A year after the FDA warning, a strong response to the question: are SGLT-2 inhibitors safe?
This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.
Participants: Yehuda Handelsman, MD, FACP, FNLA, FACE, Co-Chair1; Robert R. Henry, MD, FACE, Co-Chair2; Zachary T. Bloomgarden, MD, MACE3; Sam Dagogo-Jack, MD, DM, FRCP, FACE4; Ralph A. DeFronzo, MD, BMS, MS, BS5; Daniel Einhorn, MD, FACP, FACE6; Ele Ferrannini, MD7; Vivian A. Fonseca, MD, FACE8; Alan J. Garber, MD, PhD, FACE9; George Grunberger, MD, FACP, FACE10; Derek LeRoith, MD, PhD, FACE11; Guillermo E. Umpierrez, MD, FACP, FACE12; Matthew R. Weir, MD13
The FDA warning in May 2015 that SGLT-2 inhibitors may lead to ketoacidosis.generated considerable attention. In October, experts at a joint meeting between the American Association of Clinical Endocrinologists and the American College of Endocrinology concluded that the risk for DKA when using SGLT-2 inhibitors is infrequent and the risk-benefit ratio favors continued use. Now, ACE/AACE have issued a joint position statement concluding that the incidence of diabetic ketoacidosis in patients with type 2 diabetes taking an SGLT-2 inhibitor is no greater than the low levels occurring in the general diabetes population.
In an interview with Endocrine Today, study co-author Zachary T. Bloomgarden, MD, MACE, stated that “There is no definite evidence that these agents are associated with DKA in type 2 diabetes, and some reports have actually described patients with ketosis, or even just ketonuria, which likely are not clinically significant. The DKA cases that have been reported generally involve patients with type 1 diabetes, although reports in atypical diabetes (such as that with pancreatic disease) and in patients with longstanding type 2 diabetes who require multiple-dose insulin treatment similar to that used in type 1 diabetes suggests that a necessary mediator of DKA is marked insulin deficiency.”
The consensus group reviewed over 82 DKA cases from the literature, including those involving SGLT-2 inhibition and cases occurring before SGLT-2 inhibitor therapy was available. In patients taking an SGLT-2 inhibitor, DKA occurred most often in insulin-deficient individuals, including those with longstanding type 2 diabetes, type 1 diabetes or latent autoimmune diabetes in adults. SGLT-2 inhibitors are not FDA approved for patients with type 1 diabetes, and 7 out of 9 patients in the American case series that prompted the FDA safety warning had type 1 diabetes, the authors wrote.
Nonetheless, the authors urge further study of SGLT-2 inhibitors in type 1 diabetes because initial studies have shown promise in glycemic regulation for patients with type 1. For future T1D trials, lower SGLT-2 inhibitor doses should be considered and insulin doses should not routinely be reduced when SGLT-2 inhibitors are begun, but adjusted based on the individual response.
Further, the statement notes that almost all cases of SGLT-2 inhibitor-associated DKA occurred in patients challenged with metabolically stressful events, which acted as precipitants of DKA, such as surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions.
The statement recommends that SGLT-2 inhibitors be stopped at least 24 hours before planned stressful events, such as surgery, or very intensive exercise, such as running a marathon. Patients prescribed SGLT-2 inhibitor therapy should also avoid excess alcohol intake and very low carbohydrate diets, both of which are potentially ketogenic, the researchers wrote.
Once diagnosis of DKA is suspected, the SGLT-2 inhibitor should be stopped immediately and a DKA protocol initiated, including fluids, insulin and other standard interventions.
Key points defined in the position statement:
- For individuals with type 2 diabetes (T2D), it is unclear whether DKA occurs at a higher frequency than it did before the advent of SGLT-2 inhibitors. In 2010 in the United States, 142,000 hospitalizations were associated with DKA, 23% of which occurred in patients with T2D (2). In Denmark, the rate of DKA before the SGLT-2 inhibitor era was 1 to 2 cases per 1,000 patients with diabetes. The incidence of DKA in clinical trials of SGLT-2 inhibitors with T2D was 0.2 to 0.8 cases per 1,000 patient-years (3,4). However, the low observed incidence in clinical trials may not reflect real-world experience. Seemingly, most of the reported cases have come from clinical practice rather than trials. Patients with type 1 diabetes (T1D) have a higher risk of DKA than those with T2D, and their risk of developing DKA while taking SGLT-2 inhibitors should be further elevated. Up to 9.4% of patients with T1D participating in SGLT-2 inhibitor clinical trials developed ketosis, and up to 6% experienced DKA (5,6).
- However, more data are needed to elucidate this relationship, as many recently reported cases have been poorly documented. Not all cases may have been actual DKA, but rather ketosis (buildup of ketones)—which is not necessarily harmful— perhaps resulting from an earlier shift to fat metabolism potentially impacted by a mechanism related to SGLT-2 inhibition.
- The majority of cases of SGLT-2 inhibitor–associated DKA have occurred in individuals with diabetes who are insulin deficient, such as those with latent autoimmune diabetes in adults (LADA) and T1D, but cases have also occurred in some patients with long-standing T1D. Generally, these patients presented with classical DKA signs and symptoms. However, some cases had an atypical presentation with a lower-than-expected degree of hyperglycemia. Lower-than-expected hyperglycemia, however, was observed with other agents years before the introduction of SGLT-2 inhibitors (7,8).
- Precipitants of DKA in T1D and T2D include surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions; almost all cases of SGLT-2 inhibitor–associated DKA occurred in patients challenged with metabolically stressful events. In both T1D and T2D, diabetes-associated metabolic changes commonly shift substrate metabolism from carbohydrate to fat oxidation, thereby predisposing patients to more readily develop ketonemia and DKA during SGLT-2 inhibitor use.
- For patients taking an SGLT-2 inhibitor who present with symptoms suggestive of DKA, such as abdominal pain, nausea, vomiting, fatigue, and dyspnea, a diagnosis of DKA should be considered and appropriate work-up carried out. Although a low bicarbonate and/or the presence of positive urinary ketones may be suggestive of DKA, these measures may be inaccurate. Therefore, AACE/ACE recommends direct measurement of blood ketones (β-hydroxybutyrate) and arterial pH as necessary to confirm the diagnosis. Normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT-2 inhibitor use.
- For management of DKA in patients taking SGLT-2 inhibitors, stop the drug immediately and proceed with traditional DKA treatment protocols. Note that although the drug is discontinued, SGLT-2 inhibitor–mediated increases in urinary glucose loss may persist for several days.
- To minimize the risk of DKA associated with SGLT-2 inhibitors, AACE recommends the following:
- Consider stopping the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. As noted above, urinary glucose loss due to SGLT-2 inhibition may persist after the drug is stopped.
- Avoid stopping insulin or decreasing the dose excessively.
- For emergency surgery or any extreme stress event, the drug should be stopped immediately, and appropriate clinical care should be provided.
- Routine measurement of urine ketones is not recommended during use of SGLT-2 inhibitors because this measurement can be misleading. Instead, measurement of blood ketones is preferred for diagnosis of DKA in symptomatic patients.
- Patients taking SGLT-2 inhibitors should avoid excess alcohol intake and
- very-low-carbohydrate/ketogenic diets.
- SGLT-2 inhibitors are not approved for use in T1D. However, AACE/ACE encourages continuation of ongoing studies because initial study results have shown that SGLT-2 inhibition has a promising impact on glycemic regulation in this population. AACE/ACE suggests that in future T1D trials, lower SGLT-2 inhibitor doses should be considered and insulin dose should not routinely be reduced when SGLT-2 inhibitors are begun. Instead, insulin should be adjusted based on the individual response to the SGLT-2 inhibitor, and carbohydrate intake should be maintained. These recommendations should also be applied if SGLT-2 inhibitors are prescribed off-label to patients with T1D and may be considered for patients with T2D who receive exogenous insulin therapy.
Conclusion: Review of available data on the prevalence of SGLT-2–associated DKA as well as the impact of SGLT-2 inhibitors on human metabolism suggests that DKA occurs infrequently and that the risk-benefit ratio overwhelmingly favors continued use of SGLT-2 inhibitors with no changes in current recommendations. However, DKA diagnosis may be missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values. This presentation has been seen with SGLT-2 inhibitors, but has also been observed for decades before the introduction of these agents (9). Gaps in understanding call for more studies of the mechanisms behind the metabolic effect of SGLT-2 inhibitors as well as more healthcare professional education focused on the proper diagnosis and treatment of DKA.
- Medical Director & Principal Investigator, Metabolic Institute of America, Immediate Past President, American College of Endocrinology, Tarzana, California
- Professor of Medicine, University of California San Diego, Chief, Section of Diabetes, Endocrinology & Metabolism, VA San Diego Healthcare System, San Diego, California
- Clinical Professor, Icahn School of Medicine at Mount Sinai, Editor, the Journal of Diabetes, New York, New York
- A.C. Mullins Professor & Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, Tennessee
- Professor of Medicine, Chief, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas
- Immediate Past President, American College of Endocrinology, Past-President, American Association of Clinical Endocrinologists, Medical Director, Scripps Whittier Diabetes Institute, Clinical Professor of Medicine, UCSD, Associate Editor, Journal of Diabetes, Diabetes and Endocrine Associates, La Jolla, California
- Professor of Internal Medicine, CNR Institute of Clinical Physiology, Pisa, Italy
- Professor of Medicine and Pharmacology, Tullis Tulane Alumni Chair in Diabetes, Chief, Section of Endocrinology, Tulane University Health Sciences Center, New Orleans, Louisiana
- Professor, Departments of Medicine, Biochemistry, Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT2 inhibitors on diabetic ketoacidosis [published online April 15, 2016]. Endocr Pract. 2016; doi: 10.4158/EP161292.PS – See more at: http://www.ajmc.com/newsroom/endocrinology-societies-no-greater-risk-of-dka-with-use-of-sglt2s-than-overall-type-2-diabetes-population#sthash.xyxheVBY.dpuf
“AACE/ACE position statement: DKA risk no greater with SGLT2 inhibitor,” Endocrine Today, April 20, 2016