Appraisal of Sotagliflozin as Adjunctive Therapy for Type 1 Diabetes

Article Information

Nasser Mikhail*

Professor of Medicine, David-Geffen School of Medicine, Olive View-UCLA Medical Center, USA 

*Correspondence to: Nasser Mikhail, Professor of Medicine, David-Geffen School of Medicine, Olive View-UCLA Medical Center, USA, E-mail: nmikhail@dhs.lacounty. gov

Received: March 03, 2020; Accepted: March 10, 2020; Published: March 16, 2020

Copyright: ©2020 Mikhail N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 

Citation: Mikhail N. Appraisal of Sotagliflozin as Adjunctive Therapy for Type 1 Diabetes. J Clin Endocrinol Diabetes Res. 2020; 1(1):002

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Abstract

Background: Sotagliflozin is a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2) approved in Europe as adjunctive treatment to insulin in patients with type 1 diabetes.

Objective: To review the efficacy and safety of sotagliflozin in type 1 diabetes.

Methods: Literature search (English, Spanish, French) of clinical trials, meta-analysis and expert opinions until March 2, 2020. Search terms included sotagliflozin, SGLT1 and SGLT2 inhibitors, glycated hemoglobin (HbA1c), efficacy, safety, diabetic ketoacidosis (DKA), hypoglycemia.

Results: When added to insulin, sotagliflozin is associated with modest reduction in mean levels by 0.34% compared with placebo. Incidence of overall hypoglycemia and severe hypoglycemia are significantly decreased by 22-31% with sotagliflozin versus placebo. Patients randomized to sotagliflozin had significant decrease in mean total daily insulin doses by approximately 9%, weight by 3.5%, systolic blood pressure (SBP) by 3.8 mmHg, and diastolic blood pressure (DBP) by 1.4 mmHg compared with placebo. Diabetic ketoacidosis was the most frequent and serious adverse effect of sotagliflozin, and the commonest cause of drug discontinuation. Following DKA, other adverse effects of sotagliflozin were genital mycotic infections, diarrhea, and volume depletion.

Conclusion: Sotagliflozin may be a useful addition to insulin in a limited number of patients with type 1 diabetes with body mass index ≥ 27 kg/m2, and those who are at high risk for severe hypoglycemia. These patients should be willing to monitor ketones and follow recommendations for DKA prevention, and using insulin doses of ≥ 0.5 units/kg/day as per guidelines. 

Keywords

 Sotagliflozin; Dapagliflozin; SGLT1; SGLT2; Hypoglycemia; Diabetic Ketoacidosis; Type 1 Diabetes 

Article Details

Introduction

SGLT2 are located in proximal tubules in the kidneys and are responsible for ~97% of whole kidney fractional glucose reabsorption [1]. SGLT1 are located in distal tubules and accounts for the remaining ~3% of fractional glucose reabsorption under conditions of normoglycemia and intact function of SGLT2 [1]. SGLT1 are also located in proximal intestine and mediate glucose uptake from intestine [1]. Sotagliflozin is a dual inhibitor of SGLT1and SGLT2. In vitro studies showed that sotagliflozin is 20 times more potent as an inhibitor of SGLT2 as compared with SGLT1 [2]. Inhibition of SGLT2 by sotagliflozin reduces glucose reabsorption in the renal tubules, whereas inhibition of SGLT1 delays glucose absorption in the proximal intestine and blunts postprandial hyperglycemia [2]. Sotagliflozin (Zynquista) was approved in the European Union on April 19, 2019 as add-on therapy to insulin in adults with type 1 diabetes with a body mass index ≥ 27 kg/m2 [3,4]. This approval was mainly based on 3 double-blind randomized trials called in Tandem lasting from 24 weeks (inTandem3) [5] to 52 weeks (inTandem2 and inTandem3) [6,7]. The purpose of this mini-review is to evaluate sotagliflozin as the first oral agent approved in European Union as adjunctive therapy to insulin in type 1 diabetes. All comparisons mentioned below are statistically significant unless stated otherwise.

Glycemic Efficacy of Sotagliflozin in Type 1 Diabetes - Glycated Hemoglobin

A meta-analysis of 6 randomized trials of 4-52 week-duration showed a mild decrease in mean HbA1c levels of -0.34% (95% CI -0.41 to -27%) compared to placebo [8]. Maximum reduction in values is attained after 8 weeks, followed by partial rebound [7]. Efficacy of the 400 mg-dose of sotagliflozin was slightly greater than the 200 mg-dose, difference in reduction being 0.22% (95% CI 0.28% to 0.12%) [8]. Plasma Glucose Mean reduction of fasting plasma glucose concentrations was -17 mg/ dl (95% CI -22 to -12) versus placebo, whereas corresponding reduction in 2 h postprandial plasma glucose was -39.2 mg/dl (95% CI -54.4 to -28.6) [8].

Continuous Glucose Monitoring

Continuous glucose monitoring studies showed that compared with placebo, sotagliflozin significantly increased the time in range of target blood glucose (BG) (70-180 mg/dl) by 9.5% (95% CI, 6.6% to 12.8%), and reduced average daily glucose by -15.0 mg/dl (95% CI – 21.4 to -8.8 mg/dl). Blood glucose variability, reflected by standard deviation around mean BG, was decreased by -6.7 mg/dl (95% CI, -10.6 to -2.8 mg/dl) compared with placebo [8]. This amelioration in glycemic parameters occurred despite reduction in total daily insulin doses after the addition of sotagliflozin, with a mean difference of -8.9% (95% CI -10.9 to -7.0) compared with placebo [8].

Effect on Hypoglycemia 

At 52 weeks, sotagliflozin decreased level 1 hypoglycemia (BG ≥ 54 to <70 mg/dl) by 22%, and level 2 hypoglycemia (BG<54mg/dl) by 30% compared with placebo [9]. Furthermore, sotagliflozin was associated with 31% lower risk of severe hypoglycemia (requiring assistance of another person or causing loss of consciousness or seizures) compared with placebo (RR 0.69; 95% CI 0.49 to 0.98) [8]. One exception was reported inTandem3 where frequency of severe hyperglycemia was slightly higher with sotaglifozin (3%) versus placebo (2.4%) (Statistical significance was not mentioned) [5].

Effect on Body Weight 

Sotagliflozin induced a modest degree of weight loss, with a mean difference of -3.5% (95% CI -3.9 to -3.1) compared with placebo [8]. Weight loss is likely due to glycosuria and reduction in insulin doses. Indeed, weight loss correlated with the magnitude of reduction in total insulin dosage [8].

Effect on Blood Pressure

Both SBP and DBP were mildly reduced by sotagliflozin. This is expected from its inhibition of SGLT2 causing diuresis and natriuresis. Mean difference versus placebo in SBP was -3.8 mmHg (95% CI -4.7 to -2.9) and DBP -1.4 mmHg (95% CI -1.9 to –0.9) [8].

Patient Satisfaction

Using the Diabetes Treatment Satisfaction Questionnaire Status (DTSQS) and Diabetes Distress Screening Scale, patients randomized to sotagliflozin reported statistically significant amelioration in treatment satisfaction and decrease in diabetes distress compared with placebo [6,7]. The previous finding may be related to reduction in weight and insulin doses.

Safety of Sotagliflozin

Adverse effects of sotagliflozin are generally dose-related, with DKA being the most frequent (see below). The second frequent adverse effect is genital mycotic infections occurring in 11.0%, 9.2%, and 2.3% in patients receiving sotagliflozin 400 mg/d, 200 mg/d, and placebo, respectively [7]. The third common adverse effect was diarrhea (see below), followed by volume depletion events [5,8].

Drug Discontinuation Due to Adverse Effects

Discontinuation of sotagliflozin due to adverse effects reflects the extent to which this drug is tolerated. Proportions of patients who discontinued sotagliflozin due to adverse effects across the 3 inTandem trials were 6.3-6.5%, 3.8-4.9% and 2.3-4.1% with sotagliflozin 400 mg/d, 200 mg/d, and placebo, respectively [5-7]. The most common adverse effect leading to sotagliflozin discontinuation was DKA (35.8% of patients having DKA discontinued sotagliflozin), followed by diarrhea, genital mycotic infections, severe hypoglycemia, urinary tract infection and volume depletion events [8].

Adverse Effects of Special Interest

Diabetic Ketoacidosis

Diabetic ketoacidosis is a class adverse effect of all SGLT2 inhibitors, but its frequency is much higher in patients with type 1 diabetes compared with those with type 2 diabetes. In the latter group of patients, incidence of DKA is estimated to be <0.2% [10]. Across the 3 sotagliflozin inTandem trials, DKA was the most frequent and most serious adverse effect [5-7]. Thus, proportions of patients who experienced DKA ranged from 2.3 to 4.2% among patients randomized to sotagliflozin 200 or 400 mg/d compared with 0.0% to 0.6% among patients randomized to placebo [5-7]. A meta-analysis of greater number of patients (n=3238) including trials of 4-52 week-duration showed that the relative risk (RR) of DKA associated with sotagliflozin was 3.9 (95% CI 1.9 to 7.9) [8]. The risk is particularly elevated among patients using continuous subcutaneous insulin infusion (insulin pump), RR being 6.4, 95% CI 2.8 to 15.6) [8]. Although DKA associated with SGLT2 inhibitors is described as “euglycemic DKA” [11], in case of sotagliflozin, 69% of DKA episodes (n=46) occurred at BG >250 mg/dl and the remaining 31% (n=21) occurred with BG between 150-250 mg/dl [8]. Mechanisms of increase DKA by sotagliflozin are not fully understood, but are likely multifactorial. Possible causes may be reduction in insulin doses, increase in urinary glucose excretion, and increase in glucagon levels [5,12]. The 3 previous factors lead to a shift from glucose to fat as source of energy and subsequent increase rates of lipolysis and ketogenesis [5,12]. Characteristics of sotagliflozin-induced DKA are summarized in Table 1.

Characteristics of sotagliflozin-induced DKA in patients with type 1 diabetes

Incidence rate per 100 patient-years: sotagliflozin 3.4-6.0 vs placebo 0.19-1.11 [13].

Relative risk compared with placebo 3.9 (95% CI 1.9-7.9, P < 0.0001) [8]. 

More common in patients on insulin pump [8] 

Risk increases with reduction of doses of basal insulin [8] 

Risk of DKA is higher in patients with mean baseline HbA1c <8% (RR 6.6, 95% CI 2.0-21.4) than with baseline ≥ 8.0% (RR 2.2, 95% CI 0.4-11.4) [8] 

Blood glucose concentrations > 250 mg/dl in 69% of patients, and 150-250 mg/dl in the remaining 31% (i.e. not “euglycemic” DKA). [8]. 


Table 1
. Characteristics of sotagliflozin-induced DKA in patients with type 1 diabetes.

Diarrhea

Incidence of diarrhea is not increased with SGLT2 inhibitors.This adverse effect is most likely the result of SGLT1 inhibition by sotagliflozin in the intestine. Diarrhea was described as mild to moderate in severity and transient [5-7]. It was reported by 7.2%, 4.6% and 3.5% of patients randomized to sotagliflozin 400 mg/d, 200 mg/d, and placebo, respectively [7]. Yet, diarrhea was the second cause of drug discontinuation after DKA [8].

Sotagliflozin versus SGLT2 Inhibitors in Type 1 Diabetes 

Many physicians were hoping that dual inhibition of SGLT1 and SGLT2 by sotagliflozin might increase its efficacy over SGLT2 inhibitors alone. Yet, although direct head-to head comparison is not available, data suggest that efficacy of sotagliflozin is similar to that of SGLT2 inhibitors [13,14]. Likewise, safety profile of sotagliflozin is generally similar to the SGLT2 inhibitor dapagliflozin (Edistride, Forxiga), which was also approved as adjunctive therapy to insulin in type 1 diabetes in the European Union. However, there are 2 important differences between sotagliflozin and dapagliflozin with respect to safety. First, incidence of hypoglycemia with dapagliflozin was similar to placebo, whereas it was significantly lower than placebo in case of sotagliflozin [8,9,14]. The reasons for this difference are not entirely clear but may be attributed, at least in part, to differences in protocols of insulin titration in the sotagliflozin versus dapagliflozin trials. The second difference is the presence of diarrhea as adverse effect of sotagliflozin, due to its inhibition of SGLT1 in the intestine [5-8].

Evaluation of Sotagliflozin

Sotagliflozin was only evaluated for 52 weeks in randomized trials. During this period, it offers several glycemic advantages represented by mild reduction in HbA1c levels, and glucose variability, increase time of BG in target range, reduction in insulin doses and overall and severe hypoglycemia [5-9]. In addition, it offers non-glycemic benefits represented by mild reduction in weight, blood pressure, and insulin dosage [5-8]. These benefits are counterbalanced by the increased incidence of DKA, genital mycotic infections, diarrhea, and volume depletion events [5-8]. Moreover, the use of sotagliflozin is not straightforward but requires frequent testing of ketones in urine or blood in addition to testing of blood glucose which results in extra time and costs involved in patient’s diabetes care. It should be emphasized that the incidence of DKA will be likely much higher in real-world practice than in clinical trials because of the following reasons. First, patients in sotagliflozin trials were motivated and carefully selected to follow ketone testing and DKA precautions as recommended. Second, subjects with recent DKA were excluded from the sotagliflozin trials. Third, in realworld, follow-up of patients and access to physician and nurses are not as easy as in the setting of clinical trials. Advantages and limitations of sotagliflozin are summarized in Table 2. Therefore, in order to obtain the most benefit and avoid harm, several criteria have to be fulfilled in patients with type 1 diabetes before starting sotagliflozin. Most importantly, patients should be motivated and willing to test ketones and follow manufacturer recommendations regarding DKA prevention. Moreover, patients on insulin pump and those with frequent history of DKA are not safe candidates for sotagliflozin. On the other hand, patients with history of severe hypoglycemia, and those who are attempting to lose weight may gain some benefits from adding sotagliflozin. On February 12, 2020, the National Institute for Health and Care Excellence (NICE) issued guidelines for candidate patients for use of sotagliflozin [15], The author believes that history of severe hypoglycemia may be added to these guidelines based on data showing significant reduction in hypoglycemia in general and severe hypoglycemia in particular with the use of sotagliflozin [8,9]. Meanwhile, in order to minimize risk of DKA, the author proposes that patients at high risk of DKA such as those with past history of frequent DKA and those on insulin pump should avoid using sotagliflozin. Table 3 summarizes guidelines for use of sotagliflozin.

Conclusions and Current Needs 

The use of the dual SGLT1/2 inhibitor sotagliflozin in type 1 diabetes is associated with a modest decrease in the following parameters: HbA1c levels, weight, and BP and moderate reduction in overall and severe hypoglycemia. However, the substantial increase in frequency of DKA by sotagliflozin is a major concern. This complication occurred with higher frequency than placebo despite using intensive patient education about ketone monitoring and DKA prevention. In fact, the concern about DKA is the main reason why sotagliflozin and dapagliflozin are not approved in the USA [13]. Risk factors for sotagliflozin-induced DKA require further studies. Unfortunately, no data exist about safety and efficacy of sotagliflozin beyond 1 year. Results of ongoing long-term randomized trials should further clarify the safety of sotagliflozin and its effects on renal outcomes and cardiovascular morbidity and mortality.

 

Advantages

Disadvantages

 

 

 

 

Sotagliflozin in type 1 diabetes

Mild reduction in HbA1c levels

Increases risk of DKA

Decreased risk of overall hypoglycemia

Requires intensive patient education about DKA monitoring

Decreased risk of severe hypoglycemia

Increases risk of genital fungal infections and diarrhea

Mild weight loss

Not recommended with eGFR <60 ml/min/1.73 m2

Mild decreases in systolic blood pressure and diastolic blood pressure

Lack of data regarding cardiovascular and renal events

Decreases insulin doses by approximately 9%

Absence of efficacy and safety data beyond 1 year

 

Increased cost due to the price of medication itself added to strips required for ketone monitoring in urine or blood


Table 2.
Advantages and limitations of Sotagliflozin in type 1 diabetes. 

Use of Sotagliflozin

1.                   Highly motivated patients willing to monitor blood or ketone as recommended after completion of a structured education program [15].

2.                   Patients without history of frequent DKA episodes (i.e. more than once every 1-2 years) 

3.                   Patients not on insulin pump [8]

4.                   Patients with frequent severe hypoglycemia [8,9] 

5.                   Patients with overweight or obesity with body mass index ≥ 27 kg/m2 [15]

6.                   Follow-up by Endocrinologist and stop sotagliflozin if glycemic control has not improved by an HbA1c of about 0.3% or 3.0 mmol/mol [15]

7.                   Insulin doses ≥ 0.5 units/kg/day [15]


Table 3
. Candidate patients with type 1 diabetes for use of sotagliflozin

Conflict of Interest

The author has no conflict of interest to declare.

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