In spite of the FDA warning a year ago,
the American association of Clinical Endocrinologists (AACE) and the
American College of Endocrinology (ACE) has taken a strong position
in opposition to the FDA warning.
This position paper represents the official position of the AACE and ACE and is meant to provide
guidance. It is not to be considered prescriptive for any individual
patient and cannot replace the judgment of a clinician.
The FDA warning in May 2015 that SGLT-2
inhibitors may lead to ketoacidosis, generated considerable
attention. Now, AACE/ACE 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. While
this is true, the cases are not considered similar to what develops
in those with type 1 diabetes. The AACE/ACE concluded that the risk
of DKA when using inhibitors is infrequent and the risk-benefit ratio
favors continued use.
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 those 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 position 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.
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. 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.
