Summary

Sodium glucose cotransporter (SGLT) inhibitors are new oral antidiabetic medications shown to

effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure and body

weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes.

However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated

increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with nearnormal

blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of

DKA and potentially delaying treatment. Several SGLT-inhibitors are currently under review by

US Food and Drug Administration (FDA) and European regulatory agencies as an adjunct to

insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to

the medical community to mitigate the associated DKA risk.

 

This consensus report reviews current data regarding SGLT- inhibitor use and provides recommendations to enhance the safety of SGLT-inhibitors in people with type 1 diabetes.

 

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From the article

Introduction

Intensive insulin management remains the only option for effective treatment of type 1

diabetes mellitus. However, fear of hypoglycemia (1-3) and weight gain (4) are often barriers to

optimal use of insulin therapy. Consequently, there exists an unmet need and great patient

interest in adjunct therapies of type 1 diabetes to improve glycemic control without increasing

the risk of hypoglycemia and weight gain. Most non-insulin adjunctive therapies approved for

type 2 diabetes are not effective in type 1 diabetes. The only one approved in the US is

pramlintide and it is not used much clinically due to limited efficacy and unfavorable side

effects. One novel strategy studied to improve outcomes in patients with type 1 diabetes is the

addition of sodium glucose cotransporter (SGLT) inhibitors as an adjunct to insulin therapy in

type 1 diabetes.

 

SGLT-2 inhibitors block the SGLT-2 transporter in the proximal tubule of the kidney

resulting in glycosuria and natriuresis. SGLT-1+2 inhibitors have the additional effect of locally

inhibiting SGLT-1 in the GI tract, delaying absorption of glucose and galactose from the

intestinal tract. The use of SGLT-2 inhibitors in the setting of type 2 diabetes is now

recommended (5) to prevent major adverse cardiovascular events (including mortality and

hospitalizations for heart failure) in patients with established atherosclerotic cardiovascular

disease as well as chronic kidney disease based on the results of the EMPA-REG (6; 7) and

CANVAS trials (8; 9). Similar reductions in hospitalizations for heart failure were seen in

patients at high risk for cardiovascular disease (10).

 

These agents are being increasingly used off-label in type 1 diabetes management (11)

and are currently under review by the US Food and Drug Administration (FDA) as well as by the

European Medicines Agency (EMA) as an adjunct to insulin therapy in adults with type 1

diabetes.

 

Decisions from the US and European agencies for sotagliflozin, a SGLT-1+2 inhibitor,

and dapagliflozin, a SGLT-2 inhibitor, are expected in 2019.

 

It should be noted that ipragliflozin, an SGLT-2 inhibitor currently available in Japan, Korea and Thailand, has recently been approved in Japan for adults with type 1 diabetes to be coadministered with insulin (12).

 

In the setting of adults with type 1 diabetes, SGLT-inhibitor therapy with dapagliflozin

added to intensified insulin therapy showed moderate efficacy, reducing A1C by ~0.4% (4.4

mmol/mol) at 6 months and ~0.3% (3.3 mmol/mol) at 12 months while demonstrating

improvement in time in range (70-180 mg/dl [3.0-10.0 mmol/L]) by continuous glucose

monitoring (CGM) without an increase in time with hypoglycemia (<70 mg/dl [<3.9 mmol/L])

(13-15). Importantly, this benefit was demonstrated in the setting of blinded studies where

patients treated with both SGLT-inhibitor and placebo had ongoing protocol-driven adjustments

of basal and bolus therapy (16).This improvement in glycemia was achieved in the context of a

~11.0% reduction of total daily insulin dose compared to ~8.0% reduction in the placebo group

(p<0.0001) (16).Interestingly, although no substantial dose dependency to the improvement in

glycemic control was observed, weight change did seem to be somewhat dose dependent (16).

Moderate weight loss (~3.2% at 6 months and ~3.5% at 12 months) with the SGLT-inhibitor as

compared to placebo (~0.1%) was observed (16).

 

The EASE Phase 3 program included 2 double-blind, placebo-controlled trials

investigating the efficacy and safety of empagliflozin as an adjunct to insulin therapy in adults

with type 1 diabetes (17). Significant reductions in A1C were observed in the three

empagliflozin doses studied: 2.5 mg (−0.28% [3.1 mmol/mol]), 10 mg (−0.54% [5.9

mmol/mol]),) and 25 mg (−0.53% [5.8 mmol/mol]), all p<0.0001, with no increase in

hypoglycemia. Significant reductions in weight, blood pressure and total daily insulin dose were

also observed in the empagliflozin treatment groups. Treatment with sotagliflozin (SGLT-1+2

inhibitor) showed similar improvements in A1C, weight loss, systolic blood pressure, and

reductions in total daily insulin dose but also with reductions in systolic blood pressure (18).

In studies that reported patient reported outcomes or quality of life assessment, there were

significant benefits associated with SGLT inhibition in the setting of type 1 diabetes (19; 20).

Results regarding the incidence or rate of severe hypoglycemia were somewhat mixed, but in

general, the expected increase in severe hypoglycemia in the context of the greater reduction in

A1C with the SGLT-inhibitor was not observed. Continuous glucose monitoring further revealed

improved time in range, generally ~3 hours a day, with all three SGLT-inhibitors (sotagliflozin,

dapagliflozin, empagliflozin) studied at the highest dose, without an increase in time in

hypoglycemia.

 

Although SGLT-inhibitor therapy has shown improvements in glycemic control, weight

loss and other risk reductions, current studies have reported a significant increase in the risk for

DKA (13-15; 17; 21; 22) which appears to be dose dependent (13-15; 17). 

 

The definitions for probable/possible/potential events are very different between the programs

and the trigger event identification process to identify potential events differed. Therefore, a

direct comparison between the programs is difficult. Importantly, some study

participants who experienced DKA presented with only slightly elevated glucose levels, a

condition referred to as euglycemic DKA (euDKA). In the setting of euDKA, the usual clinical

alert provided by hyperglycemia is absent and many case reports have demonstrated substantial

delays in recognition, diagnosis and treatment.

 

In June 2018, the International Conference on Advanced Technologies & Treatment for

Diabetes (ATTD) convened a consensus conference with an international panel of 26 physicians

and researchers with expertise in using SGLT-inhibitor therapy to develop strategies to mitigate

DKA and euDKA risk. Following the conference, twenty-four conference participants completed

an online survey to better understand areas of consensus and areas of disagreement including

appropriate cut-points for DKA diagnosis, risk factors, patient selection, and patient

management. This review summarizes our consensus recommendations and key considerations

for the safe use of SGLT-inhibitors in patients with type 1 diabetes. Scientific questions

requiring further research were also identified.

 

Background

Ketoacidosis with SGLT-inhibitors in type 1 diabetes: possible mechanisms

Several mechanisms likely operate to predispose individuals with type 1 diabetes to

develop ketosis (increased levels of ß-hydroxybutyrate and acetoacetate) and ketoacidosis in the

setting of SGLT-inhibitor therapy. The reduction of total daily insulin doses and particularly

basal insulin when treating patients with an SGLT-inhibitor may cause failure to suppress

lipolysis and ketogenesis even if blood glucose levels do not rise (23; 24). SGLT-inhibitors are

associated with an increase in glucagon, perhaps as a result of urinary glucose loss or through

direct action upon pancreatic alpha-cells, which increases lipolysis and ketogenesis (25; 26). The

balance of glucagon and insulin are critical to regulating these metabolic pathways (23; 27-29). It

has also been proposed that SGLT-inhibitors decrease renal clearance of ketone bodies (23).

 

Starvation ketosis, which is also mediated by reduced insulin levels and increased

glucagon levels, can occur in non-diabetic individuals with prolonged periods of fasting or very

low carbohydrate diets (often referred to as ketogenic diets) and is accelerated by physical

activity, physiological stress (e.g., infection or pregnancy) and alcohol consumption. SGLT

inhibition, by increasing urinary glucose loses, may be causing a pharmacologic push towards

ketosis, particularly when the behavioral and physiological factors mentioned are present (23;

30). Readers are referred elsewhere for comprehensive review of the physiology and

pharmacology of this system (23; 31).

 

Diagnosing DKA

The spectrum of ketosis (measured ketones in the blood or urine) to ketoacidosis (ketosis

associated with anion-gap metabolic acidosis) is quite broad involving an approximately 10-fold

range of ketone body concentration. The increase in ketonemia and ketonuria is not due to

reduced renal ketone excretion (9) unless there is severe dehydration (hence, frequently with

DKA).

 

DKA is usually associated with hyperglycemia in the setting of diabetes and serum

ketones >3.0 mmol/L. Similar to DKA, the development of euglycemic DKA (euDKA) is

characterized by anion-gap metabolic acidosis, ketonemia and ketonuria but with normal or

modestly elevated blood glucose levels (<250 mg/dL [13.9 mmol/L]) (31; 32). As such, patients

can present with full-blown DKA but with glucose levels <250 mg/dL (<13.9 mmol/L). Table 1

lists the levels of serum/urine ketones that are associated with concern and what should be done

in response to the values.

 

Approaches to Prevention of DKA Related to SGLT-Inhibitor Therapy

Patient selection

Selection of appropriate patients for SGLT- inhibitor therapy is critical to minimizing

DKA risk. The paramount criterion for patient selection is presentation with normal ketone levels

(<0.6 mmol/L blood ketones; negative urine ketones). However, the risk factors associated with

each patient’s lifestyle/behaviors (Table 2) and willingness/ability to follow prescribed regimens

for monitoring ketones and responding appropriately to elevated ketone levels when present must

also be considered (Table 3).

 

As a general guideline, SGLT-inhibitor therapy should not be used in patients using lowcarbohydrate

or ketogenic diets as, anecdotally, they seem to be at increased risk of adverse

ketosis effects and certainly create a diagnostic dilemma in evaluating the clinical significance of

ketosis. Also, with regards to diet, patients who skip meals and/or consume excessive alcohol

seem to be at increased risk. Patients who use an insulin pump are also at increased risk due to

the possibility of pump or insulin infusion set malfunction. Patients with type 1 diabetes who

miss insulin doses, have recurrent episodes of DKA or experience prolonged significant

hyperglycemia (particularly >350 mg/dl) and/or display low engagement with their diabetes

regimen are certainly at high risk of DKA in the setting of SGLT-inhibitor therapy. However,

these patients may be considered candidates if they can demonstrate the sustained necessary

changes in lifestyle and self-management behaviors, as well as monitor their capillary/urine

ketone levels.

 

Because adequate studies of SGLT inhibitors have not been performed in pregnant

women, SGLT2 inhibitors should not be used in pregnant women with type 1 diabetes as

pregnancy is associated with an increased risk of ketoacidosis which is associated with a high

risk of fetal mortality (33). No data are currently available for use of SGLT-inhibitor therapy in

children and youth with type 1 diabetes <18 years of age.

 

Insulin dose adjustments

When initiating SGLT-inhibitor therapy in individuals with type 1 diabetes, insulin must

be reduced cautiously in order to prevent ketosis and DKA. In clinical trials of SGLT-2

inhibitors, the proportional dose reductions seen for basal and bolus insulin were similar (13; 14)

or primarily in basal insulin doses (34). However, when using sotagliflozin, the dose reductions

observed in the clinical trials were largely in the prandial or meal associated insulin (18).

Therefore, the clinician needs to individualize such reductions for each patient based primarily

on degree of hyperglycemia as well as the specific SGLT-inhibitor used.

 

In patients who are relatively well controlled (A1C <7.5% [<58 mmol/mol]), 10-20%

reductions in insulin doses, accompanied by frequent blood glucose monitoring or CGM, and

rapid readjustment with healthcare provider input is recommended. Some patients may need to

decrease their carbohydrate intake in order to accommodate the reduced insulin dose as long as

ketone levels do not rise. Others may need to increase their carbohydrate intake in order to

maintain adequate exogenous insulin levels to prevent ketosis. Adjustments in insulin doses

should be made at least every 24-48 hours initially.

 

For less well-controlled patients (A1C ≥7.5% [≥58 mmol/mol]), only slight or no

reductions in prandial and basal insulin may be needed. Determination of which insulin doses

should be reduced should be based on detailed assessment of blood glucose profiles or,

preferably, CGM data as well as hypoglycemia history and awareness.

 

Initiation and dosing of SGLT-inhibitors

As discussed, blood ketone (ß-hydroxybutyrate) levels should be <0.6 mmol/L prior to

initiating SGLT-inhibitor therapy. If blood ketones are ≥0.6 mmol/L, additional baseline blood

ketone values should be obtained to determine whether the elevated ketones are normal for the

patient (due to lifestyle factors) or an indication of chronic inadequate insulin coverage in the

fasting state.

 

We recommend that SGLT-inhibitor therapy be initiated at the lowest dose available.

Some suggest even splitting tablets for the currently marketed SGLT2 inhibitors to get to lower

than marketed doses. Patients who had a good experience with low dose SGLT-inhibitor therapy

could be considered for dose escalation based on clinical response.

 

As observed in clinical trials, lower doses of SGLT-inhibitors are associated with

reasonable efficacy and lower risks of DKA (13; 14). Specifically, the EASE program included a

lower dose (i.e. empagliflozin 2.5 mg) which is not currently available in addition to the doses

approved for use in patients with type 2 diabetes (i.e. empagliflozin 10 and 25 mg) (17). The

ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with

10 mg and 25 mg. These data suggest that SGLT2 inhibitor dose selection itself is an important

factor in terms of DKA risk mitigation.

 

Ketone monitoring

Ketone testing is required because development of euDKA cannot be detected by glucose

monitoring. Although laboratory testing is the most precise method for ß-hydroxybutyrate levels

in clinical settings (35), self-testing via a blood ketone meter or urine testing, is sufficient for

patient use in detecting ketosis and early development of DKA — blood ketone (ßhydroxybutyrate)

concentrations >0.6 mmol/L or trace (or greater) urine ketones (acetoacetate).

 

We recommend patient self-measurement of capillary blood ketones, specifically ßhydroxybutyrate

(the most prevalent ketone body) as a matter of routine in assessing the

metabolic state of patients with type 1 diabetes treated with SGLT-inhibitors (36-40). In patients

who cannot afford or do not have access to capillary blood ketone measurements, urine ketone

measurements are acceptable. However, it must be recognized that the urine test only measures

acetoacetate, not ß-hydroxybutyrate, and estimation of urine ketones will be an average of the

concentration within the urine held in the bladder since the last void (41). Moreover, urine output

is frequently low in patients with DKA due to dehydration, and it may take several hours until

urine is produced again, which may delay appropriate treatment (41). Because β-hydroxybutyrate

is oxidized to acetoacetate with treatment of DKA, urine ketone readings will rise with treatment

even if blood β-hydroxybutyrate concentrations are dropping (41). The paradoxical rise in urine

ketones could give the false impression that the DKA is not resolving.

 

Patients should not rely on a single ketone measurement for definitive determination of

their metabolic state. In patients with elevated ketones, rechecking glucose and ketone

measurements every 1-3 hours should be performed to ensure resolution of ketonemia/ketonuria.

Symptoms of ketosis do not correlate well with ketone levels, which can increase rapidly.

Currently, there is no evidence to support specific testing regimens. However, it is the

consensus of the group that ketone testing frequency should be individualized, according to the

patient’s lifestyle and/or risk factors after initiating therapy. However, for all patients, we

recommend that ketones be measured with any symptoms consistent with DKA including

malaise, fatigue, nausea, and vomiting. Ketones should also be measured with changes in diet,

activity or insulin dose as well as for concomitant events such as infection, dehydration, surgery,

injury, pump occlusion/malfunction, or stress. It should be noted that treatment with SGLTPage

inhibitors in patients using insulin pumps with automated features including low glucose insulin

suspend and hybrid closed loop has not been well studied. Ketones should be measured

repetitively for as long as symptoms persist, or stressors remain. Random or periodic

measurement of ketones is also recommended to ensure that ketone testing supplies are readily

available and not expired.

 

Holding or discontinuing SGLT-inhibitor therapy

Any nausea, vomiting or abdominal discomfort should prompt discontinuation of SGLTinhibitor

therapy and evaluation of ketosis. SGLT-inhibitor therapy should be withheld

immediately if the patient is hospitalized, acutely ill or unable to eat and drink normally. SGLTinhibitors

should be withheld or discontinued prior to any medical procedure (ideally for 3 days),

particularly if they will be reducing food intake or if they will not be allowed to eat or drink for

some time before and after the procedure.

For patients who are switching the type of insulin therapy (e.g., injections to insulin

pump therapy) or from manual mode to automode on an automated insulin delivery (AID)

system, it is prudent that they hold their SGLT-inhibitor until their insulin doses are adjusted,

blood glucose is controlled, and ketone levels are normal.

 

DKA prevention

When elevated ketones are present, patients should be instructed to first discontinue

SGLT- inhibitor therapy until ketones are back to baseline. Treatment must be initiated swiftly

once elevated ketones are identified in order to avoid DKA and potential hospitalization. The key

to treatment of ketosis is for patients to inject insulin and consume carbohydrates, as well as

maintain adequate hydration. Even if the patient is on an insulin pump, the first step in treatment,

 

insulin, it is often best done by injection. If on insulin pump therapy, it is very important for

patients to begin to trouble shoot the pump and give insulin by injection until they are sure that

the insulin pump is delivering insulin and any pump or infusion set issues are resolved.

 

DKA treatment

If the symptoms and/or ketones are worsening, the patient should seek immediate

medical assistance. Whether or not to send a patient for further medical evaluation is a very

individual decision and may need to occur sooner in the presence of additional co-morbidities,

such as cardiovascular disease or pneumonia. If patients go to the emergency department or an

urgent care center, they should inform the medical personnel that they have type 1 diabetes and

are on an SGLT-inhibitor, which means they can have DKA with a relatively normal glucose

level. Patients should have an evaluation that includes measurements of capillary/venous pH,

blood bicarbonate, anion gap, and blood ketones (ß-hydroxybutyrate).

 

Patient and clinician education

Patients

All patients should receive thorough instruction in DKA risk factors, ketone monitoring

and treatment protocols. This is especially important for patients for whom administration of

both insulin and carbohydrates is counter-intuitive when glucose levels are only slightly

elevated.

 

Patients should also be instructed about anticipated situations where they may wish to

hold their SGLT-inhibitor. This includes such events as increased physical activity, situations

where they may become dehydrated or they choose to alter their dietary intake or consume more

alcohol. Therefore, it is important that patients become familiar with how these factors impact

their ketone levels. Importantly, patients should be empowered to make decisions regarding

whether or not to stop their SGLT-inhibitor. Holding it for a day, if in doubt, is prudent and

should not cause significant metabolic issues.

 

All patients treated with SGLT-inhibitor therapy should be provided with educational

materials (e.g., wallet cards, refrigerator magnets, etc.), which can serve as reminders regarding

risk factors and provide ”quick reference” resources for treatment.

 

Clinicians

Use of SGLT-inhibitor therapy in people with type 1 diabetes should be limited to

practitioners well-versed in the principles reviewed herein. In medical settings, DKA should be

considered in all patients taking SGLT-inhibitors who present with typical symptoms of DKA

even when glucose levels are normal. Because current guidelines for treatment identify DKA as

a hyperglycemic emergency, it is important that emergency departments are made aware that

DKA can present without overtly elevated glucose levels in patients treated with SGLTinhibitors.

This message must be part of all professional education initiatives. Educational

components of a risk mitigation strategy when introducing SGLT- inhibitors for type 1 diabetes

are summarized in Table 4, which includes the STICH protocol for risk mitigation (42).

 

Research Questions

Because much of the evidence for DKA risk has been garnered from randomized clinical

trials with highly-selected patients, additional research is needed to evaluate the efficacy and

DKA risk of SGLT-inhibitors in larger cohorts of type 1 diabetes patients, using real-world

methodologies. It is also important to develop a better understanding of the apparent dose-

dependent effect in both increased efficacy and increased DKA rates associated with higher

doses of SGLT-inhibitors. Current studies (13; 22) suggest these relationships but were not

definitive.

 

Another question that warrants further investigation is whether patients with extremely

elevated A1C levels (>10% [86 mmol/mol]) should receive treatment with SGLT inhibitors. The

5-year follow-up data from the T1D Exchange reported significantly higher (>15%) incidence of

DKA in patients with A1C above 10% (86 mmol/mol) but not treated with an SGLT-inhibitor

(43). Although some believe it is reasonable to recommend this therapy to all patients who are

both willing and able to monitor ketones as prescribed and take the appropriate remedial steps as

needed, some clinicians recommending adjusting insulin therapy to reduce A1C levels prior to

initiation of SGLT-inhibitor treatment, and others recommend not using these agents in anyone

with an A1C >10% [86 mmol/mol]. Additional data are needed to determine whether elevated

A1C is an independent risk factor or not for DKA in patients who are meticulous in their

diabetes self-management.

 

Developing an evidence base and algorithms to support decisions on reducing insulin

doses should also be a priority for future research. Although the recommendations for insulin

adjustment presented in this report are based on clinical trial experience, clinical judgment and

real-world experience with SGLT-inhibitor therapy, more definitive approaches to matching

each formulation and dosage to reductions in the most appropriate insulin (prandial or basal) and

the degree of reduction that will lessen DKA risk are needed. There is a strong case for a clinical

evaluation of the guidance presented here.

 

Determination of optimal frequency of ketone monitoring and how and when to respond

to ketone levels that rise above the normal range also remains as questions for further

investigation. Although daily ketone testing may reduce DKA risk, this approach could also lead

to lower adherence if ketone levels are mostly low or zero and the patient does not feel that this

frequency of monitoring is needed (44). Moreover, there is no evidence that daily ketone

monitoring actually prevents DKA; available clinical trials in type 1 diabetes patients did not use

protocols that included daily monitoring of ketones. Cost also represents a major barrier to

increased frequency of ketone monitoring, which could further discourage patients from the

practice. Although urine ketone strips are convenient and much less expensive than blood ketone

meters/strips ($0.20 vs. $2.09 per strip, not including the cost of the blood ketone meter) (45),

the sensitivity and specificity of the urine test for DKA are substantially less than blood ketone

measurement (41).

 

Finally, we recommend evaluation of both patient and clinician education programs and

materials. Although educational interventions for basic DKA prevention in type 1 diabetes

appear to be effective, many patients are not familiar with ketone testing and DKA. It will be

important to evaluate the efficacy and usability of materials specific to SGLT-inhibitor therapy.

At the very least, insulin pump-treated patients must be convinced that a “gluco-centric”

approach” to identifying infusion site problems is not appropriate when receiving adjunctive

therapy with a SGLT-inhibitor.

 

Conclusions

SGLT-inhibitor therapy is a promising option for adjunctive therapy in the treatment of

type 1 diabetes. Studies in this population have already demonstrated that use of SGLT-inhibitors

confers significant benefits, including improved glycemic control, increased time in range,

improved quality of life measures, and weight loss (13; 18; 22). Moreover, the cardiovascular

and renal benefits demonstrated in the type 2 diabetes trials (7; 8) may be a class effect that

positively impacts all patients regardless of the type of diabetes.

 

As observed in clinical trials, the rate of DKA in the placebo arm is substantially less

than incidence rates from latest registries where the incidence of DKA with SGLT inhibitor

therapy is relatively low. The increase in the absolute risk in SGLT-inhibitor-treated patients vs

placebo-treated patients was in the range of 4% per year, and in these clinical patients, it was

lower than reported in general practice but still higher than seen with placebo. The potential

benefits of SGLT inhibitors for people with type 1 diabetes appear clinically meaningful. Thus,

strategies for mitigating DKA risk are vital to the adoption and safe use SGLT- inhibitors in all

diabetes populations particularly those requiring insulin. The consensus recommendations

presented in this report are based on current evidence from clinical trials and our expertise and

experience using SGLT-inhibitors with our type 1 diabetes patients. Our goal is to provide a

starting point for the safe use of SGLT-inhibitor therapy in this population and to encourage

additional investigations that will provide more comprehensive, evidence-based- guidance for

clinicians and patients.

 

Author contributions

Christopher G. Parkin and Martin J. Kurian performed the literature search. Thomas Danne, Anne L. Peters, John B. Buse, Christopher G. Parkin, Charles M. Alexander, and MartinKurian wrote the initial manuscript draft. All author participated in the consensus conference, contributed to the manuscript content and reviewed and contributed to revisions of the manuscript. Thomas Danne is the guarantor of this work and takes responsibility for the integrity of the information and recommendations.

 

Table 3. Patient criteria for SGLT-inhibitor therapy

 >18 years of age

 Adherent to prescribed diabetes regimen

 Willing/able to perform all prescribed diabetes self-management tasks

 Performs blood glucose monitoring or uses CGM as prescribed

 Willing/able to perform ketone testing as prescribed

 Has received education/training in ketone testing and interpreting/acting upon test results

 Has access to ketone testing materials

 Has immediate access to a clinician if blood or urine ketone levels are elevated

 No or moderate use of alcohol; no use of illicit drugs

 Unimpaired cognition

 Not pregnant or wanting to become pregnant

 

Table 4. Educational components of a risk mitigation strategy when introducing SGLTinhibitors

for type 1 diabetes

 All patients initiating SGLT-inhibitor therapy should receive through training/education in

the following areas:

o DKA causes and symptoms

o Euglycemic ketoacidosis

o Importance of ketone monitoring

o Use of ketone monitoring – training in testing procedure, proactive monitoring,

situations when monitoring is indicated

o Treatment protocol for addressing ketosis

Patient

Education

o Guidance in when to seek medical attention

 

 All prescribing clinicians should acquire full understanding of the safe use and risks

associated with SGLT-inhibitor therapy:

o Criteria for patient selection — baseline ketone level, demographic/behavioral

considerations

o Training/educational needs of patients – detection (ketone levels, symptoms),

prevention strategies, treatment

o Potential for missed DKA, euDKA

o Treatment strategies – STICH protocol recommended:

 STop SGLT-inhibitor treatment for few days

 Insulin administration

 Carbohydrate consumption

Clinician

Education

 Hydration with a suitable drink (e.g., water or noncaloric athletic drink with

balanced electrolytes)

 

Risk  Product labelling, Website

Communication  Healthcare Professional Education

 Medication Guide, Patient Alert Card*

 

Table 2. Risk factors for DKA associated with SGLT-inhibitor therapy

Risk Level for DKA Factor

 Reduced basal insulin by more than 10 to 20%

 Insulin pump or infusion site failure

 Reduced or inconsistent carbohydrate intake

 Excessive alcohol use

 Use of illicit drugs

 Volume depletion/dehydration

 Acute illness of any sort (viral or bacterial)

Moderate/High

 Vomiting

 Vigorous or prolonged exercise

 Reduced prandial insulin dose by more than 10 to 20%

 Travel with disruption in usual schedule/insulin regimen

Low/Moderate

 Insulin pump use

 Low BMI (<25 kg/m2)

 Inconsistent caloric intake

 Moderate alcohol use*

Minimal/Low

 Female sex

* If ketone levels increase from baseline

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