SGLT-2 inhibitor has cardioprotective effect in different risk groups

Type 2 diabetes mellitus (T2DM) significantly increases the risk of cardiovascular complications [1]. However, SGLT-2 inhibitors may prevent cardiovascular events in addition to lowering blood glucose levels [2, 3]. For an SGLT-2 inhibitor, recent studies suggest that a broad spectrum of patients may benefit from these cardioprotective properties [4, 5].

Diabetes mellitus (DM) is a major risk factor for the development of cardiovascular disease, which is one of the leading causes of death in T2DM patients [6, 7]. In addition, approximately 40% of all T2DM patients develop diabetic kidney disease, which also contributes to increased cardiovascular risk [8, 9]. The joint prevention of renal as well as cardiovascular complications therefore plays a central role in modern T2DM management, in addition to lowering blood glucose levels [10].

SGLT-2 inhibitors reduce blood glucose and protect kidney and heart

SGLT-2 inhibitors were developed to lower blood glucose levels but also have a cardioprotective effect [3, 11-13]. In addition, canagliflozin (Invokana®) is the first and currently only SGLT-2 inhibitor approved in Switzerland to reduce the risk of progression to diabetic kidney disease in adult T2DM patients with albuminuria (ACR>300mg/g) [2]. This is based on the renal endpoint study CREDENCE, in which canagliflozin was able to reduce the risk of the primary composite endpoint of end-stage renal failure, doubling of serum creatinine levels, and death from a cardiovascular or renal cause by 30% compared to placebo (HR 0.7; 95% CI: 0.59-0.82; p=0.00001) [14]. New subgroup analyses of the CREDENCE trial demonstrate the benefit of canagliflozin treatment in terms of cardiovascular prevention in T2DM patients from different risk groups [4, 5].

Fewer hospitalizations for heart failure overall

For example, in a subgroup analysis published in 2019, canagliflozin was shown to reduce the risk of first-time hospitalization for heart failure (HHF)* [15]. Since the prevention of recurrent cardiovascular events is also of great importance for patients as well as treating physicians, a post-hoc analysis of the CREDENCE trial was now performed to investigate whether canagliflozin had an impact on the total number of HHF events [4]. During the course of the study, a total of 326 HHF events occurred in 230 patients. In 42% of these patients, this occurred more than once. Under canagliflozin, the overall rate of HHF was 22.0 cases per 1000 patient-years versus 34.8 under placebo, representing a relative risk reduction of 36% (RR: 0.64; 95% CI: 0.56-0.73; p<0.001) [4]. The risk of first-time HHF was reduced by 39% with canagliflozin (HR: 0.61; 95% CI: 0.47-0.80; p<0.001) [4].

Cardioprotection demonstrated in diverse subgroups.

In addition to cardiovascular pre-existing conditions, patients included in the CREDENCE trial also had a wide baseline spectrum of other pre-existing conditions and characteristics (Table) [5]. At the American College of Cardiology 2020 Congress, the results of another subgroup analysis of the CREDENCE trial were presented, which examined the impact of canagliflozin on the combined secondary outcome of HHF and cardiovascular death, taking into account patient-specific baseline characteristics [5]. During the median follow-up of 2.6 years, 432 patients were hospitalized for heart failure or died as a result of a cardiovascular event [5]. Particularly affected were patients who were already taking loop diuretics before the start of the study, had prior cardiovascular disease, a reduced estimated glomerular filtration rate (eGFR), or an elevated albumin-creatinine ratio (UACR) [5]. Overall, canagliflozin reduced the risk of HHF and cardiovascular death by 31% in the entire patient population (HR: 0.69; 95% CI: 0.57-0.83). This benefit persisted across all subgroups, including those at high as well as low risk (Pinteraction>0.246) (Table) [5].

Table: Impact of canagliflozin on cardiovascular death or hospitalization for heart failure according to patient-specific baseline characteristics (adapted from [5]).

**NYHA: New York Heart Association classification. Could not be collected in 15 patients.

Conclusion

Cardiovascular disease is one of the leading causes of death in T2DM patients, so cardiovascular risk reduction is of key importance [7, 10]. SGLT-2 inhibitors, such as canagliflozin, can not only lower blood glucose levels but have also been shown to protect the heart and kidney of affected individuals [3, 11, 14]. New subgroup analyses from the CREDENCE trial now provide evidence that canagliflozin may reduce the risk of hospitalization for heart failure in chronic kidney disease (CKD) T2DM patients with and without preexisting heart disease, underscoring the importance of canagliflozin in the joint management of renal and cardiovascular risks in the treatment of T2DM [4, 5].

*Canagliflozin is not currently approved for the primary prevention of cardiovascular events or for reducing the risk of hospitalization for heart failure (see current SmPC at www.swissmedicinfo.ch).

CH-DIAB-2100002

Post online since 19.03.2021

This article was written with financial support from Mundipharma Medical Company, Basel Branch.

Brief technical information Invokana®

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