Sodium–Glucose Cotransporter 2 Inhibitors and Diabetic Ketoacidosis: A Case Series From Three Academic Institutions

Misaghian‐Xanthos, Negin; Shariff, Afreen; Mekala, Kavya Chitra; Fearrington, Loretta R.; Setji, Tracy L.; Aloi, Joseph; Buse, John B.

doi:10.2337/dc16-2591

Cited by 19 publications

(28 citation statements)

References 3 publications

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“…Consistent with this hypothesis, only four of 64 (6.25%) patients who were receiving pioglitazone as part of their background therapy were reported to have developed ketoacidosis following SGLT2i administration compared to 36% of insulin‐treated T2DM patients . A larger study is warranted to examine whether the addition of pioglitazone to dapagliflozin therapy prevents the SGLT2i‐induced increase in plasma ketone concentration and the development of euglycaemic ketoacidosis reported with SGLT2i therapy . We did not measure plasma‐free fatty acid concentration in the present study.…”

Section: Discussionsupporting

confidence: 57%

“…No previous study has examined the impact of background insulin therapy on the increase in plasma ketone concentration caused by SGLT2i. However, the majority of T2DM patients with reported diabetic ketoacidosis attributed to SGLT2i use had received insulin as part of their background antidiabetic treatment . In one case series, 59% of T2DM patients who developed diabetic ketoacidosis (n = 34) were receiving two or more daily insulin injections .…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that, in addition to lowering plasma glucose concentration, SGLT2i exert multiple other metabolic actions in T2DM patients including improved insulin sensitivity, enhanced beta cell function, and increased plasma free fatty acid (FFA) concentration, total body fat oxidation and ketone production. Although, in absolute terms, the increase in plasma ketone concentration is small, from approximately 0.2 mM to approximately 0.4 mM, it occurs in the vast majority (>90%) of patients receiving SGLT2i therapy,, and in 10% to 20% of patients the plasma ketone level exceeds the upper limit of the normal range . Because of the reduction in daily insulin dose, the increase in plasma ketone concentration associated with the initiation of SGLT2i therapy was highest in patients receiving insulin therapy.…”

Section: Introductionmentioning

confidence: 97%

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Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

Abdul‐Ghani

Migahid

Megahed

et al. 2018

Diabetes Obesity Metabolism

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Because of the unique mechanism of action of sodium‐glucose co‐transport inhibitors (SGLT2i), which is independent of insulin secretion and insulin action, members of this class of drugs effectively lower plasma glucose concentration when used in combination with all other antidiabetic agents, including insulin. Increased plasma ketone concentration has been reported in association with SGLT2i initiation, which, under certain clinical conditions, has developed into diabetic ketoacidosis. The daily insulin dose often is reduced at the time of initiating SGLT2i therapy in insulin‐treated patients to avoid hypoglycaemia. However, reduction of insulin dose can increase the risk of ketoacidosis. In the present study, we examined the effect of the addition of dapagliflozin plus pioglitazone on plasma ketone concentration in insulin‐treated T2DM patients and compared the results to the effect of dapagliflozin alone. A total of 18 poorly controlled, insulin‐treated T2DM participants in the Qatar Study received dapagliflozin (10 mg) plus pioglitazone (30 mg), and 10 poorly controlled non‐insulin‐treated T2DM patients received dapagliflozin (10 mg) alone for 4 months. Dapagliflozin plus pioglitazone produced a robust decrease in HbA1c (−1.4%) and resulted in a 50% reduction in daily insulin dose, from 133 to 66 units, while dapagliflozin alone caused a 0.8% reduction in HbA1c. Dapagliflozin caused a four‐fold increase in fasting plasma ketone concentration, while the combination of pioglitazone plus dapagliflozin was not associated with a significant increase (0.13 vs 0.15 mM) in plasma ketone concentration or in risk of hypoglycaemia. These results demonstrate that the addition of pioglitazone to dapagliflozin prevents the increase in plasma ketone concentration associated with SGLT2i therapy.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

Abdul‐Ghani

Migahid

Megahed

et al. 2018

Diabetes Obesity Metabolism

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“…Nevertheless, currently published cardiovascular outcome RCTs did not detect a significant difference in DKA incidence; however, it should be noted that these 2 RCTs involved a limited number of ketoacidosis events (5 cases for the EMPA‐REG OUTCOME and 18 cases for CANVAS) 11, 12. Although DKA in the setting of SGLT2 inhibitor therapy is unusual,56, 57 adjunctive point‐of‐care home ketone monitoring should be considered in a subset of high‐risk patients because DKA related to SGLT2 inhibitors can present with lower blood glucose levels 10…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

104

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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“…We retrieved a total of 105 episodes of DKA in patients receiving SGLT2i from May 2014 to April 2017 . Demographic characteristics, type of diabetes and type of SGLT2i are reported in Table .…”

Section: Review Of the Literaturementioning

confidence: 99%

Sodium‐glucose co‐transporter‐2 inhibitors and diabetic ketoacidosis: An updated review of the literature

Bonora

Avogaro

Fadini

2017

Diabetes Obesity Metabolism

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Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly used for the treatment of type 2 diabetes (T2D) and can improve glucose control also in type 1 diabetes (T1D). In May 2015, regulatory agencies issued a warning that SGLT2is may cause diabetic ketoacidosis (DKA). We report details on 2 new cases of SGLT2i-associated DKA and review the literature for similar cases within randomized controlled trials (RCTs), cohort studies and single reports. We searched the medical literature for reports of SGLT2i-associated DKA cases. A quantitative analysis of frequency and clinical characteristics is reported. The 2 narrative cases illustrate that SGLT2i-associated DKA can occur in patients with T1D incorrectly diagnosed as T2D, perhaps without the presence of obvious DKA precipitating factors. The incidence of SGLT2i-associated DKA was less than 1/1000 in randomized controlled trials and 1.6/1000 person-years in cohort studies. We retrieved detailed data on 105 SGLT2i-associated DKA case reports, wherein 35% showed glucose levels of less than 200 mg/dL and 22% were not associated with typical triggers. In case reports and in pharmacovigilance databases, duration of SGLT2i treatment before DKA onset was extremely variable. Fatal SGLT2i-associated DKA episodes were found only in pharmacovigilance databases and represented 1.6% of all reported cases. DKA is a rare adverse event during SGLT2i therapy. Predisposing and precipitating factors are still incompletely understood, although a minority of cases lacked typical DKA triggers. More narrative case series and cohort studies are needed to better understand the true risk and the spectrum of this adverse event.

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Sodium–Glucose Cotransporter 2 Inhibitors and Diabetic Ketoacidosis: A Case Series From Three Academic Institutions

Cited by 19 publications

References 3 publications

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Sodium‐glucose co‐transporter‐2 inhibitors and diabetic ketoacidosis: An updated review of the literature

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