Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D)

Study rationale: Empagliflozin and dapagliflozin are sodium-glucose transporter-2 (SGLT-2)
inhibitors which prevent the reabsorption of glucose via proximal renal tubules, and are the
most recently approved class for treating hyperglycemia in type 2 diabetes. Besides effective
glucose lowering effects as documented by ~ 0.7-1.2% HbA1c reduction, these agents also
promote weight loss and reduce blood pressure (BP). Furthermore, recent data from the
Empagliflozin Cardiovascular Outcome Trial in type 2 diabetes (EMPA-REG OUTCOME) reported
significant reduction in main cardiovascular disease (CVD) outcomes and CVD death in patients
with type 2 diabetes (T2D). The exact mechanism of the beneficial effects on cardiovascular
outcomes is not yet understood, although their effects on body weight, glucose control and BP
reduction were suggested. However, other classes of drugs with similar effects such as GLP-1
receptor agonist, thiazolidinedione did not clearly show the beneficial effects in CVD
outcomes. The interesting observation is that improvement in BP with SGLT-2 inhibitors
occurred without a compensatory increase in HR and that most benefit was obtained also in
patients with some evidence of heart failure.

Thus, the investigators postulated the hypothesis that SGLT-2 may also have a modulatory
effect on the sympathetic/parasympathetic balance, and this may contribute to the potential
benefits on cardiovascular outcomes in patients with diabetes.

Study Design: The investigators plan to test this hypothesis in a randomized, double-blind,
2-period crossover clinical trial comparing 12-weeks of glycemic intervention with
dapagliflozin versus glimepiride. The investigators include an active comparator with
glimepiride which have a similar glucose lowering in patients with T2D, to account for the
effects of reductions in blood glucose on measures of CAN, and will evaluate whether changes
in measures of CAN are different among patients who are taking glimepiride or dapagliflozin.
The two crossover periods will be separated by a 2-week wash-out period.

All subjects will be allocated and randomized to each treatment sequence. Participants will
receive blindly either dapagliflozin 5 mg or glimepiride 2 mg 1 tablet daily initially for 4
weeks then titrating the dose based on blood glucose levels up to 2 tablets daily for 8 more
weeks (total 12 weeks) followed by 2-week washout period and then they will receive the study
drugs in reverse order to the first period during second crossover period for 12 weeks.

Study population: 45 patients with T2D on background metformin monotherapy who are not
meeting ADA recommended glycemic target.

Primary outcomes: changes in measures of cardiovascular autonomic neuropathy such as heart
rate variability (HRV) as defined by frequency domain measures of HRV: low frequency (LF)
power (ms2); high frequency (HF) power (ms2) as measured as LF:HF ratio.

Secondary outcomes: (i) changes in measures of HRV as defined by time domain measures of HRV:
standard deviation of the normal RR interval (SDNN) (msec) and root mean square of the
differences of successive RR intervals (rmsSD) (msec); (ii) changes in cardiovascular
autonomic reflex tests (CARTs) as defined by: expiration/inspiration (E/I) ratio, Valsalva
ratio, and 30:15 ratio; (iii) changes in measures of systolic and diastolic function will be
assessed by using stress echocardiogram and evaluate the following measures: i) LVEF, ii) LV
end diastolic volume, iii) LV end systolic volume, iv) LV mass, v) cardiac output.

Inclusion Criteria:

1. Patients with type 2 diabetes as defined on background metformin monotherapy who are
not meeting ADA standard of care recommended glucose target.

2. Age ≥18 years

Exclusion Criteria:

1. History of multiple urinary tract infections

2. Patients with mycotic infections especially genital infections.

3. Patients at risk for volume depletion due to co-existing conditions or concomitant
medications, such as loop diuretics should have careful monitoring of their volume
status. This is listed as exclusion criteria but then it says that they just need
careful monitoring. Is it an exclusion or not?

4. Severely hypotensive patients

5. History of unexplained microscopic or gross hematuria, or microscopic hematuria at
visit 1, confirmed by a follow-up sample at next scheduled visit.

6. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g.
anaphylaxis, angioedema, exfoliative skin conditions

7. Inability or refusal to comply with protocol

8. Current participation or participation in an experimental drug study in the previous
three months

9. History of diabetic ketoacidosis

10. Planned cardiac surgery or angioplasty within 3 months

11. Recent history of acute CV events such as MI, stroke, PAD within 3 months prior to
enrollment

12. Patients with severe renal impairment or unstable or rapidly progressing renal disease
or end stage renal disease.

13. Clinical conditions that could interfere with the cardiovascular autonomic function
and heart rate variability (arrhythmias)

14. Severe hepatic insufficiency and/or significant abnormal liver function (defined as
aspartate aminotransferase >3× upper limit of normal (ULN) and/or alanine
aminotransferase >3× ULN) or creatinine kinase >3× ULN.

15. History of cancer other than basal cell carcinoma and/or treatment for cancer within
the last 5 years

16. Women of child-bearing potential who may be pregnant or lactating.

17. History of pancreas, kidney or liver transplant

18. History of drug or alcohol abuse

19. History of allergy to sulfa drugs

20. Presence of any condition that, in the opinion of the investigator would make it
unlikely for the subject to complete the study

21. Congestive heart failure (CHF) defined as New York Heart Association class III and IV