Cardiorenal syndromes and SGLT2 inhibitor usage

Cardiovascular and renal dysfunctions are commonly encountered comorbid conditions in type 2 diabetes mellitus. Such dysfunction can be attributed to uncontrolled diabetes, nondiabetic disease, or iatrogenic causes.

As cardiovascular and renal complications may occur simultaneously in a chronic setting, this aspect of type 2 diabetes epidemiology has received significant research attention. What's more, cardiovascular and renal disease can also be precipitated by each other in either an acute or chronic setting. Hence, the term "cardiorenal syndromes" is used to identify and classify this vast spectrum of illness.

Cardiorenal syndromes

Cardiorenal syndromes were defined as “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other” by the Acute Dialysis Quality Initiative (ADQI) almost a decade ago. Cardiorenal syndrome is further classified into five subtypes:

• CRS type 1: Acute cardiorenal syndrome – Acute cardiac dysfunction causing renal dysfunction
• CRS type 2: Chronic cardiorenal syndrome – Chronic cardiac disease leading to renal disease
• CRS type 3: Acute renocardiac syndrome – Acute renal dysfunction causing cardiac dysfunction
• CRS type 4: Chronic renocardiac syndrome – Chronic renal disease leading to cardiac disease 
• CRS type 5: Secondary cardiorenal syndrome – Systemic conditions causing simultaneous dysfunction of heart and kidney.

All five types of cardiorenal syndrome can be encountered in people with diabetes. Acute decompensated heart failure is common in uncontrolled diabetes, and may be complicated by acute kidney injury (CRS type 1). Individuals with diabetes and atherosclerotic cardiovascular disease frequently have low estimated glomerular filtration rate (eGFR), which allows them to be labeled as CRS type 2. Acute kidney injury itself is a commonly encountered clinical condition, especially in diabetes. This may be followed by cardiac complications such as hyperkalemia-induced arrhythmias, oliguria-induced fluid overload, pericarditis, and decompensated heart failure. These situations are classified as CRS type 3. Chronic kidney disease, too, may be associated with such complications, and then considered as CRS type 4. The simultaneous occurrence of diabetic kidney disease and atherosclerotic cardiovascular disease, in the presence of diabetes, is included under CRS type 5.

Sodium-glucose cotransporter 2 inhibitors: Challenges in practice

In the past decade we have witnessed a paradigm shift in diabetes care. This is thanks, in large part, to the development of new drugs, supported by robust evidence from recent cardiovascular and renal outcome trials examining their safety and efficacy. This is especially true for the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, which is widely recognized, along with glucagon like peptide-1 receptor agonists, as the second-line medication of choice following metformin treatment in people with type 2 diabetes who have established heart failure or renal impairment.  

Read the 2018 ADA/EASD joint consensus report on the management of hyperglycemia here 

The recommendations and expert consensus to use SGLT2 inhibitors are based on the findings from various randomized controlled outcome trials. While these trials may have differed in the intricacies of their study design, they all shared one factor in common: Most studies recruited stable, “chronic” participants without any acute illness and significant nondiabetic comorbidity. This, in effect, has meant that people with CRS types 1, 2, 3, and 4 have been excluded from most trials. This is especially true for acute CRS type 1 and 3. In short, SGLT2 inhibitors have not been studied in persons with impaired renal function, who need cardiovascular safety.

Broadening the spectrum

Ongoing studies, such as the EMPA-KIDNEY study, Dapa-CKD study, and TA-7284 trial, have lowered the eGFR cutoff for the initiation of an SGLT2 inhibitor to 20, 25, and 30 mL/min per 1.73m², for empagliflozin, dapagliflozin, and canagliflozin, respectively. The criteria for the discontinuation of SGLT2 inhibitors state that the drug has also to be used until the onset of chronic renal replacement therapy. However, as these studies are still underway it remains extremely challenging to make clinical decisions regarding the use of SGLT2 inhibitors in acute situations.

Traditionally, insulin has been considered as the only means of managing hyperglycemia in inpatients. However, reports from Japan indicate that SGLT2 inhibitors help in the management of patients hospitalized with acute decompensated heart failure, and may prevent acute kidney injury. Other experts have suggested that there are mechanisms at-play allowing SGLT2 inhibitors to improve myocardial and renal health. My collaborators and I have previously used the "Robin Hood effect" to describe the beneficial effects of SGLT2 inhibitor use on myocardial bioenergetics.

The SGLT2 inhibitor “Robin Hood effect” 

This hypothesis suggests that SGLT2 inhibitors improve myocardial efficiency by shifting metabolism slightly from glucose-based to ketone-based. In this analogy “stealing” excess glucose is likened to Robin Hood’s strategy of stealing from the rich to give to the poor.

Finding a pragmatic middle ground

Newer evidence, such as that described above, conflicts with long-standing dogmas on glycemic management. Hence, I believe that there is a need to provide simplified guidance regarding the safe use of SGLT2 inhibitors in patients with cardiorenal syndromes. The following tables are my pragmatic suggestions regarding the initiation and continuation of SGLT2 inhibitors in different cardiorenal syndromes, and the various stages of acute kidney injury.

Table 1. SGLT2 inhibitor usage in patients with cardiorenal syndromes and type 2 diabetes

Table 2. SGLT2 inhibitor patients with chronic kidney disease and type 2 diabetes

Table 3. SGLT2 inhibitors in setting of acute kidney injury in diabetes

Summary of pragmatic recommendations

SGLT2 inhibitors should not be initiated in patients with CRS types 1 and 3, but can be continued with close hemodynamic and renal-function monitoring. In CRS types 2, 4, and 5, SGLT2 inhibitors are preferred drugs for glycemic as well as metabolic control. They should be prescribed in such situations, keeping prescribing information in mind.

Individuals with an eGFR >30 mL/min per 1.73 m² may take SGLT2 inhibitors safely, while those with a lower eGFR should be monitored with care. The eGFR cutoffs vary from drug to drug, and from country to country. Hence, prescribers should be aware of their national guidelines. SGLT2 inhibitors should not be initiated during an active bout of urinary- or genital-tract infection, and may be discontinued in persons with severe, refractory, or recurrent genitourinary infection.