medwireNews: Increased BMI and insulin resistance are important predictors of diabetic ketoacidosis (DKA) risk among people with type 1 diabetes using sodium-glucose cotransporter (SGLT)2 inhibitors, say the authors of a meta-analysis and meta-regression.
The study by Giovanni Musso (HUMANITAS Gradenigo, Turin, Italy) and colleagues included data from 7396 participants of 18 randomized placebo-controlled trials, which ranged in duration from 1 to 52 weeks. Overall, participants taking an SGLT2 inhibitor had a significant 2.81-fold increased risk for DKA compared with those taking placebo.
Baseline BMI and insulin resistance, indicated by the estimated glucose disposal rate, accounted for 61% of the difference in DKA risk found between the studies. DKA risk began to rise from a BMI of 27 kg/m2.
The researchers suggest that overweight, insulin-resistant people may have an increased DKA risk “because they are more prone to unrestricted [free fatty acid] lipolysis from their increased triglyceride stores during the negative glucose balance and insulin dose down-titration induced by SGLT2 [inhibition].”
The ratio of change in insulin dose to baseline insulin sensitivity was also significantly associated with DKA risk, as were volume depletion events, with the two combined explaining 37% of the variation in DKA risk between the studies. Adding them to BMI and insulin resistance explained 86% of the variation.
“In summary, our multivariable model suggests that patients with [type 1 diabetes] who are overweight and insulin resistant are at higher risk of DKA when they rapidly reduce insulin dose and are volume depleted, as these conditions concur to trigger unrestricted lipolysis and ketogenesis,” say Musso and team.
Given the influence of volume depletion events, they stress the importance of good hydration for people taking SGLT2 inhibitors.
Of note, none of these predictors were linked to efficacy, with SGLT2 inhibitor dose the only independent predictor of changes in glycated hemoglobin (HbA1c) level and measures such as fasting plasma glucose and time in range (TIR), as well as changes in BMI.
SGLT2 inhibitor dose was also significantly associated with improvements in blood pressure and albuminuria, and with a reduced risk for eye disorders, mostly accounted for by a significant reduction in the risk for hemorrhagic retinopathy. Improved TIR was also associated with a reduced risk for eye disorders.
The mean amplitude of glucose excursions was also associated with albuminuria, and the fact that this and eye disorders “were associated with an improvement in [continuous glucose monitoring] metrics rather than in HbA1c [is] consistent with emerging evidence that glucose swings are major contributors to microvascular complications,” say the researchers.
They highlight the differing predictors of DKA risk versus glycemic outcomes, and that SGLT2 inhibitor dose was associated only with efficacy, but not adverse events.
“These findings suggest potential benefits of increasing SGLT2 [inhibitor] doses may outweigh the risks of DKA, at least in patients not at increased risk of DKA,” the team writes in PLOS Medicine.
They add: “If confirmed by real-world prospective studies, the results of our analysis may enable the targeted use of SGLT2 [inhibitors] in patients with [type 1 diabetes] who have the greatest benefit and the lowest risk of DKA from the use of these drugs.”
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