- Academic Editor
Sodium-glucose cotransporter inhibitors (SGLT2i) play an increasingly important role in type 2 diabetes mellitus (T2DM) due to their significant cardiovascular benefits and renal protection in addition to their hypoglycemic effects. In recent years, the application of SGLT2i in patients with type 1 diabetes mellitus (T1DM) has attracted more and more attention. Studies have shown that SGLT2i improves glycemic control, reduces total daily insulin dose, decrease body weight in patients with T1DM, without increasing the risk of severe hypoglycemia. SGLT2i also reduces urinary protein levels, prevents atherosclerosis, and offers cardiorenal benefits in patients with T1DM. But simultaneously, they significantly increased risk of diabetic ketoacidosis (DKA), which leads to increased hospitalization and mortality. Hence SGLT2i is recommended to T1DM who are motivated, adhere to self-glucose monitoring, well-trained in identifying DKA, and closely followed to ensure the efficacy and safety.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting in severe insulin deficiency in which patients require lifelong insulin therapy to maintain life and minimize the risk of hyperglycemic events, such as diabetic ketoacidosis. New insulin preparations, the improvement of insulin pump devices and the development of continuous glucose monitoring system have enabled T1DM patients in this era to have a longer life and better quality of life. However, they still cannot solve the defects caused by intensive insulin therapy, such as weight gain, increased hypoglycemia rate and high blood glucose volatility. Most individuals with T1DM do not achieve recommended glycaemic targets [1, 2, 3]. With the increase of new hypoglycemic drugs, studies on the combination of other hypoglycemic drugs in the treatment of T1DM are continuing, while clinical studies on the combination of metformin, dipeptidyl peptidase Ⅳ (DPP-4), glucagon-like peptide 1 receptor agonist (GLP-1RA) and other drugs in the treatment of diabetes cannot achieve effective effects. SGLT2i are usually used for patients whose blood glucose are not well-controlled with metformin or those who have high risk of heart failure or chronic kidney disease (CKD) [4, 5], and given their insulin-independent mechanism of action, these agents might also be effective in patients with T1DM. Currently, a number of clinical studies have confirmed that SGLT2i can effectively reduce blood glucose in patients with T1DM, and at the same time reduce body weight without increasing the risk of hypoglycemia [6, 7, 8, 9, 10], dapagliflozin was authorized for the treatment of adult T1DM patients in Europe and Japan, while sotagliflozin was later approved in Europe. While SGLT2i increases the risk of ketogenesis and DKA, which deserves special attention as a serious adverse event in patients with T1DM [11, 12, 13]. What kind of patients with T1DM are suitable for SGLT2i treatment, and in addition to the hypoglycemic effect, whether the cardiac and renal benefits of SGLT2i observed in T2DM patients are also suitable for T1DM remains to be further explored. The purpose of this review is to summarize the potential benefits and risks of SGLT2i in patients with T1DM and explore strategies to reduce the risk of DKA.
In 1835, French scientists isolated the first natural SGLT inhibitor, phlorizin,
from apple bark, and found that it can promote urine sugar excretion and lower
blood sugar . However, due to its non-selective inhibition of SGLT1 and
SGLT2, it is easily hydrolyzed by
The history of SGLT2i application. DKD, diabetes kidney disease; CVD, cardiovascular disease; HFrEF, heart failure with reduced ejection fraction.
In 2015, 7020 T2DM patients with cardiovascular disease (CVD) were included in the
EMPA-REG OUTCOME study. The median follow-up time was 3.1 years. Results showed
that, empagliflozin was associated with a 14% reduction in the risk of major
cardiovascular outcomes (including cardiac related deaths, nonfatal myocardial
infarction, and nonfatal stroke events combined). Compared with secondary
endpoints, it can reduce the all-cause mortality by 32%, the risk of
cardiovascular death by 38%, and the risk of hospitalization for heart failure
(HF) by 35% . The CREDENCE study published in 2019 was the first SGLT2i
study to use renal outcome as the primary endpoint, demonstrating that
canagliflozin was effective in reducing the risk of renal failure and
cardiovascular events in high-risk T2DM patients with renal disease. In the 2020
American Diabetes Association (ADA) guidelines, SGLT2i (evidence Level A) is
recommended for T2DM patients with CKD, estimated glomerular filtration rate (eGFR)
Pieber et al.  explored the potential beneficial effect of
empagliflozin versus placebo as an insulin adjuvant on HbA1c in a small
Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes (EASE)-1 trial
of 75 T1DM patients, with a 0.49% decrease in HbA1c in the engliazine group
compared to the placebo group after 28 days. Total daily insulin dose decreased
by 0.09 U/kg and body weight decreased by 1.9 kg. In the EASE program, two
double-blind placebo-controlled phase III trials explored the efficacy of
different doses of empagliflozin and placebo as adjuvant insulin therapy, EASE-2
(comparing empagliflozin 10 mg, 25 mg, and placebo for 52 weeks) and EASE-3
(comparing empagliflozin 2.5 mg, 10 mg, 25 mg, and placebo for 26 weeks), which
enrolled 1707 patients with T1DM, results showed that patients in the
empagliflozin group had a significant decrease in HbA1c and an increase in time
in range—TIR (TIR: the proportion of time patients had blood
glucose between 3.9–10.0 mmol/L; 70–180 mg/dL). In the 5 mg and 10 mg doses, TIR
increased by more than 2 hours per day, while in the 2.5 mg group, TIR increased
by 1 hour per day, showing a significant dose-dependence. Moreover, the results
of the study also confirmed that empagliflozin could significantly reduce
systolic blood pressure by (–3.9 mmHg) and diastolic blood pressure by (–2.3
mmHg) in T1DM patients . In the magic week project, two phase III
placebo-controlled double-blind trials explored dapagliflozin 5 mg, dapagliflozin
10 mg, and placebo as adjunctive insulin treatment. A total of 1591 patients with
T1DM who had poor glycemic control were enrolled in this study. Patients in the
dapagliflozin 5 mg and dapagliflozin 10 mg groups had significant reductions in
HbA1c levels, fasting blood-glucose (FBG) and total daily insulin consumption at
52 weeks from baseline. TIR was improved (dapagliflozin 5 mg was 9.02%,
dapagliflozin 10 mg was 10.70%), and 24-hour mean amplitude of glucose
fluctuation (MAGE) was decreased (dapagliflozin 5 mg was –0.69 (0.08)
mmol/L; –12.48 (1.37) mg/dL, dapagliflozin 10 mg was –0.72 (0.08) mmol/L; –13.06
(1.39) mg/dL) . Dapagliflozin also improved treatment satisfaction .
Another 52-week phase III trial involving 151 patients with T1DM from Japan
assessed the efficacy and safety of dapagliflozin at 5 mg and 10 mg as adjuvant
therapy . Patients in the 5 mg and 10 mg groups had a mean reduction in HbA1c
of 0.33% and 0.36% at week 52 of the experiment. The mean daily insulin dose
changes were 12.27% and 13.13%. Two clinical trials, InTandem-1 and InTandem-2
[7, 8, 27] evaluated the efficacy and safety of sotagliflozin in combination with
insulin as compared with placebo in the treatment of T1DM and showed that
sotagliflozin significantly improved HbA1c, reduced FBG and daily insulin dose in
patients with T1DM compared with placebo. Moreover, patients receiving
sotagliflozin were more satisfied with treatment and experienced less
diabetes-related distress [7, 8]. In addition, compared with baseline
measurements, patients in the 400 mg sotagliflozin group had a 2.98 kg weight
reduction . The results of the study on the effect of sotagliflozin combined
with insulin on TIR and MAGE in patients with T1DM showed that the glucose
measurement within the target range of patients using sotagliflozin increased by
13.4%, and did not increase the time below 3.9 mmol/L. MAGE decreased by 0.7
The above studies showed that different SGLT2i combined with insulin had similar effects on the reduction of HbA1c level in T1DM, and increased TIR and decreased MAGE, body weight and blood pressure. The durability of the effects was comparable even in those studies up to 52 weeks.
Many mechanism studies have shown that the renal protection of SGLT2i is not related to hypoglycemia [36, 37, 38] but through the reduction of glomerular pressure and urinary sodium excretion [39, 32]. In high glucose conditions, SGLT2 mRNA expression increases by 36% due to excessive glucose in renal tubules, leading to increased sodium reabsorption and weakened sodium transport to dense macula . This results in decreased adenosine release from macula densa cells, which causes afferent arteriole vasodilation via tubule feedback (TGF). Attenuation of TGF leads to increased glomerular perfusion, increased glomerular pressure, increased glomerular filtration rate (GFR), and ultrafiltration [41, 42]. Importantly, chronic ultrafiltration is closely associated with glomerular injury and is thought to be associated with DKD progression in T1DM and T2DM . Studies have shown that SGLT2i plays a role in T1DM by reducing the dilatation of the entering arteriole through tubule feedback, which has a significant impact on renal protection by attenuating the ultrafiltration process. After reducing sodium reabsorption by the proximal tubules, sodium delivery to the dense macula increases, and afferent arteriolar vasoconstriction increases, thereby restoring TGF function to normal physiological levels and causing a decrease in glomerular pressure and GFR levels .
Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease
(DAPA-CKD) was the first SGLT2i renal endpoint study in patients with CKD
(participants with CKD due to T2DM and to causes other than diabetes). 4304
patients with stage 2–4 CKD were enrolled (2906 participants (68%) had a
diagnosis of T2DM and of these, 396 had CKD ascribed to a cause other than
diabetes), and baseline eGFR was 25–75 mL/min/1.73 m
In a post hoc pooled analysis of the InTandem-1 and InTandem-2 trials , The
baseline eGFR levels of enrolled T1DM patients were 90.2 mL/min/1.73 m
SGLT2i can significantly reduce urinary protein and delay the progression of renal dysfunction in non-diabetic CKD patients. SGLT2i can also reduce urinary protein levels in patients with T1DM, which may be favorable evidence for the selection of SGLT2i in T1DM patients. However, studies on the long-term benefits of SGLT2i in T1DM patients with DKD are still lacking. Future clinical trials need to observe the effect of SGLT2i on T1DM patients with kidney disease.
SGLT2i can reduce cardiac preload by sodium and osmotic diuresis, and improve
cardiac function by lowering blood pressure, improving arterial elasticity and
vascular endothelial function by reducing cardiac afterload [49, 50, 51]. Studies
have shown that SGLT2i can inhibit the sodium hydrogen exchanger 1 (NAH1) in the
myocardium and reduce the levels of Na
With the increasing longevity of T1DM patients, CVD is increasingly recognized as a clinical problem in patients with T1DM, so the reversal and even prevention of CVD is an important goal for patients with T1DM. Relevant studies have provided experimental evidence  showing that oral administration of SGLT2i (dapagliflozin) prevents metabolic decline, cardiac hypertrophy, and myocardial injury in streptozotocin - induced T1DM within 6 weeks. The decrease in aortic intima-media thickness suggests that dapagliflozin also prevents atherosclerosis. In a small randomized study (n = 40) , empagliflozin - metformin significantly improved arterial stiffness compared with metformin in patients with T1DM, and endothelial function improved similarly in all treatment groups. The results from the study on the antioxidant and anti-inflammatory properties following the combination of empagliflozin - metformin in T1DM showed that, compared to a single drug or placebo, there was improved arterial function , empagliflozin - metformin combination increased total antioxidative status, superoxide dismutase and glutathione peroxidase level is as high as 1.1 times, Decreased pro-oxidants (advanced oxidation protein products and inopportune decreased 1.2 times, advanced glycosylation end products decreased 1.5 times), and decreased inflammatory parameters (C-reactive protein and interleukin-6 decreased 1.5 times). The antioxidant effect was related to the improvement of arterial function. Therefore, it is believed that the combination of empagliflozin and metformin has strong antioxidant and anti-inflammatory effects in T1DM, leading to the improvement in arterial function and providing strong vascular protection. A 19-week mechanistic study  evaluated the effect of SGLT2i (empagliflozin 25 mg QD) combined with an angiotensin-converting enzyme inhibitor (ramipril 10 mg QD) on cardiac function in T1DM patients with potential renal hyperfiltration, 30 patients were enrolled, and results showed that no significant changes in ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output were observed with the addition of empagliflozin in patients with T1DM. This may be due to the short duration of the study and the small number of cases.
SGLT2i can not only safely reduce blood glucose in diabetic patients, but can also offer significant clinical benefits in cardiovascular endpoints, which have been observed in T2DM patients with heart failure and in non-diabetic patients with heart failure. According to these findings, SGLT2i (dapagliflozin) can prevent cardiac hypertrophy and myocardial injury, as well as atherosclerosis. However, the study period is short and the sample size is small. In addition, it is unclear whether SGLT2i is beneficial for T1DM patients with cardiovascular disease and aging. More research should be conducted to investigate the effects of SGLT2i on cardiovascular events in T1DM patients.
SGLT2i stimulates glucagon secretion through the direct action of drugs on pancreatic alpha cells or indirectly by reducing insulin secretion. Glucagon inhibits acetyl-coA carboxylase and therefore increases carnitine palmitoyltransferase-I activity in the liver, resulting in increased keto production [60, 61]. Adjuvant therapy with SGLT2i reduced the total daily insulin dose in patients with T1DM, and ketone bodies increase when low doses of insulin are insufficient to inhibit lipolysis in surrounding adipose tissue. Therefore, the use of SGLT2i in T1DM patients may increase the incidence of ketone-body related events.
The first trial by Henry et al.  showed that the incidence of
severe DKA requiring hospitalization in T1DM patients with canagliflozin 100 mg
and canagliflozin 300 mg was 4.3% and 6.0%, respectively, compared with zero
events in the placebo group. Five of these patients had blood glucose levels of
less than 13.9 mmol/L; 250 mg/dL, which suggests that SGLT2i may not only increase
the risk of DKA but also lead to misleading clinical manifestations of DKA with
normal blood glucose. In the Dapagliflozin Evaluation in Patients with
Inadequately Controlled Type 1 Diabetes (DEPICT)-1 and DEPICT-2 studies, in the
24 week first published results of DEPICT -1, no increase in DKA was observed in
patients treated with dapagliflozin, while the risk of DKA at 52 weeks was 4.0%,
3.4% and 1.9% in the dapagliflozin 5 mg, 10 mg and placebo groups,
respectively. Results of DEPICT-2 showed an increased risk of DKA at 24 weeks. By
52 weeks, 4.1%, 3.7%, and 0.4% of patients in the dapagliflozin 5 mg, 10 mg
and placebo groups had developed DKA, respectively [12, 62, 63]. Another phase
III study conducted in Japan with safety as the primary endpoint also showed a
higher overall incidence of diabetic ketoacidosis in patients with T1DM (2.6%
and 1.3% in the 5 mg and 10 mg groups, respectively), all of them were women
with blood glucose levels
Actual data on the use of SGLT2i in patients with T1DM are still scarce, but the
efficacy and safety are consistent with clinical trial data. A real-world
observational study in Japan  also reported a higher incidence of DKA in T1DM
patients who received SGLT2i than those who did not (RR = 1.66, 95% CI:
Thus, all items showed an increase in DKA except for the empagliflozin 2.5 mg (EASE-3) report. The description of DKA cases in these research projects is limited, but in terms of traceability, in all cases of DKA that emerged, patients had at least one precipitant (disease, infection, lack of insulin dose, reduced carbohydrate intake, etc.). Nonetheless, more real-world research evidence is needed to guide clinicians in assessing the true DKA risk in patients with T1DM outside the strict supervision of clinical trials, with careful patient selection and intensive patient and clinical team education.
In the trial of DEPICT, there were no significant differences in hypoglycemic
events between dapagliflozin treatment and placebo in T1DM [11, 12, 48, 62, 63].
Results from the EASE test were similar to the trial of DEPICT, with no
significant difference in the overall risk of hypoglycemia between the different
doses of empagliflozin and placebo in T1DM . Studies on canagliflozin also
showed that the incidence of hypoglycemia was similar in the canagliflozin group
compared with the placebo group . In a study evaluating the effect of
sotagliflozin on hypoglycemia in patients with T1DM, the incidence of grade 1
hypoglycemia events was 58.25%, 44.86%, and 45.68% in the placebo and
sotagliflozin 200 mg and 400 mg groups. The incidence of grade 2 hypoglycemia was
15.95%, 11.51% and 11.13%, and the incidence of grade 3 hypoglycemia events
was 6.3%, 2.6%, and 2.2%, respectively . Grade 1 and 2 use American
Diabetes Association (ADA)/European Association for the Study of Diabetes
criteria: Grade 1 (
There was no significant difference in the risk of hypoglycemia in patients with T1DM treated with SGLT2i plus insulin compared with insulin alone. The different rates of hypoglycemia between drugs depended on the insulin combination regimen used in the study and were not caused by SGLT2i alone.
There may be more urogenital infections with SGLT2i because urine sugar may lead
to the growth of urogenital microbes. Results from all SGLT2i programs in T1DM
showed a comparable occurrence of urinary tract infections with placebo, but
increased genital fungal infections [6, 69, 70]. Results from the DEPICT studies
show that the rate of urinary tract infections in the dapagliflozin treatment
group and the placebo group were about the same, with depict-tract fungal
infections significantly higher than those in the placebo group (14.5% vs 3.1%
in DEPICT-1 and 10.7% vs 3.7% in DEPICT-2) [11, 48, 62, 63]. In addition,
sotagliflozin did not increase urinary tract infections but increased the risk of
mycotic genital tract infections (RR: 3.12, 95% CI: 2.14–4.54, p
Although the use of SGLT2i in patients with T1DM increased the risk of genital fungal infection, no serious adverse events due to genital fungal infection were reported in the study.
SGLT2i increased the concentration of phosphate and parathyroid hormone, but
caused a small decrease in the concentration of 1,25(OH)
Selecting the right patient for SGLT2i treatment is critical to reducing the
risk of DKA. The most important criteria were normal blood ketone level (
Dapagliflozin was approved in Europe and Japan in 2019 as an oral adjuvant
therapy of insulin for the treatment of adult T1DM patients with poor glycemic
control with optimal insulin alone (body mass index
When starting SGLT2i therapy in T1DM patients, insulin levels must be carefully reduced to prevent ketosis and DKA. In clinical trials of SGLT2i, basal insulin and meal insulin doses were reduced in similar proportions [11, 48] or mainly reduced basal insulin dose . However, when sotagliflozin was used, the dose reduction observed in clinical trials was mainly in mealtime insulin . Therefore, clinicians need to adjust the insulin dose for each patient based primarily on the degree of hyperglycemia and the specific SGLT2i used.
In patients with close to target (HbA1c
In terms of diet, patients who skipped meals and/or drank alcohol heavily
appeared to be at higher risk. Patients who use insulin pumps are also at higher
risk due to the possibility of pump or insulin infusion failure . Patients
with T1DM who do not adjust their insulin dose in a timely way, have recurrent
DKA or experience prolonged significant hyperglycemia (especially
The development of euDKA and the progression of DKA cannot be detected by glucose monitoring alone, so the detection of ketone bodies is recommended. Unlike ketone monitoring in the T1DM population without SGLT2i, ketone levels should be tested regardless of blood glucose levels if symptoms of DKA are present in the population using SGLT2i. In future clinical practice, continuous ketone monitoring will play a role in ketogenesis and DKA monitoring. Currently, there is no evidence to support specific testing protocols. However, the team agreed  that frequency of ketone testing needs to be individualized based on the patient’s lifestyle and/or risk factors. It is recommended to measure any symptoms consistent with DKA, including discomfort, fatigue, nausea and vomiting. Ketone bodies should also be measured by changes in diet, activity, or insulin dose and accompanying events such as infection, dehydration, surgery, injury, pump blockage/dysfunction or stress. Once an elevated ketone bodies are detected, treatment must be initiated on time .
A meta-analysis published in 1997  showed an increased risk of DKA in patients using pumps. However, recent studies have shown no increased risk of DKA in T1DM patients using pumps [65, 76]. This development may have been due to developments in pump technology (such as failure alerts or higher dose accuracy), greater understanding of infusion group problems (such as tube displacement, kinks, occlusion), and subsequent intensive education and training of patients using the pump on the importance of the insulin infusion group . However, studies have shown that DKA is more common in patients using insulin pump when SGLT2i is applied in T1DM patients (mostly due to pump failure) . The key to treating ketosis is to get patients to inject insulin and consume carbohydrates, and to stay hydrated enough. Even if a patient is using an insulin pump, it is important to first troubleshoot the pump and administer insulin by injection until it is certain that the pump is delivering insulin and any pump or piping issues have been resolved .
Before the widespread use of SGLT2i in T1DM, a survey conducted in the United Kingdom (2014–2015) showed that there were 18 cases of euDKA if the glycemic threshold of 13.9 mmol/L; 250 mg/dL was used or 29 if 16.7 mmol/L; 300 mg/dL was used. The total number of DKA cases (eu-DKA and non eu-DKA) was 334 .
Hence SGLT2i may also cause an increase in the frequency of eu-DKA with normal blood glucose. In the current medical setting, all T1DM patients taking SGLT2i should consider the possibility of DKA if they present with typical DKA symptoms, even if their blood glucose levels are normal. While patients with eu-DKA may not present with typical symptoms as they may not have significant thirst or polyuria. Symptoms may be less obvious and non-specific, which can be challenging to diagnose if they attend the Emergency Department: e.g., they may only have nausea and vomiting. Current treatment guidelines identify DKA as a hyperglycemic emergency, it is essential to raise awareness and education of medical personnel as well as non-medical personnel about the existence of eu-DKA. Not only medical professionals, but more importantly non-professionals should be aware that DKA can occur without a significant increase in blood glucose levels in patients treated with SGLT2i.
SGLT2i as an insulin adjuvant treatment for T1DM, can improve glycemic control,
reduce glycemic variability, and reduce total daily insulin dose and body weight
in patients with T1DM without increasing the risk of hypoglycemic events. It is
an effective option for patients with T1DM who have well above target blood
glucose with insulin alone. However, it has been recognized that SGLT2i increases
the risk of DKA in patients with T1DM, and multiple studies have shown that
SGLT2i increases the incidence of DKA in patients with T1DM by 2- to 4-times.
Therefore, clinicians should be aware of the possibility of DKA in patients with
T1DM using SGLT2i, including adequate knowledge of the patient’s ketone body
levels and previous DKA episodes, and remind patients to regularly test ketone
body levels during treatment (blood ketone testing is preferred to urine ketone
testing (if available/affordable) ). The current use of SGLT2i in patients
SGLT2i, Sodium-glucose cotransporter 2 inhibitors; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; DKA, diabetic ketoacidosis; HF, heart failure; ADA, American Diabetes Association; DPP-4, dipeptidyl peptidase Ⅳ; GLP-1RA, glucagon-like peptide 1 receptor agonist; TGF, tubuloglomerular feedback; GFR, glomerular filtration rate; TIR, time in range; MAGE, mean amplitude of glucose fluctuation; CGM, continuous glucose monitoring; SBP, systolic blood pressure; HDL, high density lipoprotein; CKD, chronic kidney disease; DKD, diabetes kidney disease; CVD, Cardiovascular disease; UACR, urine albumin creatine ratio; HFrEF, heart failure with reduced ejection fraction; EASE, Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes; DEPICT, Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes; eu-DKA, euglycemic DKA.
All authors (YM, QZ, HP, DLN, PS and HJ) have contributed to the conception and design of the manuscript. YM and QZ has been involved in drafting the manuscript. Authors have been involved in revisingit critically for important intellectual content. All authors contributed to editorial changes in the manuscript. All authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreedto be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity. All authors read and approved the final manuscript.
This research was supported by Medical and Health Research Project in Luoyang (2001027A) and National Key R&D Program of China (2018YFC1311705).
The authors declare no conflict of interest.
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