Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis Add-On

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.

Inclusion Criteria

1. Male or female patients >= 45 years 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 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. Glomerular filtration rate (GFR) <90 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 angiotensin-converting-enzyme inhibitor (ACE) and/or
angiotensin-resistance-blocker (ARB) therapy with no planned dose adjustments.

5. Hyperkalemia defined as serum K+≥ 5.1 meq/L at visit 0 (screening).

Exclusion Criteria

1. Uncontrolled hypertension (Systolic Blood Pressure (SBP)>160 and/or Diastolic Blood
Pressure (DBP)>95 mmHg at visit 0 (screening) and SBP >145 mm Hg at visit 2).

2. GFR (MDRD) of <20 at visit 0 (screening)

3. Hyperkalemia defined as serum K+ <5.1 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, cardiovascular accident (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, ACE/ARB, antioxidants, calcium channel
blockers (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