There is currently a huge unmet need for non-insulin add on therapy in type 1 diabetes, but are SGLT inhibitors in type 1 the right drug for the job?
According to the American Diabetes Association, only 20% of patients with type 1 diabetes maintain the recommended A1C target of <7%. The only noninsulin adjunctive therapy for type 1 diabetes is pramlintide, and it is rarely utilized due to unwanted side effects and limited efficacy. Intensive insulin regimens are the only effective FDA approved treatment for type 1 diabetes and have unwanted side effects such as hypoglycemia and weight gain.
SGLT2 inhibitors block the SGLT2 transporter resulting in glycosuria and natriuresis, and SGLT1+2 inhibitors have the added benefit of delaying the absorption of glucose and galactose. SGLT inhibitors have already proven to be safe and effective in the treatment of type 2 diabetes, reducing the risk of hypoglycemia, and simultaneously protecting the kidneys and heart. This has led to the investigation of SGLT inhibitors in type 1 diabetes, but recent study results raise serious concerns.
DKA was an event of special interest in the recent FDA drug application review for sotagliflozin, an SGLT inhibitor for use in type 1 diabetes. In this study, participants were excluded for recent DKA or ketosis. Due to the DKA concern, participants received extensive education, a ketone meter with strips, and instructions on detecting and managing ketosis. Despite this protocol, sotagliflozin SGLT inhibitor therapy increased the relative risk of DKA between 5 and 17-fold with a number needed to harm from between 21 and 31. Alternatively, the placebo group had a low incidence of DKA.
A recent international consensus on SGLT inhibitors in type 1 diabetes was released to address the risk of DKA. These recommendations were based on clinical trials and experts who used SGLT inhibitors with their type 1 diabetes patients. This consensus indicates that providers should perform a thorough risk assessment prior to initiating SGLT inhibitor therapy in type 1 diabetes.
Appropriate selection of patients for this therapy is paramount to reduce DKA risk. This criterion includes: normal ketone levels, the willingness and ability to follow a prescribed regimen to monitor ketones, access to health resources for proper monitoring, and the financial ability to purchase ketone monitoring supplies. Conversely, SGLT inhibitor therapy is not recommended in patients: on low carb diets, who skip meals, consume excessive alcohol, have recurrent DKA, or prolonged hyperglycemia (>350 mg/dL). Although not absolutely contraindicated, patients on an insulin pump need to take additional precautions due to an increased risk of complications.
The population of patients with type 1 diabetes who would most benefit from an SGLT inhibitor also carry the highest risk of DKA. Patients who have low involvement in their diabetic regimen are less likely to adhere to complex safety recommendations required for this drug therapy. For example, young adults with an AIC >9% would greatly benefit from additional glucose control with add on therapy, but are at increased risk of DKA, and are not an ideal candidate for therapy. Lifestyle choices, disease management, and behavior are directly linked to outcomes and drug therapy risk.
A major paradigm shift is necessary for both patients and providers to mitigate the risk of DKA. We must change from “glucose centric” to “ketone centric” to safely implement SGLT inhibitor therapy in type 1 diabetes. Euglycemic DKA, commonly seen in this therapy, cannot be detected by glucose monitoring, and requires ketone monitoring. In euglycemic DKA, patients can present with a blood glucose of <250 mg/dL and be in full-blown DKA. This scenario complicates the recognition and diagnosis of DKA and can delay treatment. The international consensus recommends diligent assessment of ketones in the presence of any DKA symptoms to reduce this risk.
Additional research is needed to assess the efficacy and DKA risk of SGLT inhibitors in type 1 diabetes. The safe use of SGLT inhibitors in type 1 diabetes does seem possible in patients who meet a set criterion, but due to the increase in absolute risk of DKA, providers should proceed with caution.
- The benefits of SGLT inhibitors in type 1 diabetes are clinically meaningful, but the drugs should be used with caution, and only by those who have the resources and training to carefully select patients.
- The optimal DKA risk mitigation strategy involves: clinician education, patient education, and risk communication.
- Even in the closely supervised FDA drug trial of sotagliflozin, there was an increase in absolute risk of DKA.
Wolfsdorf, Joseph I., and Robert E. Ratner. “SGLT Inhibitors for Type 1 Diabetes: Proceed With Extreme Caution.” Diabetes Care, vol. 42, no. 6, 2019, pp. 991–993., doi:10.2337/dci19-0008.
U.S. Food and Drug Administration. 2019 Meeting Materials, January 17, 2019 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. Available from https://www.fda.gov/AdvisoryCommittees/Committees
Kassey James, Pharm.D.Candidate, LECOM School of Pharmacy