The prescription of SGLT2 inhibitors, such as empagliflozin (Jardiance) and dapagliflozin (Forxiga), has increased sharply in recent years. Treatment with SGLT2 inhibitors has increased in several age groups, also in the oldest, 80 years or older. In Region Stockholm, approximately 46,000 individuals took out SGLT-2 inhibitors in 2023. Treatment with SGLT2 inhibitors occurred in 40 percent of patients with a diagnosis of heart failure, 28 percent with a diagnosis of diabetes mellitus type 2 and 18 percent with a diagnosis of kidney disease (diagnosis codes throughout the care last 5 years, data from the care analysis (VAL) database, Region Stockholm). In Sweden, in 2022, almost 163,000 individuals were treated with SGLT2 inhibitors (National Board of Health and Welfare’s statistical database).
These drugs, originally launched as blood sugar-lowering drugs for type 2 diabetes, showed positive results in cardiovascular outcome studies [1-3]. In recent years, the SGLT2 inhibitors dapagliflozin and empagliflozin have received expanded indications for the treatment of chronic heart failure and chronic kidney disease, regardless of whether the patient has diabetes or not [4-9]. Dapagliflozin and empagliflozin now have a class IA recommendation in European heart failure guidelines for chronic heart failure, both in reduced and preserved left ventricular function [10, 11].
In the two large clinical trials in heart failure and systolic left ventricular function (EF) ≤40 percent, the NNT (number needed to treat) was 20 (18 months of treatment) for dapagliflozin and 19 (16 months of treatment) for empagliflozin. Composite primary outcome variable was hospitalization for heart failure or cardiovascular death, but the main effect was primarily due to reduced incidence of heart failure [4, 5]. Approximately half of the patients had type 2 diabetes (42 and 50 percent, respectively). The patients were well treated with RAAS blockade, beta blockade and aldosterone antagonists. Subsequent studies in heart failure with mildly reduced or preserved left ventricular function (EF >40 percent) showed NNTs of 32 (28 months) and 31 (26 months) when treated with dapagliflozin and empagliflozin, respectively [6, 7].
In the two large studies of patients with chronic kidney disease (with and without type 2 diabetes), the effect on the composite primary outcome variable of cardiovascular death and progression of kidney disease was significant already after 2.5 years (NNT 19 and 24, respectively) [8, 9]. The comorbidity between diabetes, heart failure and kidney disease is significant, and a meta-analysis of SGLT2 studies with a total of 89,000 participants shows cardio- and kidney-protective effects in general in these patient groups, especially in renal impairment (eGFR <60 ml/min/1.73 m2) [12].
The risk of ketoacidosis with treatment with SGLT2 inhibitors has been known since the drugs were approved. Normoglycemic ketoacidosis, also called euglycemic ketoacidosis or »euglycemic diabetic keto-acidosis« (eDKA) in English literature, is an unusual but serious and potentially life-threatening condition with an atypical course without significant P-glucose elevation, which makes it difficult to detect and diagnose.
The medical journal has previously published case reports describing ketoacidosis in various conditions [13, 14]. In this issue, a review article describes risk factors, symptoms and preventive measures for ketoacidosis during treatment with SGLT2 inhibitors. The authors believe that there is likely an under-reporting of ketoacidosis if you look at the number of side-effect reports to the Swedish Medicines Agency. We agree with that assessment.
A not insignificant incidence of eDKA has been reported from medical inpatient care in Stockholm. To shed light on the problem, we requested data from the Swedish Medicines Agency’s side effects center for the years 2021 and 2022 regarding ketoacidosis, euglycemic ketoacidosis, diabetic ketoacidosis and acidosis. During these 2 years, there were 48 reported cases of ketoacidosis and simultaneous treatment with dapagliflozin and empagliflozin for the entire country, which speaks for an underreporting.
Underreporting of normoglycemic ketoacidosis in SGLT2 inhibitor therapy and diabetes appears to be a worrisome and potentially underestimated phenomenon. One possible reason is that healthcare professionals are not fully aware of the risk that the symptoms patients experience with the condition are confused with other conditions and thus not reported or documented correctly.
In the clinical trials, the incidence of ketoacidosis was 0.1–0.3 percent among those receiving SGLT2 inhibitors, but ketoacidosis was also seen in several cases in those receiving placebo. Most people who suffered from ketoacidosis had diabetes [1, 2, 4-9] (Table 1). Side effects that are rare in clinical trials may occur at a higher frequency when treating patients in the community. In clinical studies, there are strict inclusion criteria, and the oldest patients are rarely included in the studies. Monitoring and follow-up takes place in a way that differs from ordinary healthcare. Although the incidence of ketoacidosis in real life is consistent with the incidence in clinical trials, increased use of SGLT2 inhibitors may mean more cases of ketoacidosis in absolute terms. In Stockholm, an incidence of ketoacidosis of 0.1 percent of SGLT2-treated individuals would mean 46 cases of ketoacidosis.
Knowledge of the serious side effects of SGLT2 inhibitors is still insufficient, and measurement of blood ketones is not always available, either in health centers, in ambulances, or in departments other than internal medicine. Suggested measures for prevention during surgery, including regular monitoring of blood ketones, are probably far from practical today. Recommended time intervals for discontinuation of SGLT2 inhibitors before surgery and reintroduction after surgical procedures need to be established, not least among anesthesiologists who are responsible for the preoperative assessment and surgeons who are responsible for postoperative care and discharge prescriptions.
It is of great importance to increase the knowledge of both healthcare providers and patients about which conditions should be avoided or discontinued treatment with SGLT2 inhibitors. It is important to emphasize that patients with type 1 diabetes, latent autoimmune diabetes in adults (LADA) or insulin-treated diabetes secondary to pancreatic disease are not only risk groups but should be excluded from treatment with SGLT2 inhibitors. Risk factors for ketoacidosis include reduced carbohydrate intake (for example, intermittent fasting, nausea/vomiting, or low-carbohydrate diet), dehydration/dehydration (for example, due to vomiting, diarrhea, or high fever), acute illness requiring hospitalization, surgery, severe liver disease, and high alcohol consumption.
We suggest that prescribers print patient information on SGLT2 inhibitors and review it with the patient. Such patient information is available, for example, on Janusinfo and was added three years ago through collaboration between the expert groups for endocrine diseases, kidney diseases and cardiovascular diseases within Region Stockholm’s pharmaceutical committee [15].
In addition, it is necessary to raise awareness in both primary care and specialist care about normoglycemic ketoacidosis to enable adequate screening and early diagnosis, which can reduce the risk of hospitalization and, in the worst case, death. A strengthened communication and collaboration between the patient, primary care and other care agencies is crucial to achieving the best possible results in care.
In order to improve the effectiveness and safety of the treatment, it is necessary to increase awareness in healthcare, educate healthcare professionals about potential risks and encourage accurate reporting of side effects to the Swedish Medicines Agency.
Read also:
Overview: SGLT2 inhibitors and ketoacidosis
Potential Bonds or Jealous Relationships: None stated.
The medical journal. 2024;121:23214
The medical journal 7-8/2024
Lakartidningen.se 2024-02-13
