Clinical trial NCT03597035
Conditions: Type2 Diabetes Hyperkalemia
Sponsor: University Hospitals Cleveland Medical Center
Start date: 2018-07-17; Completion date: 2020-07-31
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patiromer add-on to a mineralocorticoid receptor antagonist (MRA) in patients with Type 2 diabetes mellitus and chronic kidney disease (CKD) will reduce blood pressure and left ventricular (LV) mass to a greater extent compared to patients with MRA alone and favorably affect key secondary hemodynamic and inflammatory variables including atherosclerosis progression.

Atherosclerosis is the leading cause of morbidity and mortality in Type II diabetes. A cell type called the monocyte/macrophage is critical to development and complications of atherosclerosis.

This project will evaluate the effectiveness of a medication called Spironolactone in addition to Patiromer in preventing atherosclerosis in Type II diabetes through its effects on cells such as the monocyte. Spironolactone has been demonstrated to be effective for the treatment of patients after a heart attack and stroke. The investigators will evaluate the impact of Spironolactone in combination with Patiromer in reducing atherosclerosis plaque and additionally evaluate its potential in changing inflammation.

The investigators envision that a strategy of simultaneously probing effect of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design hard event (heart attack, stroke etc.) based trials.

Detailed description:
There is substantial interest in preventing cardiovascular (CV) and renal disease progression in the Type 2 diabetic. Activation of the renin angiotensin aldosterone axis (RAS) and the mineralocorticoid receptor (MR) results in pro-inflammatory effects. Further the phenomenon of aldosterone escape provides a rationale for MR antagonism in addition to an ACEI/ARB agent. Agents that target the renin-angiotensin aldosterone system (RAAS) cascade have shown benefit in Type 2 Diabetics although combined RAS blockade such as using ACEI+ARB or ACEI/ARB+Renin inhibition have met with failure primarily owing to adverse effects such as hypotension and renal failure/hyperkalemia requiring dialysis. It has been speculated that dual RAS blockade or use of ACEI/ARB in conjunction with MRA may potentially be beneficial if one controls hyperkalemia and/or avoid excess hypotension. As a foundation for this current proposal, the investigators have demonstrated an important role for RAAS and MR antagonism in reducing atherosclerosis and inflammation in experimental animal models and limited studies in humans. The investigators are currently testing the efficacy of Spironolactone in reducing atherosclerosis on top of ACEI/ARB in high-risk patients with type 2 diabetes (T2DM) with concomitant CKD as part of a Randomized Double-blind controlled clinical trial. Given the fact that as much as 20-40% of a diabetic patient population with CKD may have problems of hyperkalemia on spironolactone, particularly those already on angiotensin converting enzyme inhibitor (ACEI)/ARB therapy, that would preclude their participation in this trial, the investigators would like to propose an open label supplemental arm to where patients who are ineligible for participation owing to baseline hyperkalemia or hyperkalemia on the dose escalation phase will be eligible to participate in the PRIMARY-Add on trial. The addition of Patiromer will enable introduction of MRA therapy at therapeutic doses and avoidance of hyperkalemia. The investigators thus propose a prospective open label trial with blinded assessment of end-points (PROBE) study which test the relative safety and efficacy of Patiromer on top of Spironolactone in T2DM on LV mass regression and occurrence of hypokalemia (Co-Primary End-points) as well as its effect on 24-hour ambulatory blood pressure (ABP) at 6 weeks, central aortic blood pressure at 6 weeks, atherosclerosis progression at 12 months and measures of monocyte inflammatory potential. If successful, the studies outlined in this proposal will extend the utility of Patiromer in high-risk diabetics at risk for future CV events and provide new information.

Arms: arm 1: Single arm experimental study in 50 diabetic patients with chronic kidney disease and hyperkalemia.
Interventions: intervention 1: Spironolactone
Intervention descriptions: intervention 1: The study participants will receive concomitant treatment with Veltassa 8.4 grams per day and Spironolactone 25 mg per day or maximum tolerated dose. If dictated by the potassium level, Veltassa can be increased to 16.8 grams per day.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number:  02-17-16
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Revised 1 April 2020
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Clinical Research Protocol
MINERALOCORTICOID RECEPTOR ANTAGONISM CLINICAL EVALUATION 
IN ATHEROSCLEROSIS ADD ON (MAGMA ADD-ON)
Protocol Number:
02-17-16
Funding Organization:
Relypsa
Principal Investigator:
Name: Sanjay Rajagopalan, MD
E-mail: sanjay.rajagopalan@UHhospitals.org  
Co- Investigator
Name: Mirela Dobre, MD
E-mail: Mirela.Dobre@UHhospitals 
Name: Chris Longenecker, MD
Email: Chris.Longenecker@UHhospitals
Name: Edward Horwitz, MD
Email: ehorwitz@metrohealth.org
Medical  Monitor
Name: Matthew Weir, MD
E-mail: mweir@medicine.umaryland.edu 
Medical Monitor
Name: Jeffrey Fink, MD
E-mail:jfink@medicine.umaryland.edu 


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TABLE OF CONTENTS
1
SUMMARY....................................................................................................................................4
2
BACKGROUND ............................................................................................................................5
2.1
PRELIMINARY STUDIES .......................................................................................................................6
3
STUDY RATIONALE .................................................................................................................10
3.1
RISK / BENEFIT ASSESSMENT............................................................................................................11
4
STUDY OBJECTIVES ................................................................................................................12
4.1
PRIMARY OBJECTIVE ........................................................................................................................12
4.2
SECONDARY OBJECTIVES..................................................................................................................12
5
STUDY DESIGN..........................................................................................................................12
6
CRITERIA FOR EVALUATION................................................................................................13
6.1
AIM 1A PROTOCOL ...........................................................................................................................13
6.2
AIM 2 MONOCYTE AND INFLAMMATION STUDIES..............................................................................16
6.3
SAFETY EVALUATIONS......................................................................................................................16
7
SUBJECT SELECTION..............................................................................................................17
7.1
STUDY POPULATION .........................................................................................................................17
7.2
INCLUSION CRITERIA ........................................................................................................................17
7.3
EXCLUSION CRITERIA .......................................................................................................................17
7.4      RECRUITMENT STRAEGY……………………………………………………………………...18
7.5 
MULTI-SITE RESEARCH …………………………………………………………………………….18
8
CONCURRENT MEDICATIONS...............................................................................................18
8.1
PROHIBITED MEDICATIONS AND TREATMENTS .................................................................................18
9
STUDY TREATMENTS..............................................................................................................18
9.1
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................18
9.2
BLINDING..........................................................................................................................................18
9.3
FORMULATION OF TEST AND CONTROL PRODUCTS...........................................................................18
9.4
STUDY DRUG ACCOUNTABILITY.......................................................................................................19
9.5
MEASURES OF TREATMENT COMPLIANCE.........................................................................................19
10
HYPERKALEMIA MANAGEMENT.........................................................................................19
10.1
TREATMENT OF HYPERKALEMIA FOR POTASSIUM > 5.0 MEQ/L: DIETARY POTASSIUM .................20
10.2
TREATMENT OF HYPERKALEMIA FOR POTASSIUM > 5.5 MEQ/L ....................................................21
10.3
TREATMENT OF HYPERKALEMIA FOR POTASSIUM > 6.0 MEQ/L ....................................................21
11
STUDY PROCEDURES AND GUIDELINES.............................................................................22
11.1
SCHEDULE OF EVENTS..................................................................................................................22
11.2
CLINICAL ASSESSMENTS ..............................................................................................................23
11.3
CLINICAL LABORATORY MEASUREMENTS ...................................................................................23
11.4
URGENT STUDY ALERTS ..............................................................................................................23
12
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ......................................24
12.1
ADVERSE EVENTS ........................................................................................................................24


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12.2
SERIOUS ADVERSE EXPERIENCES (SAE)......................................................................................26
12.3
MEDICAL MONITORING................................................................................................................26
13
DISCONTINUATION OF SUBJECTS .......................................................................................27
13.1
EARLY DISCONTINUATION OF STUDY DRUG ................................................................................27
14
DATA SAFETY MONITORING.................................................................................................27
15
STATISTICAL METHODS AND CONSIDERATIONS ............................................................27
16
DATA COLLECTION, RETENTION AND MONITORING.....................................................28
16.1
DATA COLLECTION INSTRUMENTS...............................................................................................28
16.2
DATA MANAGEMENT PROCEDURES .............................................................................................28
16.3
ARCHIVAL OF DATA.....................................................................................................................28
16.4
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ................................................28
16.5
SUBJECT CONFIDENTIALITY .........................................................................................................29
17
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................................29
17.1
INFORMED CONSENT FORM..........................................................................................................29
17.2
PUBLICATIONS..............................................................................................................................29
17.3
REFERENCES ................................................................................................................................30


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1
SUMMARY
Patiromer add-on to an MRA in patients with Type 2 diabetes mellitus and CKD will 
reduce blood pressure and LV mass to a greater extent compared to patients with MRA 
alone and favorably affect key secondary hemodynamic and inflammatory variables 
including atherosclerosis progression. 
Atherosclerosis is the leading cause of morbidity and mortality in Type II diabetes. A cell 
type called the monocyte/macrophage is critical to development and complications of 
atherosclerosis. 
This project will evaluate the effectiveness of a medication called Spironolactone in 
addition to Patiromer in preventing atherosclerosis in Type II diabetes through its effects 
on cells such as the monocyte. 
Spironolactone has been demonstrated to be effective for the treatment of patients after a 
heart attack and stroke.  We will evaluate the impact of Spironolactone in combination 
with Patiromer in reducing atherosclerosis plaque and additionally evaluate its potential in 
changing inflammation. 
We envision that our strategy of simultaneously probing effect of a drug combined with 
analysis of mechanisms of action and predictive response will likely provide key 
information with which to design hard event (heart attack, stroke etc.) based trials.


Protocol Number:  02-17-16
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2
BACKGROUND
Hyperkalemia is a condition that frequently occurs in patients with Type 2 Diabetes with 
chronic kidney disease (CKD). Patients at the highest risk for hyperkalemia are those 
taking renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or higher 
CKD. Clinicians frequently either avoid using RAAS inhibitors or use them at lower than 
recommended doses in these patient populations and as a consequence these patients, 
who are often the highest risk from a cardiovascular (CV) and renal disease perspective 
are often not on RAAS antagonists and/or blockers of the mineralocorticoid receptor 
(MR). Patiromer is an orally administered drug approved for the treatment of 
hyperkalemia. The active moiety, a nonabsorbed polymer that binds potassium in the 
gastrointestinal tract, increases fecal excretion of potassium and lowers serum potassium 
levels. Previous Phase 2 and 3 studies in the CKD population and those with concomitant 
Diabetes and CKD population have demonstrated the safety of this drug and the ability to 
introduce RAAS antagonists without fear of precipitating hyperkalemia. Additionally, 
continued lowering of blood pressure along with reduction in aldosterone levels have 
been demonstrated. There is substantial interest in preventing CV and renal disease 
progression in the Type 2 diabetic. Activation of the renin angiotensin aldosterone axis 
(RAS) and the mineralocorticoid receptor (MR) results in pro-inflammatory effects. 
Further the phenomenon of aldosterone escape provides a rationale for MR antagonism in 
addition to an ACEI/ARB agent. Agents that target the RAAS cascade have shown 
benefit in Type 2 Diabetics although combined RAS blockade such as using ACEI+ARB 
or ACEI/ARB+Renin inhibtion have met with failure primarily owing to adverse effects 
such as hypotension and renal failure/hyperkalemia requiring dialysis. It has been 
speculated that dual RAS blockade or use of ACEI/ARB in conjunction with MRA may 
potentially be beneficial if one controls hyperkalemia and/or avoid excess hypotension. 
As a foundation for this current proposal, we have demonstrated an important role for 
RAAS and MR antagonism in reducing atherosclerosis and inflammation in experimental 
animal models and limited studies in humans. We are currently testing the efficacy of 
Spironolactone in reducing atherosclerosis on top of ACEI/ARB in high-risk patients 
with T2DM with concomitant CKD as part of a Randomized Double-blind controlled 
clinical trial. Given the fact that as much as 20-40% of a diabetic patient population with 
CKD may have problems of hyperkalemia on spironolactone, particularly those already 
on ACEI/ARB therapy, that would preclude their participation in this trial, we would like 
to propose an open label supplemental arm to where in patients who are ineligible for 
participation owing to baseline hyperkalemia or hyperkalemia on the dose escalation 
phase will be eligible to participate in the PRIMARY-Add on trial. The addition of 
Patiromer will enable introduction of MRA therapy at therapeutic doses and avoidance of 
hyperkalemia. We thus propose a prospective open label trial with blinded assessment of 
end-points (PROBE) study which test the relative safety and efficacy of Patiromer on top 
of Spironolactone in T2DM on LV mass regression and occurrence of hypokalemia (Co-
Primary End-points) as well as its effect on 24-hour ABP at 6 weeks, central aortic blood 
pressure at 6 weeks, atherosclerosis progression at 12 months and measures of monocyte 
inflammatory potential. If successful, the studies outlined in this proposal will extend the 
utility of Patiromer in high-risk diabetics at risk for future CV events and provide new 
information. 


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 2.1
Preliminary Studies
RESEARCH STRATEGY 
Pharmacological studies over > 20 years have defined the importance of the RAAS 
system in hypertension and heart failure. A number of trials have validated the use of MR 
antagonists in the management of patients with heart failure (RALES, EMPHASIS) and 
post myocardial infarction (EPHESUS)(1-4). Recent studies suggest that MR may link 
metabolic dysregulation with susceptibility to type II diabetes (T2DM) and 
atherosclerosis(5-12). MR is an ancient member of the 51-member, steroid-thyroid-
retinoid receptor family. In response to ligand binding, MR undergoes conformational 
changes and is translocated to the nucleus where it binds to response elements in 
promoters, increasing transcription of target genes (13, 14). Despite its importance, the 
utilization of MR antagonists (MRAs) in clinical practice is abysmally low owing the 
perception that these agents cause excessive hypokalemia. Patiromer is a nonabsorbed 
anion polymer that exchanges a calcium-sorbitol counter ion for potassium cations in the 
GI lumen. Binding of free potassium in the GI tract leads to a decrease in serum potassium 
levels. Patiromer binds to 8.5 to 8.8 mEq of potassium per gram of polymer at a pH 
similar to that found in the colon and has a much higher potassium-binding capacity 
compared with other resins, including polystyrene sulfonate. In a series of Phase 2 and 3 
clinical trials in patients with CKD, concomitant diabetes and heart failure, often 
necessitating concomitant therapies with RAAS blockers, Patiromer was shown to be 
effective in reducing potassium.(15-19) Recently Patiromer was shown to reduce 
aldosterone levels in patients receiving RAAS blockers suggesting that this strategy may 
be effective in lowering aldosterone levels in patients at risk and potentially providing a 
rationale to use this agent in patients Type 2 DM in conjunction with MR antagonists 
given the benefits of reducing MR activation articulated below. (Weir et al. Kidney 
International 2016. In press). 
Cardiovascular Effects of MR Activation: MR is widely expressed in the cardiovascular 
system (20-23) and is a major determinant of endothelial function, smooth muscle tone, 
vascular remodeling, fibrosis and blood pressure (BP)(24-37). In vitro, animal, and human 
data support a role for MR activation in promoting vascular oxidative stress, 
inflammation, proliferation, migration, vasoconstriction, vascular remodeling and fibrosis 
(FIGURE. 1)(5, 29, 32, 37-45). 
Similarly, MR antagonism is anti-
inflammatory and antifibrotic with 
evidence in humans indicating reversal of 
endothelial dysfunction, diastolic 
dysfunction and vascular stiffness (46-50). 
The visceral adipose renin-angiotensin-
aldosterone (RAS) system synthesizes aldo, 
expresses MR, and predicts IR in both 
humans and animal models (7, 51, 52). MR 
expression on macrophages could 
potentially play a pro-inflammatory role in 


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tissues such as adipose and vasculature.(53-56) MR blockade/deletion has been shown in 
both experimental and human studies to ameliorate IR (57-59). MR activation may affect 
IR through multiple mechanisms that include attenuation of insulin signaling in the heart, 
vasculature, and skeletal muscle. This may include impairment of expression of insulin 
receptor and substrate, decreased GLUT4 expression, abnormal phosphorylation of IRS, 
and activation of multiple stress kinases downstream of insulin receptor/IRS (leading to 
attenuation of insulin signaling)(60-63). MR activation also promotes hepatic oxidative 
stress, gluconeogenesis and enhances hyperglycemia (64). Recently, MR activation has 
been shown to promote lipid storage in brown adipose and inhibit UCP1 expression (65, 
66). Consistent with these roles, MR antagonism in humans improves IR (57-59, 67). 
Relevant to this proposal we have provided evidence for a role for MR in pro-
inflammatory macrophage phenotype and reduction in atherosclerosis in animal models. 
MR activation potentiates classical activation while deletion of MR or antagonism results 
in AΩ (68). 
CV Trials in Type 2 DM: T2DM is recognized as a high-risk population for future CV 
events. However the risk is heterogenous with multiple factors determining risk in the 
diabetic. These factors include age, duration of diabetes, presence of concomitant risk 
factors, target organ damage and concomitant therapies including use of statins, RAAS 
blockers etc. It is widely felt that the presence of concomitant CKD characterizes a patient 
population at unusually high risk (right hand extreme of FIGURE 2) and this population 
presents many unique challenges. Importantly, very few therapies have been shown to be 
beneficial in preventing CV and renal disease progression. Angiotensin receptor blockers 
and possibly ACEI may reduce progression of renal disease and could potentially prevent 
occurrence of CV events although recent trials of RAS antagonism have been less 
conclusive than trials conducted 2 decades ago. There is good mechanistic data 
implicating continued activation of the RAAS cascade in diabetic CKD.(69) However 
trials of dual blockade or use of Renin inhibitors on top of ACEI/ARB have not been 
successful and have noted a higher incidence of mortality, hyperkalemia and 
hypotension.(69) One pathway that has been suspected to underlie the heightened risk 
posed by more complete RAAS blockade (defined as treatments that lower activation of 
the RAAS through the use of 2 or more agents such as an ACEI/ARB-MRA or 
ACEI/ARB+Renin inhibitor) is hyperkalemia. 


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FIGURE 2. Mortality rates in Type 2 DM trials. The highlighted trials are for dual RAS blockade that 
were terminated early owing to excess mortality noted with these studies. 
Hyperkalemia with RAAS Therapy: High doses of angiotensin-converting enzyme 
inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), are recommended as first 
line treatment for diabetic nephropathy by various guidelines in light of their consistent 
cardioprotective role. Similarly there is emerging consensus that MRA on top of 
ACEI/ARB therapy may be beneficial as aldosterone typically is not completely 
suppressed. Indeed in HF patients and those with prior MI with LV dysfunction the 
guidelines do emphasize a Class I indication. However many patients especially diabetics 
with concomitant CKD are unable to tolerate these drugs particularly when given 
concomitantly. Effective hyperkalemia management with Patiromer may allow physicians 
to initiate and/or maintain optimal therapy with RAAS blockers. In the Phase II/III clinical 
trial experience with Patiromer, its co-administration with RAAS blockade safely and 
conveniently prevented RAAS-induced hyperkalemia and allowed full dose RAAS 
blockade to continue. A beneficial effect of the RAAS inhibitor was seen in reducing the 
level of proteinuria and blood pressure in patients with diabetes and renal disease. In the 
AMETHYST-DN trial effectively controlled serum potassium levels thereby allowing 
optimum treatment with RAAS inhibitors for up to one year. Indeed treatment with 
Patiromer reduced aldosterone levels and together with an MRA may allow complete 
inhibition of MR activation. 
Patiromer Efficacy in CKD and Dosing Considerations: In the open-label 
AMETHYST-DN trial, reductions in serum potassium levels achieved with patiromer, 
persisted through 52 weeks of treatment.(15) In a continuation phase of the single-blind 
OPAL-HK trial, 107 patients whose serum potassium levels had fallen below 5.1 mEq/L 
after 4 weeks of treatment with patiromer were randomized to continue receiving the drug 


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or switch to placebo. The median increase in serum potassium levels after 8 weeks, the 
primary endpoint, was significantly greater in patients switched to placebo than in those 
who continued taking the active drug (0.72 vs 0.00 mEq/L). Patients who continued 
receiving patiromer were less likely to experience recurrent hyperkalemia than those 
switched to placebo (15% vs 60%) and more likely to remain on a RAAS inhibitor (94% 
vs 44%).(17) In another study in 25 patients with hyperkalemia and chronic kidney 
disease, patiromer 8.4 g twice daily significantly decreased serum potassium levels as 
early as 7 hours after administration of the first dose (-0.21 mEq/L). After 48 hours, mean 
levels had dropped by 0.75 mEq/L.(18)The Phase 3 studies confirm that the 16.8 g per day 
dose is reasonable is patients with mild hyperkalemia (defined as potassium concentration 
>5.0 to 5.5 mEq/L at baseline or at any time during dose titration] while a starting dose of 
16.8 g/d is reasonable in patients with moderate hyperkalemia [potassium concentration 
>5.5 to <6.0 mEq/L]). The mean reduction in K+ with doses in AMETHYST-DN with 
this dose was 0.51 (95% CI, 0.38-0.64) mEq/L in the mild hyperkalemia group and 0.87 
(95% CI, 0.60-1.14) mEq/L in the moderate hyperkalemia group. 
Risk of Hypokalemia/Hypomagnesemia with Patiromer: In the PEARL-HF trial, the 
incidence of hypokalemia was 5% in the 30 g/d fixed dose group compared to 0% of the 
placebo group (titration of Patiromer was not allowed). The incidence of hypomagnesemia 
was 24% and 2% in the placebo group. In an open-label of Patiromer (RLY5016-204 
trial), the starting dose of RLY5016 was 20 g/d and was titrated at weekly visits according 
to potassium level. With careful titration and follow-up, only one of 63 patients developed 
hypokalemia (serum K+<3.5), which was promptly reversed by decreasing the dose of 
Patiromer. Hypomagnesemia (serum Mg2+< 1.8 mg/dL) occurred in 8/63 (13%) of 
patients. In AMETHYST-DN, over the 52 week duration of the trial, hypomagnesemia 
(7.2%) was the most common treatment-related adverse event, with hypokalemia (<3.5 
mEq/L) occurring in 5.6% of patients.
3
STUDY RATIONALE
There is substantial interest in preventing CV and renal disease progression in the Type 2 
diabetic. Activation of the renin angiotensin aldosterone axis (RAS) and the 
mineralocorticoid receptor (MR) results in pro-inflammatory effects. Further the 
phenomenon of aldosterone escape provides a rationale for MR antagonism in addition to 
an ACEI/ARB agent. Agents that target the RAAS cascade have shown benefit in Type 2 
Diabetics although combined RAS blockade such as using ACEI+ARB or 
ACEI/ARB+Renin inhibtion have met with failure primarily owing to adverse effects 
such as hypotension and renal failure/hyperkalemia requiring dialysis. It has been 
speculated that dual RAS blockade or use of ACEI/ARB in conjunction with MRA may 
potentially be beneficial if one controls hyperkalemia and/or avoid excess hypotension. As 
a foundation for this current proposal, we have demonstrated an important role for RAAS 
and MR antagonism in reducing atherosclerosis and inflammation in experimental animal 
models and limited studies in humans. We are currently testing the efficacy of 
Spironolactone in reducing atherosclerosis on top of ACEI/ARB in high-risk patients with 
T2DM with concomitant CKD as part of a Randomized Double-blind controlled clinical 


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trial. Given the fact that as much as 20-40% of a diabetic patient population with CKD 
may have problems of hyperkalemia on spironolactone, particularly those already on 
ACEI/ARB therapy, that would preclude their participation in this trial, we would like to 
propose an open label supplemental arm to where in patients who are ineligible for 
participation owing to baseline hyperkalemia or hyperkalemia on the dose escalation 
phase will be eligible to participate in the PRIMARY-Add on trial. The addition of 
Patiromer will enable introduction of MRA therapy at therapeutic doses and avoidance of 
hyperkalemia. We thus propose a prospective open label trial with blinded assessment of 
end-points (PROBE) study which test the relative safety and efficacy of Patiromer on top 
of Spironolactone in T2DM on LV mass regression and occurrence of hypokalemia (Co-
Primary End-points) as well as its effect on 24-hour ABP at 6 weeks, central aortic blood 
pressure at 6 weeks, atherosclerosis progression at 12 months and measures of monocyte 
inflammatory potential. If successful, the studies outlined in this proposal will extend the 
utility of Patiromer in high-risk diabetics at risk for future CV events and provide new 
information. 
3.1
Risk / Benefit Assessment
All potential patients will be informed of the potential side effect profile prior to 
enrollment in the study and full informed consent will be utilized.
3.1.1
Risks of an MRI Scan
There are no risks associated with the MRI scan. In our center approximately 10% of 
patients are genuinely claustrophobic. Side Effects Related to Study Drug
3.1.2 Reproductive Risks
Spironolactone may cause risks to the unborn fetus and or the baby of a nursing mother. 
Therefore, pregnant women and women who are nursing their babies should not 
participate in the study. Woman must be either post-menopausal for one year, surgically 
sterile, or using effective contraception. A pregnancy test will be required at screening for 
all woman who may become pregnant. A negative test is required for the individual to 
enroll in the study. Participants who become pregnant will report to the study PI 
immediately, and stop taking the pills. 
Spironolactone can decrease the effectiveness of birth control pills. Women who use oral 
birth control methods will be excluded from the study. Women of child bearing potential 
should use another reliable form of contraception. Acceptable methods of birth control 
include subcutaneous implants, intrauterine devices (IUD), barrier methods, surgical 
sterility, transdermal birth control path, and abstinence.
3.1.1.1
Common Side Effects

Hyperkalemia:  We anticipate that approximately 1% of patients may develop 
serious hyperkalemia that may warrant discontinuation.  However this may be 
considerably higher in patients with GFR of 40-50 ml/minute who will constitute a 
minority of the patients in the trial. 

Increases in BUN and creatinine


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
Hypomagnesemia 

Gynecomastia or breast discomfort. Gynecomastia is a well-described adverse 
effect of spironolactone and is related to dose and duration of treatment; we 
anticipate that approximately 10% of patients may develop gynecomastia that may 
warrant discontinuation. Generally, discontinuation of treatment results in 
resolution of gynecomastia.
3.1.1.2
Other Side Effects

Cardiovascular: Vasculitis

Central nervous system: Ataxia, confusion, drowsiness, headache, lethargy

Dermatologic: Erythematous maculopapular rash, Stevens-Johnson syndrome, 
toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Amenorrhea

Gastrointestinal: Abdominal cramps, diarrhea, gastritis, gastrointestinal 
hemorrhage, gastrointestinal ulcer, nausea, constipation, flatulence, vomiting

Genitourinary: Impotence, irregular menses, postmenopausal bleeding

Hematologic & oncologic: Agranulocytosis, malignant neoplasm of breast

Hepatic: Hepatotoxicity

Hypersensitivity: Anaphylaxis

Immunologic: DRESS syndrome

Renal: Increased BUN, renal failure, renal insufficiency

Miscellaneous: Fever
3.1.2
Potential Benefits of the Proposed Research to the Subjects and Others
It is possible that there may be a benefit with Spironolactone in terms of organ protection 
and patients may see benefits relating to reduction of atherosclerotic plaque including 
reduction in risk for events such as heart attacks, stroke, renal failure and need for 
hospitalization. The potential benefits must obviously be contrasted with the risk for renal 
failure and hyperkalemia.  Adding Patiromer to Spironolactone in patients with Type 2 
diabetes mellitus and chronic kidney disease may reduce blood pressure and left 
ventricular mass to a greater extent compared to patients with Spironolactone alone, and 
favorably affect key secondary hemodynamic and inflammatory variables including 
atherosclerosis progression. 
3.1.3
Importance of the Knowledge to be Gained
There is an urgent need for clinical trials aimed at reducing the disproportionate 
cardiovascular disease burden and mortality in Type II diabetes. The multiple 
cardiovascular benefits of mineralocorticoid receptor (MR) blockade (using 
spironolactone or eplerenone) are well recognized in patients without Type II diabetes in 


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the setting of congestive heart failure or myocardial infarction. However, randomized 
trials of MR Blockade have not been conducted in patients with atherosclerosis. A 
potential role for MR blockade for slowing atherosclerosis progression as well as 
influencing cardiovascular outcomes in diabetic patients is only beginning to attract the 
attention of cardiologists.  Patients with atherosclerosis may benefit from MR blockade if, 
on one end of the spectrum, such intervention is made relatively early in the course of 
Type II diabetes to slow progression and of atherosclerosis and inflammation or plausibly 
at the other extreme when patients are already at very high risk patient population for 
cardiovascular events and mortality. The use of Spironolactone in conjunction with 
Patiromer in patients with type II diabetes and atherosclerosis has not been well studied.  
The addition of Patiromer will enable introduction of MRA therapy at therapeutic doses 
and avoidance of hyperkalemia. 
3.2
Safety Evaluations
Change in clinical laboratory findings (e.g. BUN, Creatinine, electrolytes).
Incidence of adverse events.
4. STUDY OBJECTIVES
4.1 Primary Objective
Specific Aim 1: To conduct a prospective open label proof-of-concept clinical trial in 50 
patients with Type II diabetes evaluating the effects of MRA + Patiromer on LV mass and 
plaque regression over 12 months of treatment by MRI.  Primary outcome measures will 
be change in LV mass of patients receiving Patiromer + Spironolactone at the end of 12 
months and end-point of safety during this period.  An additional co-primary measure will 
include percent change in atheroma volume (PAV) in the thoracic aorta on Patiromer + 
Spironolactone at the end of 12 months.  Additional secondary measures will include 
central aortic blooc pressure, 24-hour mean systolic blood pressure and measures of 
insulin resistance (HOMA-IR) at 12 weeks.
4.2 Secondary Objective
Specific Aim 2: To compare monocyte polarization and inflammatory activation (flow 
cytometry and gene expression) after 6 weeks of Patiromer therapy.  Specific Aim 2b: 
Results from this aim will help provide insights into mechanisms of disease progression 
and preservation of pathways by Patiromer.
5. STUDY DESIGN
OVERALL STUDY DESIGN AND EXECUTION 
This will be a multicenter trial that will provide a logical extension to a recently funded 
NIH sponsored trial to assess efficacy of Spironolactone in patients with Type 2 DM and 
CKD (GFR 20-90ml/m2) compared to placebo (NCT02169089). In this extension study to 


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NCT02169089, patients with GFR 20-70 ml/m2 who are hyperkalemic at baseline (with 
or without RAAS therapy) precluding an MRA and/or develop hyperkalemia on an MRA 
(FIGURE 3) will be enrolled and placed on Spironolactone. The primary efficacy 
variables being LV mass change and in patients treated with Patiromer and MRA. Our 
hypothesis is that Patiromer use in conjunction with an MRA will result in more effective 
blood pressure lowering, LV mass regression and plaque regression due to more effective 
lowering of aldosterone and inflammation. The primary safety variable is development of 
serious hyperkalemia on treatment in Patiromer+Spironolactone arm. Several secondary 
variables will be obtained, including monocyte-macrophage inflammatory indices, central 
aortic blood pressure and 24-hour blood pressure at 6 weeks and arterial compliance. 
  
Figure 3.
6. CRITERIA FOR EVALUATION
6.1
Aim 1A Protocol 
Cardiac and aortic MRI images will be obtained at Visit 2 and Visit 8. Patients will be 
imaged on a 3T 32-channel whole-body MR imaging system (Trio 3.0T, Siemens, 
Erlangen) with maximum gradient amplitude of 60 mT/m and a slew rate of 400 
mT/m/ms. The system’s integrated body coil will be used for radiofrequency signal 
transmission. Signal reception will be accomplished with the use of two flexible 6-element 
phase array body coil matrix in combination with the spine coil. After acquiring the low 
resolution, images for localization, each patient will undergo trueFISP cine imaging (8–10 
short axis and 3 LV long axis with 20–30 cardiac phases depending on heart rate). 
Additional details on sequence parameters are provided on the Manual of operations. 
Following acquisition of cardiac MRI images, fat suppressed 3D turbo-spin echo (TSE) 
images using, dark blood acquisition protocol, based on SPACE sequence with 1mm3 
resolution. MRI parameters are as follows: TR/TE= R-R interval/22ms, field of view 
FOV=320x272 mm2, slices per slab 56, averages =1.7, bandwidth-BW=781Hz/px, echo 
spacing=2.9ms, turbo factor= 45, echo train/slice=3. 
Quantitative evaluation: 
LV mass estimation: the images from the participating sites will be loaded onto a 
dedicated workstation (Leonardo™, Siemens Medical Solutions, Erlangen, Germany). 
Using specialized software (Argus™, Siemens Medical Solutions, Erlangen, Germany), 
the short-axis views of the heart will be automatically sorted into slice positions (rows) 


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and cardiac phases (columns). End-diastole (ED) and end-systole (ES) will be visually 
identified as those phases with maximum and minimum area in a midventricular short-
axis view of the LV cavity, using the position of the mitral and aortic valve as an aid to 
identify the phase of the cardiac cycle. The images will be cropped and zoomed to 
enhance detection of the myocardium-blood pool and myocardium-fat interfaces. 
Endocardial contours will be traced automatically in each of the short-axis views both in 
ED and ES. To improve the accuracy of the measurement, subsequent manual correction 
will be performed. In addition, the epicardial contour will be traced in ED. The papillary 
muscles will be included within both contours and considered ventricular wall, as this 
method has proven close agreement with pathologic quantifications of myocardial mass 
(70-72). The contours will lie on the ventricular “side” of the interface myocardium-blood 
(72). One of the major sources of variability in the analysis of LV function is the correct 
determination of the most basal slice of the LV, as this moves during the cardiac cycle 
with longitudinal shortening of the heart in systole (73). In our experience, the LV base is 
typically located in one slice position in ED and in the contiguous more apical slice in ES. 
The determination of the most basal slice of the LV both in ED and ES will be aided by 
simultaneous display of the slice position overlaying the four-chamber cine image used to 
prescribe the short-axis slices. An equivalent approach will be used for the most apical 
segment. The criteria for inclusion of the basal slice will follow standard 
recommendations (74): a rim of ventricular myocardium has to encircle at least 50% of 
the blood pool area; if both ventricular and atrial myocardium are clearly seen in the same 
slice, both ends of the ventricular wall are joined by a straight line and the resulting 
portion is included in the LV quantification; the LV outflow tract is included up to the 
level of the aortic valve. The sum of the areas contained inside the endocardial contours in 
ED and ES in each slice, multiplied by the section thickness (Simpson’s method) yields 
the left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV 
respectively) (74, 75). No geometrical assumptions are made and therefore the method can 
be used in the presence of segmental abnormalities (76). The software automatically adds 
the interslice gap to the slice thickness. The same approach will be used to calculate LV 
myocardial volume, defined as the volume between the endocardial and epicardial 
contours, subsequently multiplied by the specific density of the myocardium (1.05 g/cm3) 
to obtain LV mass (70). The LV mass will be obtained systematically from ED images 
(71). Left ventricular stroke volume (LVSV) is calculated as LVEDV-LVESV, and the 
LVSV times the heart rate will be used to derive the cardiac output (CO). Left ventricular 
ejection fraction (LVEF) will be quantified using the formula: (LVSV/LVEDV)*100. 


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Plaque Volume Calculation: For each patient MRI images acquired from baseline and 
post studies will be co-registered on a workstation (FUSION, Siemens Healthcare, Inc.). 
Multiplanar images perpendicular to the aorta will be generated from both data sets at the 
same location and evaluated using a custom designed plaque analysis tool (Terarecon, 
CA). A dedicated and trained technician will perform manual measurements of lumen 
cross section area (LCSA) and media-adventia cross section area or MCSA. Vessel wall 
area measurements will be generated by subtracting the luminal area from outer border of 
the vessel wall for the images. Total Plaque Area (TPA) at each time point (1-baseline, 2-
post-treatment) for each patient will be defined as the sum of the difference between 
media-adventitia cross section area (MCSA) and the lumen cross section area (LCSA) in 
each slice. The change in total plaque volume (TPV) and the percentage change (%
TPV or PAV) for each of the two groups (Spiro and Placebo) will be calculated as 
follows: 
Formula 1: Derivation of total plaque area (TPA)
TPA = 
. Using Formula 1 we will obtain TPAbase(baseline) and 
∑𝑁 𝑝𝑎𝑡𝑖𝑒𝑛𝑡(𝑀𝐶𝑆𝐴‒ 𝐿𝐶𝑆𝐴)
TPApost(post-treatment) for each patient, where Npatient is the number of slices per patient. 
To account for different number of acquired slices in different patients, the atherosclerotic 
plaque volume (TPV) for each patient at each time point will be normalized to the median 
number of slices in that group (N median-group) as shown below in Formula 2. 
Formula 2: Derivation of total plaque volume (TPV) 
TPV =
. We will then obtain 
 (baseline) and 
(end-of 
𝑍×
𝑁𝑚𝑒𝑑𝑖𝑎𝑛‒ 𝑔𝑟𝑜𝑢𝑝
𝑁𝑝𝑎𝑡𝑖𝑒𝑛𝑡
× 𝑇𝑃𝐴
𝑇𝑃𝑉𝑏𝑎𝑠𝑒
𝑇𝑃𝑉𝑝𝑜𝑠𝑡
treatment) for each patient; Z=slice thickness. The change in total plaque volume (∆
 ) and percentage change in total plaque volume (%∆
 ) in each group 
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
(Spiro/placebo) will be calculated as indicated in Formula 3 (A and B). 
Formula 3: Derivation of absolute change (∆
 ) and percent change in atheroma 
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
volume (PAV or %∆
) 
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
∆
=
-
)          (A)
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
1
𝑁𝑔𝑟𝑜𝑢𝑝∑𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠(𝑇𝑃𝑉𝑝𝑜𝑠𝑡𝑇𝑃𝑉𝑏𝑎𝑠𝑒
 = %∆
 = 100×
 = 100×
   (B)
𝑃𝐴𝑉𝑔𝑟𝑜𝑢𝑝
𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
1
𝑁𝑔𝑟𝑜𝑢𝑝∑𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠
𝑇𝑃𝑉𝑝𝑜𝑠𝑡‒ 𝑇𝑃𝑉𝑏𝑎𝑠𝑒
𝑇𝑃𝑉𝑏𝑎𝑠𝑒
∆𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
𝑇𝑃𝑉𝑏𝑎𝑠𝑒‒ 𝑔𝑟𝑜𝑢𝑝
where 
 is the number of patients in the group. PAV or % change in total 
𝑁𝑔𝑟𝑜𝑢𝑝
atheroma volume= Primary end-point 
To account for possible different median number of slices 
 of the two 
𝑁𝑚𝑒𝑑𝑖𝑎𝑛‒ 𝑔𝑟𝑜𝑢𝑝
groups, the normalized total plaque volume change in Spiro and placebo will be 
additionally calculated as: 
 = 
×
.
𝑁𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑 ∆𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
∆𝑇𝑃𝑉𝑔𝑟𝑜𝑢𝑝
𝑁𝑚𝑒𝑑𝑖𝑎𝑛‒ 𝑔𝑟𝑜𝑢𝑝
𝑁𝑚𝑒𝑑𝑖𝑎𝑛‒ 𝑜𝑝𝑜𝑠𝑖𝑡𝑒‒ 𝑔𝑟𝑜𝑢𝑝


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Secondary End-points: Patients will undergo 24-hour ABP and Central Aortic Blood 
pressures using a validated device (Oscar 2™system from SunTech Medical®), 
measuring BP at 15–minute intervals during the day (07.00 h–22.00 h) and at 30–minute 
intervals during the night (22.00 h–07.00 h), was used to measure ABPM. 
Aldosterone and HOMA-IR measurements after overnight fast after resting for 30 minutes 
after arrival and prior to IV placement and/or MR assessment. Fasting (9 hour) basal 
insulin sensitivity will be measured by the validated HOMA-IR index. HOMA-IR = 
insulin (μU/mL)x glucose (mmol/L))/22.5] (77). 24-hour ABP will be performed at visit 2 
and visit 6. 
6.2
Aim 2 Monocyte and Inflammation Studies: Peripheral blood mononuclear cells 
(PBMC) will be isolated via and purified with anti-human CD14 mAb immobilized on 
magnetic beads using the MACS system (Miltenyi Biotec) and purity confirmed by flow 
cytometry. Isolated cells will be lysed for RNA purification (see below). A portion of the 
PBMCs will be frozen at -80°C in RPMI medium with 20% FBS and 10% DMSO 
(1x107cells/vial) for concurrent future flow analysis. This protocol has been shown to not 
affect future analysis of surface marker staining (78). We have considerable experience 
performing flow analysis in batched frozen monocytes to enhance reproducibility. 
Multicolor flow cytometry analysis will be performed using Anti-human CD14, CD16, 
CD206, and CD163 antibodies (BD Biosciences). Analysis will initially enumerate the 
quantity of CD14hiCD16lo, CD14hiCD16hi and CD14loCD16hi monocytes which are similar 
to what has been described (79). The CD14hiCD16hi and CD14loCD16hi monocytes are 
believed to represent inflammatory monocytes in the human. Isolated mRNA will be 
analyzed for classic inflammatory genes (M1) M2 markers (alternate activation) as well as 
candidate miRs. 
6.3  
Safety Evaluations

Change in clinical laboratory findings (e.g. BUN, Creatinine, electrolytes).

Incidence of adverse events
7. SUBJECT SELECTION
7.1
Study Population
Subjects with a diagnosis of Type II Diabetes who meet the inclusion and exclusion 
criteria will be eligible for participation in this study.  Labs drawn within 3 months of the 
screening visit may be used to determine eligibility.
7.2
Inclusion Criteria
1.  Male or female patients > 45 or > 40 years with known atherosclerotic events 
(examples include MI, Stroke) and able to provide informed consent (females must 
be either post-menopausal for one year, surgically sterile, or using effective 
contraception. Oral contraceptives are disallowed.
2. Patients with type II diabetes with HbA1c ≤ 9.0 on stable anti-glycemic regimen 


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that may include oral and/or injectable therapy (GLP-1/Insulin etc.). Changes in 
dose of glycemic regimen is allowed during the course of the trial if felt to be 
clinically appropriate. 
3. GFR <70 and evidence of proteinuria (Urine Albumin/Creatinine Ratio of >30 mg/g 
or equivalent) in a urine specimen within 12 months OR GFR <60 mg/g regardless 
of proteinuria
4. Patients must be on ACE and/or ARB therapy with no planned dose adjustments. 
5. Serum K+≥ 4.6 meq/L at visit 0 (screening).
7.3
Exclusion Criteria
1. Uncontrolled hypertension (SBP>160 and/or DBP>95 mmHg at visit 0 (screening) 
and SBP >145 mm Hg at visit 2).
2. GFR (MDRD) of <15 at visit 0 (screening)
3. K+ <4.6 meq/L at visit 0 (screening). 
4. LDL cholesterol >150 mg/dL
5. Plasma triglycerides > 400 mg/dl
6. Contraindications to MRI (metallic implants, severe claustrophobia).
7. Acute coronary syndrome, Transient ischemic attack, CVA or critical limb ischemia 
during the last 6 months or coronary/peripheral revascularization within the last 3 
months.
8. Evidence of a secondary form of hypertension.
9. Initiation of new therapy with statins, ACEI/ARB, antioxidants, CCBs, diuretics, β 
blockers. 
10. Type I diabetes mellitus
11. Known contraindication, including history of allergy to Spironolactone or Patiromer
12. Any surgical or medical condition which might alter pharmacokinetics of drug (e.g. 
renal transplant, liver failure, liver transplant) 
13. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia.
14. Significant hyponatremia defined as Na <130 meq/L.
15. History of prior malignancy including leukemia and lymphoma (but not basal cell 
skin cancer, cured squamous cell cancer and cured prostate cancer).
16. History of any severe, life-threatening disease.
17. Any surgical or medical conditions which place the patient at higher risk derived 
from his/her participation into the study, or likely to prevent patient from complying 
with requirements.
18. History of drug abuse within the last 2 years, noncompliance and 
unwillingness/inability to consent.
19. Pregnant women and nursing mothers
20. Class III or IV Congestive Heart Failure
21. Primary Hyperaldosteronism
7.4 Recruitment Strategy
All patients will be carefully evaluated for study eligibility during screening and will be 
recruited from clinics at University Hospitals’ healthcare systems. The medical records 


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will be accessed to determine eligibility. PHI will be accessed during the pre-screening 
portion for medical review. A full waiver is requested. The 2 -week run-in-phase- period 
will permit assessment of patient compliance as well as determination of baseline sitting 
blood pressures. Patients must have met all inclusion/exclusion criteria before starting any 
parts of the study phase. We may call patients who have expressed interest in the study, 
using an approved phone script. No cold calling will be done. The phone script will be 
used for patients who would like to be contacted regarding more information about the 
study after their physician has given them some initial background in person or by letter.
Patients will also be recruited from referrals of the private practice of Tom Tanphaichitr, 
MD. 
7.5 Multi-Site Research 
MAGMA Add On is a multi-site study that includes NYU Winthrop, University of
Maryland, and MetroHealth Systems. NYU Winthrop and the University of Maryland are 
responsible for their own local IRB while UH will be the IRB of record for MetroHealth 
System.
In addition to University Hospital CMC recruited patients, UH clinical staff including, 
DCRU nurses, clinical coordinators, radiology technicians, and PI(s) will also be 
responsible for assisting Visit 2 & 8 for Metro Health. A research coordinator from Metro
Health will be primarily in charge of the coordination of the visit which includes escorting 
the patient, documentation, and record keeping.
8
HEALTH WILL BE PRIMARILY IN CHARGE OF THE 
COORDINATIOCONCURRENT MEDICATIONS
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible.  
Changes in dose of glycemic regimen is allowed during the course of the trial if felt to be 
clinically appropriate.
Patients must be on ACE and/or ARB therapy and statin therapy with no planned dose 
adjustments.
8.1
Prohibited Medications and Treatments
The following medications are prohibited during the study:
Oral contraceptives
9
STUDY TREATMENTS
9.1
Method of Assigning Subjects to Treatment Groups
Up to 50 eligible patients will participate in the study.  All study participants will undergo 
a two week run-in period with Patiromer.  Then study medication will be commenced at 
12.5 mg Spironolactone and Patiromer 8.4 g/d and escalate to 25 mg Spironolactone over 


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4 weeks.  If needed, to manage K+, Patiromer will increase to 16.8 g/d. Then the treatment 
phase will commence with tolerated dose of Spironolactone along with Patiromer for 48 
weeks.
9.2
Blinding
This research protocol is not blinded.
9.3
Formulation of Test and Control Products
9.3.1
Formulation of Test Product
Spironolactone is an antihypertensive potassium sparing diuretic and Mineralocorticoid 
(Aldosterone) Receptor Antagonist.
Patiromer (Veltassa) is a potassium binder indicated for the treatment of hyperkalemia.
9.3.2
Formulation of Control Product
There is no control product in this research protocol.
9.3.3
Dosage
If screening K 4.6-5.2; start Spironolactone “run-in phase” 25 mg qd x 1 week; at 1 week 
recheck K and creatinine and add Veltassa 8.4 mg qd and continue with the treatment 
phase 
If screening K 5.3-5.5 start Spironolactone 12.5 mg and Veltassa 8.4 mg without a run-in 
phase and follow the Spironolactone dose escalate phase as in current protocol followed 
by the treatment phase 
If screening K >5.5 start Veltassa “run-in phase” 8.4 mg qd x 2 weeks and Add 
Spironolactone after 2 weeks 12.5 mg qd with plan to dose escalate to 25 mg qd as per 
current protocol 
The dose may need to be adjusted during the study due to safety lab results (e.g. K+) or if 
BP <100 mmHg.  The study physician will adjust dose as needed.
The active ingredient is patiomer sorbitex calcium, which consists of the active moiety, 
patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. 
Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer 
sorbitex calcium. Therefore, patients will be dosed at 8.4g of patiromer = 16.8g of 
patiromer sorbitex calcium (one packet) at the start of the study, increasing to 16.8g of 
patiromer = 33.6g of patiromer sorbitex calcium (two packets) as needed, according to the 
potassium levels during the study.
9.4
Study Drug Accountability
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded.


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9.5
Measures of Treatment Compliance
Subjects will be asked to keep a patient diary noting the day and date they take their study 
drug and any adverse events. They will be asked to bring their patient diary to each study 
visit along with all used and unused study drug containers.
10 HYPERKALEMIA MANAGEMENT
One of the most significant complications of the study medications is hyperkalemia. This 
risk is of particular importance in this study population as diabetic patients with chronic 
kidney disease are at increased risk for selective aldosterone deficiency, predisposing 
them to the development of hyperkalemia. Mild to moderate hyperkalemia is generally not 
associated with significant cardiac toxicity, especially when it is chronic (e.g., in dialysis 
patients) or slowly developing. In contrast, severe (> 6.5 mEq/L) or rapidly developing 
hyperkalemia is likely to be associated with the development of ECG abnormalities 
ranging from peaking of the T- wave; to atrial, AV nodal and ventricular conduction 
delays; and ultimately, with very severe hyperkalemia, to ventricular fibrillation.
Dietary intake of potassium is a major factor in producing hyperkalemia and transient 
dietary increases in potassium intake can precipitate hyperkalemia in our patients. For 
example, a single high potassium meal prior to blood draw could result in high potassium 
at the time of the draw but later on a repeat the potassium may be much lower, as much as 
1 mEq/L lower.
Decreased cellular uptake of potassium occurs when insulin is relatively deficient.  Even a 
patient who is not on insulin can have relative insulin deficiency (also known as insulin 
resistance). Generally decreased cellular uptake of potassium occurs when a patient has 
ingested a high potassium diet but does not have enough insulin to drive potassium into 
the cell. This can result in transient hyperkalemia.
Factors that impair renal excretion of potassium and can contribute to hyperkalemia in 
addition to the study medication include:  1) decreased GFR; 2) drugs including NSAIDS 
(e.g. ibuprofen), COX-2 inhibitors (e.g. celecoxib) and 3) any process which decreases 
distal tubular flow rate such as can occur in the setting of volume depletion.
One or all of the above factors can be operative in the same patient. For example, a 
volume depleted patient can have relative insulin deficiency, a high potassium intake and 
have taken NSAIDS for pain while ingesting the study medication.
Subjects will be counseled to avoid medications that may increase the risk of 
hyperkalemia, such as non-prescription non-steroidal anti- inflammatory medications, and 
potassium-containing salt substitutes. All subjects will be monitored for the development 
of hyperkalemia at each follow-up visit and an ECG will be obtained for any potassium 
value > 6.0 mEq/L.
The aggressiveness of treatment of hyperkalemia will depend on the degree of elevation 
and the presence or absence of ECG findings.
10.1 Treatment of hyperkalemia for Potassium > 5.0 meq/L: Dietary potassium
If during follow-up, a subject's potassium level increases to > 5.0 mEq/L, he/she will be 
prescribed a low potassium diet (0.7-0.8 meq/kg/day to a maximum daily intake of 60 


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meq/day). An initial step would be to restrict potassium in the diet. Input from a dietician 
can be helpful.
There is potassium in most foods, but certain foods are especially high in potassium and 
should be avoided. Some high potassium foods can be eaten after leaching the potassium 
by soaking. Many salt substitutes are potassium chloride and should be avoided. Fruits 
and vegetables should be limited to four servings per day. Dairy products should be 
limited to 1 cup/day.
High Potassium Foods (avoid):
Fruits and juice: apricots, avocado, banana, cantaloupe, honeydew, dried fruit (dates, 
raisins, prunes, figs), citrus fruits (orange, grapefruit, nectarines)
Vegetables: artichoke, butter beans, dried peas or beans, potatoes (unless leached), sweet 
potatoes, Swiss chard, winter squash.
Other: chocolate, molasses, nuts, peanuts
Medium potassium foods: Limit to one serving (1/2 cup)/day:
Fruits: blackberries, cherries, peach (1), pear (1), raspberries, strawberries, watermelon (1 
cup), plums (2)
Vegetables: broccoli (cooked), carrot, mushroom, peas, corn, cabbage, eggplant, spinach 
(cooked), pumpkin, tomato, potato (leached), beets
Low potassium foods (note that portion size is 1/2 cup, eating a large amount of a lower 
potassium food will make it a higher potassium food)
Fruits (including juice): Apple, blueberries, cranberries, grapes, tangerine (1 small)
Vegetables: green beans, wax beans, cucumber, green pepper, lettuce, yellow squash
Leaching vegetables:  For potatoes, sweet potatoes, carrots, beets and rutabagas:
Peel and slice vegetables 1/8 inch thick 
Rinse
Soak for a minimum of two hours in warm water, using 10 times the amount of water to 
the amount of vegetables. If soaking longer, change the water every few hours
Rinse under warm water
Cook with five times the amount of water to the amount of vegetable
10.2 Treatment of hyperkalemia for Potassium > 5.5 meq/L
In addition to a low potassium diet, if the potassium level increases to >5.5 mEq/L, 
conservative measures should be instituted. 
Possible approaches include:


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Increase in diuretics if volume depletion is not a concern. Volume depletion could worsen 
hyperkalemia
Administration of chronic alkali supplements, such as sodium bicarbonate 1300mg bid if 
acidosis is present
Liberalization of salt intake (if volume status and uncontrolled blood pressure are not 
concerns)
Chronic use of low-dose sodium polystyrene sulfonate (15-30 grams 3x/week)
10.3 Treatment of hyperkalemia for Potassium > 6.0 meq/L
If the potassium level is > 6.0 mEq/L, the study medication will be held until the level 
decreases to < 5.5 mEq/L.
Acutely to treat the potassium:
An ECG should be checked. If there are no ECG changes and potassium level is < 6.5, 
then Kayexalate alone (60 grams) may be sufficient. If there are ECG changes, treatment 
would include insulin/glucose, beta-agonists and possibly calcium and bicarbonate. If 
there are ECG changes or if the potassium level is > 6.5 meq/L, the patient should be 
treated in the emergency room. If there are ECG changes, the patient should be placed on 
a cardiac monitor.
Reinstitution of Study Medication
If the potassium level was > 6.5, then the study medication will be permanently 
discontinued and the patient will be removed from the trial. If this is the second episode 
where potassium > 6.0, then the study medication will be permanently discontinued and 
the patient will be removed from the trial.
Recheck potassium level 7- 14 days after discontinuation. If K+ is > 5.5 mEq/L, do not 
restart study medications. Repeat potassium again in 7-14 days. If K+ is ≤ 5.5 mEq/L, the 
study medication will be reinstituted at 50% of prior dose. 
If the study medication was restarted, check potassium level again in two weeks, if K+ 
is:
o
> 6.0: stop study the study medication permanently
o
5.5-6.0: treat K+, maintain current dose of the study medication
o
< 5.5: mEq/L  and  patient  is on  at  least  12.5 mg spironolactone, increase 
spironolactone to 25mg daily.
11  STUDY PROCEDURES AND GUIDELINES
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject.  If appropriate, assent must also be obtained prior to conducting any 
study-related activities.  Study visits will be conducted on the scheduled day or within +/-
2 days for weekly study visits and +/- 7 days for monthly visits.


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11.1 Schedule of Events
11.1.1 Main Study Phase
TABLE 4
SCREEN
RUN-IN 
PHASE
DOSE ESCALATE
TREATMENT PHASE
   MONTH*
M1
M1
M2
M2
M 2
M 3
M 5
M 7
M 9
M 11
M 12
M13
WEEK
W 1
W2
W3
W 4
W5
W6
W8
W9
W11
W17
W25
W33
W41
W45
W53
VISIT NUMBER
0
1
2
3
4
5
6
TF1
7
TF2
TF3
TF4
8
Screening Labs (Renal function panel, 
Lipid panel, HbA1C, Urine sample 
Alb/Creat)
X
Safety Labs (Renal function panel) Mag 
level*
X*
X
X
Optional
X*
X
X*
History & Targeted Assessment
X
X
X
EKG
X
Vital Signs or 24-hour BP SphygoCor 
cuff * (includes central aortic BP))
X
X
X*
X
X*
X
X
Phone Call
X
X
X
X
MRI
X
X
Research Labs/Monocyte Studies, 
(including PIP, PIINP, CITP and 
chemokines CCL2, CX3, CL1, and 
CCL5)
X
X
X
Insulin/Glucose (HOMA-IR)
X
X
HbA1C
X
X
X
Plasma Renin/Aldosterone
X
X
Medication Log
X
X
X
X
X
X
X
X
X
Pill counts
X
X
X
X
Dietary survey/instructions
X
X
Urine sample (Albumin/Creat)
X
X
X
X
X
Spot Urine Na/K/Creat
X
Interim Event log
X
X
X
X
X
X
X
X
X
Questionnaire & Instructions 
X
A complete medical history and physical exam will be performed at baseline and will 
include a 12-lead electrocardiogram (EKG), cardiovascular risk factor assessment, 
intercurrent CV events, 7-day physical activity recall, active/passive smoking 
questionnaires and dietary recall questionnaire. Sitting systolic blood pressure, pulse rate, 
body weight, interim event logs, pill counts, medication logs will be recorded at most 
clinic visits. Central aortic blood pressure and pulse wave velocity will be obtained during 


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visit 2 (base), 6 (mid-point) and 8 (exit) while 24-hour BP will be measured at Visit 2 and 
6. 
Dietary Na+ consumption: Since Na intake is an important determinant of MR 
responsiveness we will ensure that all patients receive dietary survey/instructions (Visit 0) 
on maintaining a personalized diabetic diet that is stable and is medium to low in sodium 
(<4 g). We will obtain Na, K and Creatinine levels (Visit 1) to assess Na intake. The 
kawasaki formula will be used to estimate 24 hour urine.
11.1.2 Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.
11.1.3 Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
11.2 Clinical Laboratory Measurements
Urinary Na levels, albumin, and creatinine
Serum levels of carboxyl-terminal peptide of procollagen type I (PIP), carboxyl-terminal 
telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III 
(PIIINP) and chemokines 
Safety labs (BUN, creatinine, electrolytes), HOMA-IR, Hem A1C and Plasma Renin 
Aldosterone, magnesium 
11.3 Urgent Study Alerts
An Investigator should be notified immediately if any of the following are noted at study 
visits:
Blood Pressure Immediate Alert Values: 

Systolic Blood Pressure < 80 

Systolic Blood Pressure >180 

Diastolic Blood Pressure >110 
Acute Distress: (signs or symptoms constituting an emergency): 

Chest Pain 

Severe Respiratory Distress 

Acute Neurological Symptoms 
Urgent Lab Values:

Potassium ≤ 3.0 mEq/L 

Potassium ≥ 6.0 mEq/L 

Glucose < 50 mg/dL 


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
Glucose >350 mg/dL 

Creatinine doubling from last value 
Coronavirus Outbreak (COVID-19) Management Plan under Public Health 
Mandates
The following guidelines were developed under polices set forth by UH Cleveland 
Medical Center, the University of Maryland, NYU Winthrop, and MetroHealth Systems. 
Recruitment and Enrollment 
The new public health mandates concerning the COVID-19 have led to the decision to 
permanently close enrollment. At the time COVID-19 policies were implemented, 
University of Maryland, NYU Winthrop, and MetroHealth Systems had not enrolled any 
patients. Study procedures for the remaining UH participants will revert to the original 
procedures described in Section 11 “Procedures and Guidelines” once the mandates are 
lifted. 
Active Participants and Follow up Visits
At University Hospitals, all active participants fell into the “treatment phase” of the study 
procedures timeline of events (See 11.1.2 Main Study Phase).
TREATMENT-PHASE
In order to simultaneously reduce transmission of the virus while maintaining the 
management of participant’s follow up care to the best extent possible, pertinent study 
activities (i.e. safety labs & vital signs) will be attempted in conjunction with any provider 
scheduled clinical encounter deemed essential for clinical care. If this is not possible, 
patients will be given an additional prescription until the essential study activities can be 
performed safely (length of prescription may vary based on patients’ recent bloodwork 
and BP/HR, policies, and investigator’s medical judgment).
Additional important details
Remote study visits are not appropriate for this study.
Participants will be compensated for their participation at the same amount specified in 
the original consent.
All enrolled participants will be notified by phone call of these protocol changes enacted 
during the period of public health mandates.


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12 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
12.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure.
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) in Table 1 should be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant.   If the experience is not covered in the 
CTCAE, the guidelines shown in Table 2 below should be used to grade severity.  It 
should be pointed out that the term “severe” is a measure of intensity and that a severe AE 
is not necessarily serious.  K+ >6.0 will be considered an adverse event.  K+<6.0 will be 
considered an expected side effect of the medication.  As previously described, all K+>5.0 
will be treated according to the hyperkalemia protocol.
Table 1.  National Cancer Institute’s Common Terminology Criteria for Adverse 
Events
Severity (Toxicity Grade)
Description
Grade 1, Mild
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated.
Grade 2, Moderate
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL*.
Grade 3, Severe
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care 
ADL**.
Grade 4, Life-threatening
Life-threatening consequences; urgent intervention 
indicated.
Grade 5, Death
Death related to AE.


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Table 2.  AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; 
no medical intervention or therapy required. The 
subject may be aware of the sign or symptom but 
tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal 
medical intervention/therapy required.
Severe (3)
Marked limitation in activity, medical 
intervention/therapy required, hospitalizations possible.
Life-threatening (4)
The subject is at risk of death due to the adverse 
experience as it occurred. This does not refer to an 
experience that hypothetically might have caused death 
if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 3.
Table 3.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a 
reasonable temporal sequence from administration of the drug; that 
follows a known or expected response pattern to the suspected drug; 
that is confirmed by stopping or reducing the dosage of the drug; 
and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state 
or by other interventions.
Possibly
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to that suspected drug; but that could readily have 
been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no 
relationship to the study drug.


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12.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. 
12.2.1 Serious Adverse Experience Reporting
Adverse events will be documented per the University Hospitals Cleveland Medical 
Center, Human Research Protections guidelines, reported to the IRB, DSMB and the 
sponsor.  The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed.
12.3 Medical Monitoring
Dr. Matthew Weir and/or Dr. Jeffrey Fink should be contacted directly to report medical 
concerns or questions regarding safety.
13 DISCONTINUATION OF SUBJECTS
13.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:
Subject withdrawal of consent (or assent)
Subject is not compliant with study procedures
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment
Protocol violation requiring discontinuation of study treatment
Lost to follow-up
Sponsor request for early termination of study
Positive pregnancy test (females)
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.  


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All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.
14 DATA SAFETY MONITORING 
A Data Safety Monitoring Board (DSMB) will be established to review data relating to 
safety and efficacy, to conduct and review interim analyses, and to ensure the continued 
scientific validity and merit of the study. Reviews will be conducted by the DSMB every 
3 months for the purpose of monitoring study conduct and assessing patient safety.
15 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  
General Statistical Considerations: All the tests are two-sided. We use log transformations 
for most continuous measures, and arc-sin square root transformations for percentages, 
both of which have excellent variance stabilizing properties for pooling variance.  
16 DATA COLLECTION, RETENTION AND MONITORING
16.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) OR paper 
CRF when the information corresponding to that visit is available.  Subjects will not be 
identified by name in the study database or on any study documents but will be identified 
by a subject number.
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the 
person entering or updating eCRF data and creates an electronic audit trail.  For paper 
CRFs:  If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change.
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study.


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16.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials.
16.3 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.
16.4 Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived.
16.5 Subject Confidentiality
In order to maintain subject confidentiality, only a subject number will identify all study 
subjects on CRFs and other documentation submitted to the Sponsor. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number only.  All study records will be kept in a 
locked file cabinet and code sheets linking a patient’s name to a patient identification 
number will be stored separately in another locked file cabinet.  Clinical information will 
not be released without written permission of the subject, except as necessary for 
monitoring by the FDA.  The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC).


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17.1 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Subjects will be given ample opportunity to inquire 
about details of the study.  If a subject is unable to sign the informed consent form and the 
HIPAA authorization, a legal representative may sign for the subject.   A copy of the 
signed consent form will be given to the subject or legal representative of the subject and 
the original will be maintained with the subject’s records.
17.2 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement with the 
study Sponsor.  The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996. 


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17.3 References
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Kleiman J, and Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left 
ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(1309-21. 
3. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, 
Pocock SJ, and Pitt B. Eplerenone in patients with systolic heart failure and mild 
symptoms. N Engl J Med. 2010;364(11-21. 
4. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, and Wittes J. The 
effect of spironolactone on morbidity and mortality in patients with severe heart failure. 
Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine. 
1999;341(709-17. 
5. Gilbert KC, and Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes 
Obes. 2010;17(199-204. 
6. Briet M, and Schiffrin EL. The role of aldosterone in the metabolic syndrome. Current 
hypertension reports. 2011;13(163-72. 
7. Whaley-Connell A, and Sowers JR. Aldosterone and Risk for Insulin Resistance. 
Hypertension. 2011;58(6):998-1000. 
8. Garg R, and Adler GK. Role of mineralocorticoid receptor in insulin resistance. Curr Opin 
Endocrinol Diabetes Obes. 2012;19(3):168-75. 
9. Bender SB, McGraw AP, Jaffe IZ, and Sowers JR. Mineralocorticoid receptor-mediated 
vascular insulin resistance: an early contributor to diabetes-related vascular disease? 
Diabetes. 2013;62(313-9.
10. Duquaine D, King S, Pitt B, and Patel P. Mineralocorticoid Receptor Antagonism in 
Experimental Atherosclerosis. Circulation. 2002;105(2212-6. 
11. Takai S, Jin D, Muramatsu M, Kirimura K, Sakonjo H, and Miyazaki M. Eplerenone 
inhibits atherosclerosis in nonhuman primates. Hypertension. 2005;46(1135-9. 
12. Rader DJ, and Daugherty A. Translating molecular discoveries into new therapies for 
atherosclerosis. Nature. 2008;451(904-13. 
13. Rogerson FM, and Fuller PJ. Mineralocorticoid action. Steroids. 2000;65(2):61-73. 
14. Trapp T, and Holsboer F. Ligand-induced conformational changes in the 
mineralocorticoid receptor analyzed by protease mapping. Biochem Biophys Res Commun. 
1995;215(286-91. 
15. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, 
Berman L, Bushinsky DA, et al. Effect of Patiromer on Serum Potassium Level in Patients 
With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized 
Clinical Trial. Jama. 2015;314(2):151-61. 
16. Pitt B, Bakris GL, Bushinsky DA, Garza D, Mayo MR, Stasiv Y, Christ-Schmidt H, 
Berman L, and Weir MR. Effect of patiromer on reducing serum potassium and 
preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney 
disease on RAAS inhibitors. Eur J Heart Fail. 2015;17(10):1057-65. 
17. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-
Schmidt H, Berman L, Pitt B, et al. Patiromer in patients with kidney disease and 
hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-21. 
18. Bushinsky DA, Williams GH, Pitt B, Weir MR, Freeman MW, Garza D, Stasiv Y, Li E, 
Berman L, and Bakris GL. Patiromer induces rapid and sustained potassium lowering in 
patients with chronic kidney disease and hyperkalemia. Kidney Int. 2015;88(6):1427-33. 


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19. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ, and Investigators P-
H. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a 
double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-
HF) trial. European heart journal. 2011;32(7):820-8. 
20. Funder JW, Pearce PT, Smith R, and Campbell J. Vascular type I aldosterone binding sites 
are physiological mineralocorticoid receptors. Endocrinology. 1989;125(4):2224-6. 
21. Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, and Bonvalet JP. 
Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid 
receptor. Circ Res. 1992;71(3):503-10. 
22. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh FY, and Takeda 
R. Production of aldosterone in isolated rat blood vessels. Hypertension. 1995;25(2):170-
3. 
23. Takeda Y, Miyamori I, Inaba S, Furukawa K, Hatakeyama H, Yoneda T, Mabuchi H, and 
Takeda R. Vascular aldosterone in genetically hypertensive rats. Hypertension. 1997;29(1 
Pt 1):45-8. 
24. Brilla CG, Pick R, Tan LB, Janicki JS, and Weber KT. Remodeling of the rat right and left 
ventricles in experimental hypertension. Circulation research. 1990;67(1355-64. 
25. Campbell SE, Janicki JS, Matsubara BB, and Weber KT. Myocardial fibrosis in the rat 
with mineralocorticoid excess. Prevention of scarring by amiloride. American journal of 
hypertension. 1993;6(487-95. 
26. Blacher J, Amah G, Girerd X, Kheder A, Ben Mais H, London GM, and Safar ME. 
Association between increased plasma levels of aldosterone and decreased systemic 
arterial compliance in subjects with essential hypertension. American journal of 
hypertension. 1997;10(1326-34).
27. Takeda Y, Miyamori I, Inaba S, Furukawa K, Hatakeyama H, Yoneda T, Mabuchi H, and 
Takeda R. Vascular aldosterone in genetically hypertensive rats. Hypertension. 
1997;29(45-8. 
28. Duprez DA, De Buyzere ML, Rietzschel ER, Taes Y, Clement DL, Morgan D, and Cohn 
JN. Inverse relationship between aldosterone and large artery compliance in chronically 
treated heart failure patients [see comments]. European heart journal. 1998;19(1371-6. 
29. Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M, Vaughan DE, and 
Fogo AB. Aldosterone modulates plasminogen activator inhibitor-1 and 
glomerulosclerosis in vivo. Kidney International. 2000;58(1219-27. 
30. Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, 
Oestreicher E, Foradori A, et al. Primary hyperaldosteronism in essential hypertensives: 
prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab. 
2000;85(1863-7. 
31. Rocha R, Stier Jr. CT, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, and Adler 
GK. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. 
Endocrinology. 2000;141(3871-8. 
32. Xiao F, Puddefoot JR, and Vinson GP. Aldosterone mediates angiotensin II-stimulated rat 
vascular smooth muscle cell proliferation. Journal of Endocrinology. 2000;165(533-6. 
33. Fiebeler A, Schmidt F, Muller DN, Park J-K, Dechend R, Bieringer M, Shagdarsuren E, 
Breu V, Haller H, and Luft FC. Mineralocorticoid Receptor Affects AP-1 and Nuclear 
Factor-{{kappa}}B Activation in Angiotensin II-Induced Cardiac Injury. Hypertension. 
2001;37(787-93. 


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34. Ward MR, Kanellakis P, Ramsey D, Funder J, and Bobik A. Eplerenone Suppresses 
Constrictive Remodeling and Collagen Accumulation After Angioplasty in Porcine 
Coronary Arteries. Circulation. 2001;104(467-72. 
35. Farquharson CA, and Struthers AD. Aldosterone induces acute endothelial dysfunction in 
vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond). 
2002;103(425-31. 
36. Grandi AM, Imperiale D, Santillo R, Barlocco E, Bertolini A, Guasti L, and Venco A. 
Aldosterone antagonist improves diastolic function in essential hypertension. 
Hypertension. 2002;40(647-52. 
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