascular causes.

⁷New ESRD (chronic dialysis or renal transplant).

⁸Sustained reduction of ≥ 40% eGFR.

⁹Progression to macroalbuminuria.

¹⁰Doubling of serum creatinine levels. BMI: Body mass index; ACR: Albumin-to-creatinine ratio; CV: Cardiovascular; CVO: Cardiovascular outcomes; eGFR: Estimated glomerular filtration rate; ERSD: End-stage renal disease; HR: Hazard ratio; NA: Not available; PBO: Placebo; R: Renal; RO: Renal outcomes; NS: Not significant; O: Outcomes; HF: Heart failure; HFrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; CVD: Coronary artery disease, peripheral arterial, myocardial infarction, ischemic stroke, endarterectomy carotid.

Table 7 Major GLP-1 clinical trials and cardiorenal outcomes

Trial	n(follow-up)	BMI >30 %	eGFR %< 60 mL/min	CVD% vsHF%	DM2	CVO & RO (HR, significant)
LEADER[197] (liraglutide vs PBO)	9340 (3.8 yr)	61%	23.1%	81% vs 14% (NYHAII-III)	ALL	CVO12
						RO6: Reduction in progression to Macroalbuminuria
FIGHT[183] (liraglutide vs PBO)	300 (180 d)	50%	40%	100% vs 100%HFrEF (NYHAIII-IV)	59%	CVO:NS
						RO: Increase in cystatin C in the liraglutide group
SUSTAIN-6[198] (Semaglutide vs PBO)	3297 (2.1 yr)	64%	28.5%	83% vs 24%	ALL	CVO1245
						RO6: Reduction in progression to macroalbuminuria
EXSCEL[199] (exenatide-ER vs PBO)	14752 (3.2 yr)	63%	21.6%	73% vs 16%	ALL	CVO: NS; RO: NA
HARMONY OUTCOMES[200] (Albiglutide vs PBO)	9463 (1.6 yr)	62%	NA	100% vs 20%	ALL	CVO13; RO: NA
REWIND[201] (dulaglutide vs PBO)	9901 (5.4 yr)	46%	22%	31.5% vs 9% (NYHAII-III)	ALL	CVO14
						RO6: Reduction in Macroalbuminuria and eGFR (dulaglutide group)
PIONEER 6[202]	3183 (1.33 yr)	60%	26.9%%	85% vs 12%	ALL	CVO12 for noninferiority

¹Expanded composite cardiovascular outcome.

²Cardiovascular death.

³Non-fatal myocardial infarction.

⁴Non-fatal stroke.

⁵Revascularization.

⁶Composite Renal Outcomes (Composite new onset of macroalbuminuria, sustained decline in eGFR of ≥ 30%, a persistent doubling of serum creatinine, ESRD or new chronic renal replacement therapy comprising dialysis or renal transplantation, death attributable to renal causes). ⁶New macroalbuminuria or proteinuria. BMI: Body mass index; CVO: Cardiovascular outcomes; eGFR: Estimated glomerular filtration rate; RO: Renal outcomes; O: Outcomes; DM2: Diabetes mellitus type 2; NA: Not available; PBO: Placebo; NS: Not significant; HR: Hazard ratio; CVD: Coronary artery disease, peripheral arterial, myocardial infarction, ischemic stroke, endarterectomy carotid; HF: Heart failure.