Emerging organ protective therapies in Type 2 Diabetes

The goals of diabetes care are to prevent complications and optimize quality of life. Current developments in diabetes management have shifted focus from just glycemic control to the inclusion of organ protection. In the Boehringer Ingelheim-sponsored webinar entitled “Deep dive in EMPA-KIDNEY” held last December 9, 2022, Dr Nestor Eric Laplano, Consultant, Skyline Hospital and Medical Center and Grace General Hospital, SJDM Bulacan; and Dr David Cherney, Active Consultant, University Health Network and Mount Sinai Hospital Toronto Canada, revisited treatment strategies and discussed the EMPA-KIDNEY trial and its implications in organ protective therapies for type 2 diabetes.

Unmet needs in chronic kidney disease

Chronic kidney disease (CKD) is a global public health burden affecting 1 in 10 adults or an estimated 850 million people worldwide, and recently has been acknowledged as the ‘hidden epidemic.’^1-3 It leads to increased hospitalizations, healthcare resource utilization, and the development of kidney failure.⁴ In high- and middle-income countries, CKD is most commonly caused by diabetes or hypertension.⁵

To reduce the progression of kidney disease in diabetes, certain drugs are used to reduce the altered hemodynamic characteristics of CKD in diabetes by means of renin-angiotensin-aldosterone system inhibitors.⁶

In the past decade, several new anti‐diabetic drugs have been developed, including dipeptidyl peptidase‐4 (DPP‐4) inhibitors, sodium‐glucose cotransporter 2 (SGLT2) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP-1 RAs), and several insulin analogs.⁷

Emerging treatment options for chronic kidney disease

In addition to glycemic control, cardiovascular or renal protective effects beyond glycemic control, or the ‘organ protection’ effects, have been studied in newer or latest anti-diabetic agents. Findings from trials of SGLT2 inhibitors and GLP-1 RA have led to a paradigm shift in the treatment of type 2 diabetes.⁷

SGLT2 inhibitors inhibit glucose reabsorption in the proximal tubule of the kidneys leading to increased glucose excretion. These medications work independently of insulin secretion. Because of this unique glycosuric mechanism, SGLT2 inhibitors cause weight reduction and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits.⁸

The EMPA-KIDNEY Trial

The EMPA-KIDNEY Trial (Empagliflozin in Patients with Chronic Kidney Disease) is a new CKD trial that was released during the American Society of Nephrology on the 4^th of November 2022. EMPA-KIDNEY is the largest and broadest SGLT2i CKD-dedicated study that included patients who were underrepresented in previous renal outcome clinical trials for SGLT2 inhibitors. It was designed to assess the effects of treatment with empagliflozin in a broad range of patients with chronic kidney disease who are at risk of kidney disease progression. A total of 6,609 adults with eGFR of greater or equal to 20 to <45 ml/mi/1.73 m² or greater or equal to 45 to <90 ml/mi/1.73 m² but with UACR of more than 200 mg/g were recruited and randomly assigned to receive either empagliflozin 10 mg once daily or placebo once daily. Compared to other related trials, the population in the EMPA-KIDNEY trial has lower levels of eGFR and albuminuria. Another distinction is that a large number of patients have non-diabetic kidney disease.


Figure 1. Progression of Kidney Disease or Death from Cardiovascular Causes. Shown are the results of the primary composite outcome of progression of kidney disease or death from cardiovascular causes. Over a median of 2 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group, representing 42 fewer primary- outcome events per 1000 patients in the empagliflozin group than in the placebo group over 2 years. The inset shows the same data on an enlarged y axis.

During a median of 2.0 years of follow-up, empagliflozin demonstrated a robust clinical benefit and safely reduced the primary composite outcome of kidney disease progression or CV death by 28% (Figure 1). The trial ended early because of an overwhelming efficacy in the treatment arm. Relative benefits were consistent in the patients with and without diabetes and across the range of eGFR studied.

The positive key secondary outcome that is unique to the EMPA-KIDNEY trial is the all-cause hospitalization. It is the only renal outcomes trial to demonstrate a 14% relative risk reduction of first and recurrent hospitalization for any cause. In the subgroup analysis, there was a slowed, chronic eGFR decline in all albuminuria subgroups.⁹


Figure 2. Analysis of change from baseline in eGFR across all albuminuria subgroups.

Conclusion 

The results of the EMPA-KIDNEY trial indicate that empagliflozin has beneficial effects on renal function among patients with CKD, with or without diabetes, who are already on appropriate doses of ACE inhibitors or ARBs. EMPA-KIDNEY is the broadest and largest SGLT2i CKD trial, enrolling patients with a kidney function of at least 20mL/min/1.73m², a higher proportion of patients without diabetes, and patients who are non-albuminuric. The study included patients who were underrepresented in previous SGLT2i CKD trials. With the results of these trials, SGLT2 inhibitors will likely change paradigms of clinical practice and have a prominent role in future CKD management guidelines.