Recommendation for Appropriate Use of Sodium Glucose Cotransporter 2 Inhibitors in Treatment of Heart Failure

Sodium glucose cotransporter 2 (SGLT2) inhibitors were approved in Japan in 2014 for the treatment of diabetes by inhibiting SGLT2 in the proximal tubule, which increases urinary glucose excretion and lowers blood glucose levels. Cardiovascular outcome trials published since 2015 in patients with type 2 diabetes (T2D) at high risk for cardiovascular disease have shown that SGLT2 inhibitors reduced the risk of heart failure (HF) events requiring hospitalization.^1–3 Consequently, in the Japanese Circulation Society (JCS)/Japan Heart Failure Society (JHFS) 2017 guideline on diagnosis and treatment of acute and chronic heart failure,⁴ SGLT2 inhibitors were placed in recommendation Class I and Level of Evidence A for preventing HF in patients with T2D at high risk of cardiovascular disease. In the JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure,⁵ SGLT2 inhibitors are now recommended as Class I with Level of Evidence A for treatment of patients with T2D complicated by HF. Subsequently, large clinical trials published after 2019 in patients with chronic HF with reduced ejection fraction (HFrEF), with and without T2D,^6,7 reported that dapagliflozin and empagliflozin reduced the risk of HF events, which subsequently led to expansion of the indication to patients with HF after 2020 in Japan. Dapagliflozin and empagliflozin are now recommended as Class I with Level of Evidence A for treating patients with symptomatic chronic HFrEF who are already receiving optimal medical therapy.⁵ Furthermore, large clinical trials of patients with chronic HF with preserved ejection fraction (HFpEF), with and without T2D,^8,9 reported that dapagliflozin and empagliflozin also reduced HF events and have been recently indicated for patients with HFpEF. Thus, SGLT2 inhibitors are increasingly being used both to prevent HF in patients with T2D at high risk for cardiovascular disease and as one of the standard treatments for HF, irrespective of complications of T2D or left ventricular ejection fraction. Therefore, we have issued this recommendation to promote appropriate use of SGLT2 inhibitors in patients with HF. When using SGLT2 inhibitors in these patients, please refer to this recommendation and the recommendations on the appropriate use of SGLT2 inhibitors issued by the Japan Diabetes Society and Japanese Society of Nephrology.

Recommendations

• In patients with T2D at high risk of cardiovascular disease, SGLT2 inhibitors reportedly reduce HF events requiring hospitalization, so their use is strongly recommended after carefully considering the risks and benefits.

• In patients with HF, SGLT2 inhibitors (dapagliflozin and empagliflozin) reportedly reduce HF events in patients with and without T2D and regardless of left ventricular ejection fraction, so their use is strongly recommended after carefully considering the risks and benefits.

• Because diuretics are used more frequently in patients with HF and there is a possible risk of excessive fluid loss with concomitant use of diuretics and SGLT2 inhibitor, renal function and electrolytes should be monitored appropriately, and diuretic and antihypertensive agents should be adjusted as needed.

• In patients with T2D and HF who are taking an SGLT2 inhibitor and plan to undergo surgery with restricted food intake, the SGLT2 inhibitor should be withdrawn 3 days preoperatively and restarted postoperatively when food intake is started. On the other hand, in patients without T2D but with HF who are taking an SGLT2 inhibitor, the SGLT2 inhibitor should be withdrawn on the all-day preoperative fasting day and begun postoperatively when food intake is restarted. Accordingly, SGLT2 inhibitor withdrawal is not always necessary before surgery that does not require all-day fasting. In the case of patients with HF, with and without T2D, who must undergo emergency surgery while taking an SGLT2 inhibitor, an on-site decision regarding withdrawal of the SGLT2 inhibitor is permissible after carefully considering the risks and benefits of withdrawal. In any case, referral to a cardiologist is recommended before withdrawal of an SGLT2 inhibitor in patients with HF and for possibly related exacerbations if withdrawal has already occurred. This advice is represented schematically in the Figure.

Figure.

(A–C) Schema of recommendation for the use or withdrawal of SGLT2 inhibitors before surgery in patients with heart failure.

• Because SGLT2 inhibitors may cause or exacerbate urinary tract and genital tract infections, in both diabetic and non-diabetic patients with HF, the indication of SGLT2 inhibitors should be fully considered with an assessment of the risks and benefits, and followed by careful monitoring after initiation.

• In patients with HF, SGLT2 inhibitors should be used appropriately according to the package insert of each drug and this recommendation. Depending on the comorbid conditions of diabetes and chronic kidney disease, the recommendations of the Japan Diabetes Society and of the Japanese Society of Nephrology regarding the appropriate use of SGLT2 inhibitors should be referred to as well.

Acknowledgments

We appreciate the critical review and important feedback by administrative board members of the Japanese Circulation Society, Japanese Heart Failure Society, Japan Diabetes Society, and Japanese Society of Nephrology.

Sources of Funding

None.

Disclosures

See details Appendix. Drs. Koichiro Kinugawa, Koichiro Kuwahara, Hiroshi Ito, Toyoaki Murohara, Ken-ichi Hirata and Koichi Node are members of Circulation Jouranl’s Editorial Team.

Appendix. Disclosure of Potential Conflicts of Interest (COI): Recommendation for Appropriate Use of Sodium Glucose Cotransporter 2 Inhibitors in Treatment of Heart Failure (2020/1/1–2022/12/31)

Author	Member’s own declaration items									COI of the marital partner, first-degree family members, or those who share income and property			COI of the head of the organization/department to which the member belongs (if the member is in a position to collaborate with the head of the organization/department)
	Employer/ leadership position (private company)	Stakeholder	Patent royalty	Honorarium	Payment for manuscripts	Research grant	Scholarship (educational) grant	Endowed chair	Other rewards	Employer/ leadership position (private company)	Stakeholder	Patent royalty	Research grant	Scholarship (educational) grant
Atsushi Tanaka, MD, PhD				Nippon Boehringer Ingelheim Co., Ltd.		GlaxoSmithKline K.K. Takeda Pharmaceutical Company Limited	Bristol-Myers Squibb
Koichiro Kinugawa, MD, PhD				AstraZeneca K.K. Nippon Boehringer Ingelheim Co., Ltd. Mitsubishi Tanabe Pharma Corporation
Koichiro Kuwahara, MD, PhD				Alnylam Japan Astellas Pharma Inc. AstraZeneca K.K. Novartis Pharma K.K. Novo Nordisk Pharma Ltd. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Janssen Pharmaceutical K.K. Kyowa Kirin Co., Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Mitsubishi Tanabe Pharma Corporation Eli Lilly Japan K.K. Nippon Boehringer Ingelheim Co., Ltd.		EP-CRSU Co., Ltd. AstraZeneca K.K. Janssen Pharmaceutical K.K. Kowa Company, Ltd. Nippon Boehringer Ingelheim Co., Ltd.	Fukuda Denshi Nagano hanbai Co., Ltd Taisho Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd.	Abbott Medical Japan LLC. (2 courses) Cardinal Health Japan TERUMO CORPORATION Nipro Corporation BIOTRONIK Japan, Inc. Boston Scientific Japan K.K. (2 courses) Medtronic Japan Co., Ltd. Japan Lifeline Co.,Ltd.
Hiroshi Ito, MD, PhD				Daiichi Sankyo Company, Limited. Novartis Pharma K.K. Nippon Boehringer Ingelheim Co., Ltd. Bayer Yakuhin, Ltd. Ono Pharmaceutical Co., Ltd. AstraZeneca K.K. Mochida Pharmaceutical Co.,Ltd. Otsuka Pharmaceutical Co., Ltd. Kowa Company, Ltd.			Daiichi Sankyo Company, Limited. Bayer Yakuhin, Ltd. Otsuka Pharmaceutical Co., Ltd. Mochida Pharmaceutical Co.,Ltd. Ono Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation	Medtronic Japan Co., Ltd
Toyoaki Murohara, MD, PhD				AstraZeneca K.K. Kowa Company, Ltd. Nippon Boehringer Ingelheim Co., Ltd. Bayer Yakuhin, Ltd. Janssen Pharmaceutical K.K. Ono Pharmaceutical Co., Ltd. Novartis Pharma K.K. MSD K.K. Daiichi Sankyo Company, Limited.			Daiichi Sankyo Company, Limited. Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Teijin Pharma Limited Pfizer Japan Inc. Bayer Yakuhin, Ltd. Astellas Pharma Inc. Takeda Pharmaceutical Company Limited
Ken-ichi Hirata, MD, PhD				Novo Nordisk Pharma Ltd. Kowa Company, Ltd.		Daiichi Sankyo Company, Limited. Sysmex Corporation TERUMO CORPORATION RIKEN Kobe Pharmaceutical University Japan PH Registry	Abbott Medical Japan LLC. Otsuka Pharmaceutical Co., Ltd. Kowa Company, Ltd. Takeda Pharmaceutical Company Limited Nippon Boehringer Ingelheim Co., Ltd. Nihon Medi-Physics Co., Ltd. BIOTRONIK Japan, Inc. FUJIFILM Toyama Chemical Co., Ltd. Pfizer Japan Inc. Janssen Pharmaceutical K.K.	Abbott Japan LLC (formerly St. Jude Medical Japan Co., Ltd.) Medtronic Japan Co., Ltd. BIOTRONIK Japan, Inc. Sysmex Corporation
Koichi Node, MD, PhD				MSD K.K. Astellas Pharma Inc. AstraZeneca K.K. TSUMURA & CO. Novartis Pharma K.K. Novo Nordisk Pharma Ltd. Bayer Yakuhin, Ltd. Kowa Company, Ltd. Mochida Pharmaceutical Co.,Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Mitsubishi Tanabe Pharma Corporation Eli Lilly Japan K.K. Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited		Astellas Pharma Inc. Novartis Pharma K.K. Asahi Kasei Corp. Mochida Pharmaceutical Co.,Ltd. Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. FUJI YAKUHIN CO., LTD.	Bayer Yakuhin, Ltd. Teijin Pharma Limited Medtronic Japan Co., Ltd.

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