ABSTRACT
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are highly selective, effective, and generally well-tolerated antihyperglycemic agents targeting the SGLT-2 transmembrane protein. Despite being primarily registered for diabetes treatment, due to their cardiorenal protective properties, SGLT-2 inhibitors caused a paradigm shift in the treatment of other diseases on the cardiorenal spectrum, becoming a fundamental part of heart failure and chronic kidney disease management. With their rapidly increasing use, there are also increased reports of a rare, often under-recognised and potentially deadly side effect, SGLT-2-inhibitor-induced euglycemic diabetic ketoacidosis (EDKA). The primary pathophysiological process behind its multifactorial aetiology comprises glucosuria and osmotic diuresis, which produce a significant carbohydrate deficit, leading to an increase in the glucagon-insulin ratio, thus resulting in accelerated ketogenesis. Although EDKA has a similar clinical presentation as diabetic ketoacidosis (DKA), the absence of the high glucose levels typically expected for DKA and the presence of urine ketone reabsorption contribute to a significant delay in its recognition and timely diagnosis. Given the broad use of SGLT-2 inhibitors, increased awareness, early recognition, and prompt identification of precipitating factors are essential. In this narrative review, we comprehensively explore the pathophysiological mechanisms of SGLT-2-inhibitor-induced EDKA, analyse its clinical manifestation, and identify the most common triggers for its development. We also discuss EDKA management and preventive strategies.
ABSTRACT
BACKGROUND: There are insufficient data on continuous glucose monitoring (CGM) in nonintensive insulin therapy patients. Using CGM and the recommended CGM targets, we wanted to evaluate low-premix insulin analogue therapy (biphasic aspart/NovoMix 30 and biphasic lispro 25/Humalog Mix 25) in real-world type 2 diabetes patients for glycaemic efficacy and especially hypoglycaemia. METHODS: The prospective observational study was performed on 35 patients who were treated with a low-premixed insulin. We used the Dexcom G6 system for CGM (9.6 ± 1 days) to measure the clinically relevant CGM parameters: glycaemic variability (%CV), TBR (time below range) < 3.0 mmol/l = 54 mg/dl (level 2 hypoglycaemia), TBR 3.0-3.8 (= 54-69 mg/dl), TIR (time in range) 3.9-10-0 mmol/l (70-180 mg/dl), TAR (time above range) 10-13.9 mmol/l (180-250 mg/dl) and TAR > 13.9 mmol/l (250 mg/dl). We also assessed clinical and demographic characteristics, laboratory HbA1c, fasting blood glucose, peak postprandial glucose values, and the percentage of hypoglycaemia between 00:00 and 06:00. RESULTS: In our patients, the average ± SD age was 70.4 ± 9.2 years, diabetes duration 17.4 ± 7.1 years, 51% were females, average daily insulin dose was 46.4 units (80% received biphasic aspart). The average ± SD TIR was 62.1 ± 12.2%, TBR < 3.0 mmol/l 0.8 ± 2.0%, TBR 3.0-3.8 mmol/l 1.5 ± 1.5%, TAR 10-13.9 mmol/l 29.2 ± 12.4%, TAR > 13.9 mmol/l 6.4 ± 7.2% and %CV 29.9 ± 7.1%. The average time in hypoglycemia was 33.1 min daily in our patients (11.5 min in the level 2 range). In the older/high-risk population, the TBR/TIR/TAR/level 2 TAR targets were met in 40/80/77/80%, respectively. For the general T2D people, level 2 TBR/TBR/TIR/TAR/level 2 TAR would be met in 74/83/34/77/49%. Average fasting blood glucose was 8.0 ± 2.5 mmol/l (144 ± 45 mg/dl), BMI 31.3 ± 5.1 kg/m2, daily insulin dose 46.4 ± 12.1 units, HbA1c 57.4 ± 5.4 mmol/mol (7.4 ± 0.7%). The glycaemic variability goal was met in 80% (with 66% meeting the lower 33% CV goal). 17 ± 12% of hypoglycaemia was nocturnal. People with TBR > 4% were significantly older. CONCLUSIONS: Most of our type 2 diabetes patients, treated with low-premixed insulin, did not meet the recommended TBR target for older/high-risk patients while meeting the TIR and TAR targets. Nevertheless, the time spent in (total and nocturnal) hypoglycemia was short. The study indicates that the general type 2 diabetes population targets would mostly be met for TBR and %CV in our patients but not the TIR and TAR targets. CGM appears to be a useful clinical tool in these patients.