By Florencia Moraga Masson, Zheng Cheng Zhu
Key reference:
Hamblin, P. S., Wong, R., Ekinci, E. I., Sztal-Mazer, S., Balachandran, S., Frydman, A., Hanrahan, T. P., Hu, R., Ket, S. N., Moss, A., Ng, M., Ragunathan, S., & Bach, L. A. (2021). Capillary Ketone Concentrations at the Time of Colonoscopy: A Cross-Sectional Study With Implications for SGLT2 Inhibitor–Treated Type 2 Diabetes. Diabetes Care, 44(6), e1–e3. https://doi.org/10.2337/DC21-0256
Quick Summary
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Recent case series highlighted an association between diabetes patients taking sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) undergoing colonoscopy and development of diabetic ketoacidosis (DKA).
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Previous guidelines recommend postponing colonoscopies if capillary ketone concentrations exceed 1.0 mmol/L without withholding SGLT2 inhibitors for 72 hours, but this was formulated without data on non-diabetic patients ketone levels during colonoscopy.
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To address this gap, the multicentre observational study by Hamblin et al. (2021) study investigated capillary ketone concentrations in patients undergoing colonoscopies and compared normoglycemic adults with those of diabetic patients, taking and not taking SGLT2 inhibitors.
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In normoglycemic individuals undergoing colonoscopy, the reference capillary ketone concentrations was determined to be 0.0–1.7 mmol/L
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However, the study found no statistically significant differences in ketone concentrations between diabetics treated with SGLT2 inhibitors and those who are not diabetic or not treated with SGLT2 inhibitors (p=0.051)
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Caution is warranted in interpreting the 1.7 mmol/L threshold as safe for those taking SGLT2 inhibitors (i.e not withheld for 72hrs)
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The study highlights the need for appropriate monitoring and management strategies to mitigate the risk of DKA in SGLT2 inhibitor-treated patients undergoing colonoscopy
CASE
James Smith is a 70 year-old gentleman with Type 2 diabetes who presents for a Cat 2 colonoscopy for investigation of iron deficiency anaemia. Despite instructions to withhold his sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor) medication 2 full days before the procedure and on the day of procedure, he admits that he has taken his regular empagliflozin, having forgotten which pill not to take.
“I’m sorry, doc. It shouldn’t be a problem, right?”
The Basics
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus characterised by hyperglycaemia (high blood sugar levels), ketosis (elevated ketone bodies in the blood), and metabolic acidosis (increased acidity in the blood).
It typically occurs in individuals with type 1 diabetes (T1DM) but can also affect those with type 2 diabetes (T2DM), particularly in cases of severe insulin deficiency.
In DKA, the body’s cells are unable to access glucose for energy due to insulin deficiency, leading to increased fat breakdown and the production of ketone bodies as an alternative fuel source.
This results in elevated blood ketone levels, leading to metabolic acidosis, dehydration, electrolyte imbalances, and potentially life-threatening complications if left untreated.
Table 1: Risk Factors for DKA
Patient Factors |
Surgical Factors |
Anaesthetic Factors |
Absolute insulin deficiency (eg. undiagnosed or untreated type 1 diabetes) Relative insulin deficiency (eg. reduced insulin effectiveness due to illness or stress) Reduced fluid intake due to nausea, vomiting, or inability to drink Pregnancy Infections, such as urinary tract infections, pneumonia or gastroenteritis |
Surgical procedures or traumatic events leading to increased stress on the body Duration of surgery Intraoperative fluid shifts Blood loss or hypovolaemia |
Inadequate preoperative fasting instructions Interruption of insulin therapy during the perioperative period Inadequate perioperative medication management (eg. continuing with SGLT-2 inhibitor treatment rather than ceasing 2 full days and day of surgery) |
Symptoms of DKA may include excessive thirst, frequent urination, nausea, vomiting, abdominal pain, rapid breathing, and confusion.
Prompt medical intervention, including intravenous fluids, insulin therapy and correction of electrolyte abnormalities is essential to manage DKA and prevent complications. The specific diagnostic criteria and management of DKA are beyond the scope of this article, and local protocols and relevant departments (Endocrine, Intensive Care) should be consulted immediately.
Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2 inhibitors) and DKA:
Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) are a class of medications used in the management of T2DM.
These medications work by inhibiting the action of the SGLT2 protein in the kidneys, which is responsible for reabsorbing glucose from the urine back into the bloodstream. SGLT2 inhibitors promote the excretion of glucose in the urine, leading to a decrease in blood sugar levels.
They are typically used as second or third-line therapy to diet and exercise in patients with T2DM who have not achieved adequate glycemic control with other antidiabetic medications, such as metformin or sulfonylureas.
SGLT2 inhibitors have also been incorporated into the management of heart failure with reduced ejection fraction (HFrEF) and chronic nephropathy, with robust evidence demonstrating reductions in hospitalisation and mortality rates independent of diabetes status.
There is also emerging evidence to show benefits for patients with heart failure with preserved ejection fraction (HFpEF). The EMPEROR-Preserved trial demonstrated that SGLT2 inhibitors, specifically empagliflozin, reduced the risk of decompensation-related hospitalisation irrespective of their diabetes status. This landmark trial highlighted the efficacy of SGLT2 inhibitors in improving outcomes for patients with HFpEF, a condition for which effective treatment options remain limited.
SGLT2 inhibitors are generally well-tolerated but may be associated with side effects such as urinary tract infections, genital yeast infections, and an increased risk of DKA, particularly in patients with additional risk factors such as dehydration or acute illness.
DKA can occur in patients treated with SGLT2 inhibitors with both high blood glucose levels and normal or only slightly elevated blood glucose levels (euDKA). Specifically, interventional gastroenterology procedures like colonoscopies present a significant risk for DKA when using SGLT2 inhibitors. This risk is heightened by factors such as bowel preparation, fluid-only dietary restrictions, and fasting.
The pathophysiology of SGLT2 inhibitor-related euDKA has not been fully elucidated. Hypothesised mechanisms suggest that, in response to lower baseline plasma glucose levels secondary to concurrent glycosuria (from SGLT2 inhibition) and carbohydrate deficit (from fasting), there is a homeostatic reduction in insulin release. This insulinopenia can be further exacerbated by acute illness or metabolic stress in part due to elevated catecholamine and cortisol. Subsequently, there is an upregulation of glucagon release, lipolysis and ketogenesis as alternative energy sources, leading to DKA.
Figure 1: Proposed pathophysiology of SGLT2-inhibitor induced euglycaemic ketoacidosis
As SGLT2 inhibitors become increasingly prevalent, It is essential for healthcare providers to be aware of this potential risk and to carefully monitor patients treated with SGLT2 inhibitors for signs and symptoms of DKA.
In patients with signs and symptoms of DKA, but normal glucose levels, a blood gas to assess bicarbonate and anion gap is critical to not miss the diagnosis.
Table 2: Symptoms and signs of DKA
A |
Usually preserved, but may become unprotected with reduced GCS and nausea + vomiting |
B |
Rapid, deep breathing (Kussmaul’s breathing) Fruity-smelling breath (often described as “fruity” or “sweet” odor) |
C |
Tachycardia Hypotension Volume-deplete fluid status (cool periphery, dry membranes, reduced JVP) with normal/elevated urine output (reducing in late stage) |
D |
Fatigue/weakness Confusion/delirium/coma |
E |
Nausea and vomiting Generalised abdominal pain or discomfort |
F |
Polyuria Polydipsia |
G |
Hyperglycaemia > 13.9 Hyperketonaemia > 1.0 mmol/L |
How do we monitor for DKA? The Study Rationale
Ketone monitoring plays a crucial role in patients on SGLT2 inhibitors undergoing surgical procedures, particularly in the context of preventing DKA.
In response to emerging case series of SGLT2 inhibitor-related DKA in patients undergoing colonoscopy, a clinical alert update in 2020 recommended canceling colonoscopies if capillary ketone concentrations exceeded 1.0 mmol/L without discontinuation of SGLT2 inhibitors therapy for 72 hours prior.
However, this recommendation lacked empirical data regarding the normal range of ketone concentrations during colonoscopy procedures in non-diabetic patients.
Given the potential consequences of unnecessary procedure cancellation, such as delays in cancer detection and psychological impacts, the study by Hamblin et al. (2021) aimed to assess this normal range and to establish a more precise ketone concentration threshold to balance risks associated with procedure cancellation and the risk of DKA. This approach aims to mitigate the risk of adverse outcomes, such as DKA, while ensuring timely medical interventions when necessary.
Study Design
Inclusion Criteria:
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Normoglycemic adults undergoing colonoscopy
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Participants with T2DM (treated or not treated with SGLT2 inhibitors were also included for comparison
Exclusion Criteria:
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Global exclusion criteria:
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pancreatitis, pancreatic cancer, pancreatic surgery, hemochromatosis, cystic fibrosis or pregnancy
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Non-diabetic group specific:
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Fasting capillary glucose >5.5 mmol/L (100 mg/dL)
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Participants:
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Normoglycemic reference interval population: 151 participants
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Participants with type 2 diabetes:
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Non-SGLT2 inhibitor treated subgroup: 105 participants
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SGLT2 inhibitor treated subgroup: 37 participants
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Control:
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The control group comprised normoglycemic individuals undergoing colonoscopy
Data Points:
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Capillary ketone and glucose concentrations measured before colonoscopy (<90 minutes prior)
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Assessment of blood gases when ketone concentrations were >1.0 mmol/L
Outcome:
The reference interval for capillary ketone concentrations in non-diabetic individuals undergoing colonoscopy was determined to be 0.0–1.7 mmol/L.
However, the findings did not show statistically significant differences in ketone concentrations between diabetics treated with SGLT2 inhibitor and those that are not diabetic or not treated with SGLT2 inhibitor (p=0.051).
Therefore, those taking SGLT2 inhibitor can have ketones up to 1.7 mmol/L and still be at a theoretically elevated risk of DKA.
While higher ketone concentrations were observed in patients with T2DM treated with SGLT2 inhibitors compared to those not on SGLT2 inhibitor therapy, the lack of statistical significance means that the 1.7 mmol/L ketone level cannot be confidently applied to those treated with SGLT2 inhibitors.
Given the study’s limitations, such as its cross-sectional design, small sample size of patients treated with SGLT2 inhibitors, and statistically insignificant findings, caution is warranted when interpreting the 1.7 mmol/L threshold as safe for those taking SGLT2 inhibitors.
The study underscores the need for appropriate monitoring and management strategies to mitigate the risk of DKA in SGLT2 inhibitor treated patients undergoing colonoscopy.
Revised Ketone Monitoring Guideline in diabetic patients receiving SGLT2 inhibitors
Pre-operative plan:
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Withhold SGLT2 inhibitors for 2 full days prior to surgery AND on the day of surgery (i.e. withhold for 72 hrs) for:
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Surgery requiring admission
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Colonoscopy requiring bowel prep and carbohydrate restrictions
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Withhold SGLT2 inhibitors on the day of surgery for day procedures NOT requiring above
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Patients should monitor blood sugar levels (BSLs) and seek medical assistance if 2 readings are above 15 mmol/L in a a 24 hour period
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If a combination antihyperglycaemic medication is is prescribed to a patient, cease the SGLT2 inhibitors and prescribe the non SGLT2 inhibitors medication as a sole agent
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If possible, educating patient on signs and symptoms of DKA, discussing risk/benefit and providing written information prior to their operation
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A patient who is on SGLT2 inhibitor and NOT diabetic, they do not need to cease their SGLT2 inhibitor prior to surgery
Day of Surgery (DOS):
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Global recommendations:
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Strongly consider postponing non-urgent procedures if the patient is unwell
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Measure both blood glucose and blood ketone levels
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SGLT2 inhibitor appropriately withheld:
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If the patient is clinically well and ketones are < 1.7 mmol/L, proceed with the procedure
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Consider hourly blood glucose and blood ketone testing during the procedure and every 2 hours following the procedure until the patient is eating and drinking normally
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SGLT2 inhibitor not withheld:
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Course of action depends on the urgency of the procedure combined with patient comorbidity, surgical factors, HbA1c, blood ketones, and base excess
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All patients on SGLT2 inhibitors undergoing emergency surgery should be admitted post procedure to a ward capable of managing diabetic ketoacidosis in collaboration with endocrinology and critical care
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Where blood gas analysis is not readily available, and the ketones are > 1.0 mmol/L, the procedure should not be performed
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Table 3: Suggested management for clinically well patients who have not ceased SGLT2 inhibitors
Ketones (mmol/L) |
Base Excess |
Implication |
<1 |
> -5 |
|
>1 |
> -5 |
|
>1 |
< -5 |
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Post Procedure:
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Resume SGLT2 inhibitor once patient is eating and drinking normally
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Provide patient with written advice to seek medical attention if unwell
Back to the case…
During the pre-operative assessment, his blood glucose levels are within the normal range, but his capillary ketone concentration is elevated to 1.5 mmol/L and base excess > -5. He denies any symptoms of DKA, such as polyuria, polydipsia or abdominal pain.
Concerned about the potential risk of DKA associated with SGLT2 inhibitor use, the gastroenterologist consults with the endocrinology team for guidance. They discuss the recent clinical alert update from 2022. On balance of the urgency of Mr. Smith’s colonoscopy, the team decides to proceed with the procedure with insulin and dextrose infusion.
The colonoscopy proceeded without complications. His intraop and post-op gas and ketones were unremarkable. Mr. Smith was discharged 2 hours later having had some light snacks with his wife.
References:
Australian Diabetes Society. (2020). Alert update: Periprocedural diabetic ketoacidosis (DKA) with SGLT2 inhibitor use. Retrieved 1st of May 2024 from https://diabetessociety.com.au/downloads/20201015%20ADS_DKA_SGLT2i_Alert_update_Sept_2020.pdf
Australian Diabetes Society. (2022). Alert update: Periprocedural diabetic ketoacidosis (DKA) with SGLT2 inhibitor use. Retrieved 1st of May 2024 from https://www.diabetessociety.com.au/downloads/20220726%20ADS%20ADEA%20ANZCA%20NZSSD_DKA_SGLT2i_Alert_Ver%20July%202022.pdf
Ceriotti, F., Kaczmarek, E., Guerra, E., et al. (2015). Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. Journal of Diabetes Science and Technology, 9, 268–277.
Chirila, A., Nguyen, M. E., Tinmouth, J., & Halperin, I. J. (2023). Preparing for Colonoscopy in People with Diabetes: A Review with Suggestions for Clinical Practice. Journal of the Canadian Association of Gastroenterology, 6(1), 26–36. https://doi.org/10.1093/jcag/gwac035
Meyer, E. J., Mignone, E., Hade, A., Thiruvenkatarajan, V., Bryant, R. V., & Jesudason, D. (2020). Periprocedural euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter 2 inhibitor therapy during colonoscopy. Diabetes Care, 43, e181–e184.
Thiruvenkatarajan, V., Meyer, E. J., Nanjappa, N., Van Wijk, R. M., & Jesudason, D. (2019). Perioperative diabetic ketoacidosis associated with sodium-glucose co-transporter-2 inhibitors: A systematic review. British Journal of Anaesthesia, 123, 27–36.
Zannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filippatos, G., et al. (2020). SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. The Lancet, https://doi.org/10.1016/S0140-6736(20)31824-9
Wagdy, K., & Nagy, S. (2021). EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction. Global Cardiology Science & Practice, https://doi.org/10.21542/gcsp.2021.17