Abstract
Diabetic ketoacidosis has been described as a rare complication of acromegaly and may be observed in 1% of affected patients. The well-described direct lipolytic effect of growth hormone results in increased availability of free fatty acids (FFAs) for hepatic ketogenesis and is an important pathogenic event. More recently, ketoacidosis has been identified as an important complication of sodium-glucose-transport-protein 2 inhibitors (SGLT2i). Increased pancreatic glucagon secretion, impaired renal ketone body clearance, and an increase in FFA concentrations secondary to decreased insulin concentrations are likely precipitating factors.
We report a case of rapid-onset severe ketoacidosis within 2 days after adding empagliflozin to metformin, sitagliptin, and gliclazide in a presumably type 2 diabetic patient with unrecognized acromegaly and chronic hyperglycemia. Transsphenoidal resection of the growth-hormone secreting macroadenoma restored normal growth-hormone and insulinlike growth factor 1 concentrations and the diabetes was well controlled thereafter.
We hypothesize that SGLT2i, through their intrinsic effects on ketone body metabolism, may possibly precipitate ketoacidosis in patients with active acromegaly and diabetes mellitus.
A 52-year-old white man came to the emergency department because of new-onset asthenia, loss of appetite, polyuria of up to 6 L daily and tachydyspnea. His medical history was remarkable for type 2 diabetes diagnosed 6 years ago, overweight (body mass index, 27.4 kg/m2), and chronic lumbar pain. He felt well until two days earlier, when his general practitioner added empagliflozin 10 mg daily to the pre-existing antidiabetic regimen of metformin (1000 mg twice daily), sitagliptin (50 mg twice daily), and gliclazide (30 mg daily) because of chronic hyperglycemia (hemoglobin A1c level, 9.6%). Aside from the occasional use of acetaminophen and metamizole for his lumbar pain, the patient was not taking any regular medication.
On arrival, the patient was oriented and fully awake but tachycardic (132 bpm), tachydyspneic (respiratory rate, 30/min), and mildly hypertensive (blood pressure, 147/98 mm Hg). Laboratory testing (Table 1) showed moderate hyperglycemia (14 mmol/L), +++ ketonuria, and anion-gap metabolic acidosis and led to the diagnosis of euglycemic diabetic ketoacidosis, presumably triggered by the addition of empagliflozin to the pre-existing drug regimen. However, the patient refused to be admitted and left the hospital after 10 U of glargine had been administered. He followed the advice to discontinue his oral antidiabetic medication. His condition rapidly deteriorated, and he returned the next day with severe hyperglycemia and worsened acidosis (Table 1) but was still hemodynamically stable (blood pressure, 160/90 mm Hg; heart rate, 140/min). Intravenous fluid and insulin replacement resulted in rapid metabolic recovery, and glucose values were controlled with multiple daily insulin injections. Islet-specific autoantibodies (GAD-Ab, IA2-Ab, and islet cell antibodies) were negative.
Plasma, Whole Blood (Venous Blood Gas Analysis), and Urine Test Results on Initial Presentation
| Test Result | Day Before Admission | On Admission |
|---|---|---|
| Glucose, mmol/L | 14.9 | 26.0 |
| Creatinine, μmol/L | 110 | 173 |
| pH | 7.13 | 6.95 |
| Bicarbonate, mmol/L | 7.3 | 4.6 |
| Chloride, mmol/L | 111 | 108 |
| Sodium, mmol/L | 137 | 133 |
| Anion gap, mmol/L | 18.4 | 24.7 |
| Lactate, mmol/L | 1.6 | 4.2 |
| Urine ketone bodies | +++ | n.d. |
| Test Result | Day Before Admission | On Admission |
|---|---|---|
| Glucose, mmol/L | 14.9 | 26.0 |
| Creatinine, μmol/L | 110 | 173 |
| pH | 7.13 | 6.95 |
| Bicarbonate, mmol/L | 7.3 | 4.6 |
| Chloride, mmol/L | 111 | 108 |
| Sodium, mmol/L | 137 | 133 |
| Anion gap, mmol/L | 18.4 | 24.7 |
| Lactate, mmol/L | 1.6 | 4.2 |
| Urine ketone bodies | +++ | n.d. |
Abbreviation: n.d., not determined.
Plasma, Whole Blood (Venous Blood Gas Analysis), and Urine Test Results on Initial Presentation
| Test Result | Day Before Admission | On Admission |
|---|---|---|
| Glucose, mmol/L | 14.9 | 26.0 |
| Creatinine, μmol/L | 110 | 173 |
| pH | 7.13 | 6.95 |
| Bicarbonate, mmol/L | 7.3 | 4.6 |
| Chloride, mmol/L | 111 | 108 |
| Sodium, mmol/L | 137 | 133 |
| Anion gap, mmol/L | 18.4 | 24.7 |
| Lactate, mmol/L | 1.6 | 4.2 |
| Urine ketone bodies | +++ | n.d. |
| Test Result | Day Before Admission | On Admission |
|---|---|---|
| Glucose, mmol/L | 14.9 | 26.0 |
| Creatinine, μmol/L | 110 | 173 |
| pH | 7.13 | 6.95 |
| Bicarbonate, mmol/L | 7.3 | 4.6 |
| Chloride, mmol/L | 111 | 108 |
| Sodium, mmol/L | 137 | 133 |
| Anion gap, mmol/L | 18.4 | 24.7 |
| Lactate, mmol/L | 1.6 | 4.2 |
| Urine ketone bodies | +++ | n.d. |
Abbreviation: n.d., not determined.
Clinical appearance and further exploration revealed several signs and symptoms suggestive of acromegaly, such as prognathism, coarse facial features, enlarged hands, an increasing shoe size, periodic bifrontal headache, and snoring. Insulinlike growth factor 1 (111 nmol/L; age- and sex-specific reference range, 7 to 31 nmol/L) and growth hormone (GH) concentrations (18.6 μg/L) were elevated and confirmed the diagnosis. Sellar magnetic resonance imaging showed a right-sided intrasellar and infrasellar macroadenoma (Fig. 1), and the further workup revealed normal visual fields and normal function of the remaining pituitary with no cosecretion of prolactin (11.4 μg/L; normal, <15 μg/L). Polysomnography confirmed moderate obstructive sleep apnea.
Contrast-enhanced T1-weighted magnetic resonance images showing a left-sided intrasellar and infrasellar macroadenoma adjacent to the left cavernous sinus (left panel) and a corresponding follow-up scan 3 months postoperatively with no residual tumor (right panel).
The subsequent endoscopically navigated transsphenoidal surgery resulted in complete macroscopic tumor resection of a histologically somatotrophic adenoma with strong positive immunostaining for GH and a mitotic index <3%. The further course was favorable with rapid improvement or resolution of several typical symptoms associated with acromegaly, and both insulin-like growth factor 1 (34 nmol/L) and GH (0.5 mg/L) levels returned to the normal range at 3-month follow-up. A repeated magnetic resonance scan showed no residual tumor (Fig. 1). Insulin was switched to metformin and sitagliptin upon discharge from the hospital, and the patient’s diabetes continued to be well controlled 3 months later (hemoglobin A1c, 6.4%).
Discussion
Sodium-glucose transport protein 2 inhibitors (SGLT2i), including empagliflozin, are widely used hypoglycemic agents in type 2 diabetes and are currently investigated in patients with type 1 diabetes. Effective glucose lowering occurs through their glycosuric effect, and improved cardiovascular and renal outcomes have been reported in subjects who are high risk (1). Euglycemic ketoacidosis has been recognized as a rare, though life-threatening, adverse event associated with the use of SGLT2i and may also occur in type 2 diabetes (2). SGLT2i increase plasma ketone levels through enhanced fat oxidation and increased synthesis as a result of an increased glucagon-to-insulin ratio. Renal glucose losses result in decreased insulin secretion, which is followed by decreased paracrine intraislet insulin inhibition of glucagon secretion. The latter is further stimulated by decreased α-cell glucose uptake resulting from SGLT2 inhibition. In addition to increased production, diminished renal ketone-body elimination occurs during SGLT2 inhibition (3–5). If additional events promoting ketone-body synthesis, such as systemic infection, surgery, alcohol excess, or carbohydrate or caloric restriction, occur, mild ketonemia may rapidly progress to ketoacidosis within a few days. Owing to ongoing renal glucose wasting, this progression occurs in the presence of only mildly elevated glucose levels (6). An additional increase in plasma lactate, probably secondary to enhanced intraerythrocytic l-lactate formation via the glycolytic pathway, further contributed to the severe anion-gap metabolic acidosis in the patient.
Diabetes is a well-known feature of acromegaly, occurring in up to 18% to 38% of patients with the condition, and it may be diagnosed at initial presentation in 20% of these patients (7). In contrast to type 2 diabetes, it is associated with a relatively lean phenotype, and insulin resistance secondary to a shift from glucose to fatty acid oxidation after enhanced GH-induced lipolysis is a hallmark pathogenic feature (8). The lipolytic and ketogenic actions of GH are well described, have a rapid onset, and are further enhanced by acute insulin deficiency (9). Although rare, several cases of diabetic ketoacidosis—during the course of the disease and as initial presentation—have been reported. A recent Japanese series suggests that ketoacidosis may be the initial clinical presentation of acromegaly in up to 1% of patients (10). From the limited literature, it is difficult to draw a firm picture of patient characteristics or conditions conferring an increased risk of acromegaly-associated ketoacidosis. Surgery and acute infections have been reported as precipitating factors and may lead to β-cell glucose toxicity, impaired insulin secretion, and/or further enhanced lipolysis and ketogenesis. Control of GH excess usually resulted in improved glucose metabolism, and insulin therapy could be withdrawn during follow-up in most patients with an initial ketoacidotic presentation (10).
To our knowledge, we report the first patient with unrecognized acromegaly in whom use of an SGLT2 inhibitor was the likely precipitating event leading to the rapid occurrence of ketoacidosis within only 2 days. This may be well explained by the additive effects of both conditions (i.e., uncontrolled GH excess and SGLT2 inhibition) on free fatty acid and ketone-body metabolism. After enhanced free fatty acid flux through GH-induced lipolysis, the initiation of empagliflozin further promoted hepatic ketogenesis due to an increase in the glucagon-to-insulin ratio and decreased renal clearance of ketone bodies, resulting in initially euglycemic ketoacidosis. β-cell glucose toxicity and subsequent insulin deficiency secondary to severe chronic hyperglycemia certainly may have contributed to both enhanced lipolysis and ketogenesis and the subsequent rapid onset of ketoacidosis. A thorough workup, including tests for anti-islet antibodies, failed to identify any further risk factors and a patient who was asymptomatic and in good general condition until the start of empagliflozin, suggest that empagliflozin was the main trigger leading to the rapid onset of severe ketoacidosis.
In summary, SGLT2i, through their intrinsic effects on fatty acid and ketone-body metabolism, may possibly precipitate ketoacidosis and should be used with great caution in active acromegaly. Patients with poor β-cell function resulting from severe chronic hyperglycemia may be at particular risk. Despite several typical clinical features of acromegaly, the rather early onset of diabetes at age 46, a relatively lean phenotype, and a negative family history, the patient’s diabetes was misclassified as type 2. If there is any clinical suspicion, acromegaly should be ruled out by further biochemical testing before SGLT2i are prescribed to improve glycemic control.
Abbreviations:
Acknowledgments
Disclosure Summary: The authors have nothing to disclose.
References
Author notes
Address all correspondence and requests for reprints to: Stefan Bilz, MD, Division of Endocrinology and Diabetes, Kantonsspital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland. E-mail: stefan.bilz@kssg.ch.
