Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives

Abstract

Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of antihyperglycemic drugs that have been approved for the treatment of type 2 diabetes mellitus (T2DM). These drugs inhibit glucose reabsorption in the proximal tubules of the kidney thereby enhancing glucosuria and lowering blood glucose levels. Additional consequences and benefits include a reduction in body weight, uric acid levels, and blood pressure. Moreover, SGLT2 inhibition can have protective effects on the kidney and cardiovascular system in patients with T2DM and high cardiovascular risk. However, a potential side effect that has been reported with SGLT2 inhibitors in patients with T2DM and particularly during off-label use in patients with type 1 diabetes is diabetic ketoacidosis. The US Food and Drug Administration recently warned that SGLT2 inhibitors may result in euglycemic ketoacidosis. Here, we review the basic metabolism of ketone bodies, the triggers of diabetic ketoacidosis, and potential mechanisms by which SGLT2 inhibitors may facilitate the development of ketosis or ketoacidosis. This provides the rationale for measures to lower the risk. We discuss the role of the kidney and potential links to renal gluconeogenesis and uric acid handling. Moreover, we outline potential beneficial effects of modestly elevated ketone body levels on organ function that may have therapeutic relevance for the observed beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system.

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

“…The ketone bodies are released into the systemic circulation to provide an alternative energy substrate when blood glucose is low. At high levels of plasma ketone bodies, SGLT2 inhibitors may also facilitate the renal retention of ketone bodies by lowering GFR (see below) and thereby reducing the filtered amount of ketone bodies below the renal tubular reabsorption capacity [22]. Hence, increased ketonemia and DKA can occur in response to SGLT2 inhibition in the absence of hyperglycemia [21, 22].…”

“…At high levels of plasma ketone bodies, SGLT2 inhibitors may also facilitate the renal retention of ketone bodies by lowering GFR (see below) and thereby reducing the filtered amount of ketone bodies below the renal tubular reabsorption capacity [22]. Hence, increased ketonemia and DKA can occur in response to SGLT2 inhibition in the absence of hyperglycemia [21, 22]. The low basal endogenous insulin levels typical of type 1 diabetes is thought to enhance the risk of DKA compared with type 2 diabetic patients.…”

“…The low basal endogenous insulin levels typical of type 1 diabetes is thought to enhance the risk of DKA compared with type 2 diabetic patients. Several potential ketoacidosis triggers have been identified in patients with type 1 diabetes including major illness, reduced food and fluid intake, concomitant mild infection, increased physical activity, and/or reduced food intake and acute insulin dose reduction or omission, whereas in some cases, no contributing factors were identified [22, 23]. …”

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

“…Another noteworthy characteristic of SGLT2i is that they are associated with elevated plasma ketone levels in humans . SGLT2i enhance glucosuria by effectively lowering plasma glucose levels, resulting in decreased fasting insulin and increased fasting glucagon .…”

Protracted glycosuria after discontinuation of sodium‐glucose cotransporter 2 inhibitors: Implications for weekly dosing and extended risk of euglycemic diabetes ketoacidosis

“…Because SGLT2i‐induced glycosuria can correct hyperglycemia, relative insulin deficiency can lead to DKA while patients are euglycemic or even hypoglycemic . If the glycosuric effect is present beyond discontinuation of these drugs, euglycemic DKA may not be even suspected, less so predicted or prevented .…”