Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN)

Inclusion criteria: 1. Man or woman between 21 and 100 years of age 2. Type 2 diabetes mellitus as defined by: * Fasting plasma glucose ≥7.0mmol/l, or * Symptoms of hyperglycemia with casual plasma glucose ≥11.1 mmol/L, or * 2-hour plasma glucose ≥11.1 mmol/l after a 75-gram oral glucose load, or * Known type 2 diabetes mellitus diagnosed by a medical practitioner 3. Two or more measurements indicating increased urine protein excretion within 1-year Increased urine protein excretion is defined as: * Urine microalbumin/creatinine ratio (ACR) \> 3.3 mg/mmol creatinine or * Urine total protein/creatinine ratio (PCR) \> 0.2 g/urine creatinine 4. Known diabetes duration \> 3 months 5. HbA1c ≤9% (within 3 months prior to enrolment) 6. Not currently treated with an SGLT-2 inhibitor, and have not received SGLT-2 inhibitor therapy within the last 10 weeks. 7. Stable diabetes therapy for at least 3months as defined as: * No increase in dose of diabetes medications by more than two-fold or * No new agents added within the previous 3 months 8. Stable doses of angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) for at least 3 months. 9. Capable of providing informed consent Exclusion Criteria: 1. Type 1 diabetes mellitus 2. Ketosis-prone diabetes 3. Previous diabetic ketoacidosis 4. History of Fournier's gangrene or skin and soft tissue infections of the perineum 5. Recurrent or severe urinary tract or genital mycotic infections, or history of genitourinary infection within 2 weeks prior to informed consent 6. Significant renal impairment (estimated Glomerular Filtration Rate \< 45 ml/min/1.73m2\*\*) 7. Dialysis or kidney transplant 8. Renal artery stenosis 9. Alanine aminotransferase or aspartate aminotransferase above 3x upper limit of normal 10. Significant change in weight (≥10% in the preceding 6 months) 11. Treatment with anti-obesity drugs 12. Previous bariatric surgery or other gastrointestinal surgeries that induce chronic malabsorption 13. Treatment with systemic glucocorticoids 14. Blood dyscrasias or clinically significant anaemia (Haemoglobin \< 10 g/L) 15. Medical condition likely to limit survival to less than 3 years 16. Uncontrolled thyrotoxicosis, untreated hypothyroidism 17. Any ongoing acute medical illnesses 18. Hospitalization within 1 month prior to enrolment 19. Nursing mothers 20. Pregnancy, currently trying to become pregnant, or of child-bearing potential and not practicing an acceptable method of birth control or do not plan to continue using this method throughout the study 21. Excessive alcohol intake (\> 1 unit per day for women and \> 2 units per day for men) 22. History of drug abuse 23. Pancreatic insulin deficiency from any cause (history of pancreatitis, pancreatic surgery) 24. Known intolerance or allergic reactions to empagliflozin or other SGLT-2 inhibitors 25. Current participation in another clinical trial, or ingestion of investigational drug in another trial within 30 days prior to enrolment. 26. Presence of any non-DN renal glomerular disease (e.g. IgA nephropathy, lupus nephritis, membranous glomerulonephritis, focal segmental glomerular sclerosis) 27. Any previous organ transplantation 28. Any factors likely to limit adherence to interventions (e.g. dementia; alcohol or substance abuse; history of unreliability in medication taking or appointment keeping; significant concerns about participation in the study from spouse, significant other or family members) 29. Failure to obtain informed consent from participant 30. Presence of postural hypotension or clinically significant dehydration (reduced skin turgor, dry oral mucosa, hypotension)