By Max Bingham, PhD
Episodes of Euglycemic Diabetic Ketoacidosis and SGLT2 Inhibitor Use in Diabetes
Sodium–glucose cotransporter 2 (SGLT2) inhibitors, such as canagliflozin, appear to be associated with euglycemic diabetic ketoacidosis (DKA) episodes in both type 1 and type 2 diabetes, according to a series of case reports published in this issue of Diabetes Care (p. 1687). Peters et al. describe episodes of euglycemic DKA in nine U.S. individuals with diabetes and warn that, in particular, off-label use of SGLT2 inhibitors in patients with type 1 diabetes should be considered only with “great” caution, extensive counseling, and close monitoring. Notably in all cases described, the patients did not recognize that they had ketoacidosis, and the absence of hyperglycemia delayed their decision to change insulin dosing. Upon typical presentation at the emergency room (which happened in many cases), diagnosis tended to focus on the acidosis without thinking it was related to ketosis, meaning that DKA was not initially recognized, and that led to unnecessary testing and delays in treatment. Eventually, all patients received intravenous insulin and dextrose and recovered. In some cases, reoccurrence of DKA episodes followed resumption of SGLT2 inhibitor use. The authors conclude that in the setting of SGLT2 inhibitor therapy, awareness should be raised toward DKA and that it seemingly can occur even when relative euglycemia is apparent. They state that this might well be critical for treatment of this acute life-threatening complication of diabetes. In a stark warning, they suggest that this is a “worrisome” adverse event and that during the review process it became clear that they were not alone in experiencing such events in relation to this type of intervention. Indeed, the U.S. Food and Drug Administration issued a warning about such risks at the same time the review process was under way. “While the frequency and mechanism of this complication require more study, clinicians and patients need to appreciate the potential risk when prescribing these agents,” the authors warn further.
Type 2 Diabetes Risk Reduction From Moderate Alcohol Consumption Limited to Women
A new meta-analysis appearing in this issue of Diabetes Care (p. 1804) suggests that moderate alcohol consumption may be associated with reduced risk of type 2 diabetes, but only in women and not in men or Asian populations. Moderate alcohol consumption has been previously linked to risk reductions in a wide number of studies. However, concerns have consistently been raised about the use of certain comparator groups and the potential for overestimations of risk reduction. The systematic review and meta-analysis by Knott et al. examined 38 studies that in total covered just more than 1.9 million individuals. This included approximately 126,000 cases of type 2 diabetes. Thirty-three studies reported noncurrent drinkers as the control, whereas only five studies reported never-drinkers as the comparator group. According to the analysis of all data combined, risk reduction was present at all levels of alcohol intake up to <63 g/day. Risk then increased at higher levels. Peak risk reduction of 18% was seen at between 10 and 14 g/day. Crucially, however, stratification of these data revealed that risk reduction might be specific only to women and completely absent when studies compared risk to never-drinkers or were conducted in Asian populations. While highlighting that the use of former drinkers as a control group may have resulted in overestimation of risk reduction, the study suggests that caution is needed in recommending moderate alcohol consumption to reduce risk of type 2 diabetes. Commenting more widely on the implications of this study, Craig Knott stated: “Given that people’s alcohol consumption can vary markedly over time, conventional analyses reliant upon a single baseline measure of exposure are likely too simplistic to fully explain the relationship between alcohol consumption and the development of type 2 diabetes. In the absence of studies that take into account the complex longitudinal association between alcohol consumption and diabetes risk, and with the caveat that current data are highly heterogeneous, evidence from the 38 observational studies analyzed appears to suggest that drinkers may be wise to moderate their consumption.”
Cognitive Impairment in Middle Age Linked to Childhood-Onset Type 1 Diabetes
Middle-aged adults diagnosed with type 1 diabetes in childhood are much more likely to suffer clinically relevant cognitive impairment than similarly aged adults without type 1 diabetes, according to a study in this issue of Diabetes Care (p. 1768). Nunley et al. suggest that the rate of impairment is likely to hit five times that of individuals without type 1 diabetes in middle age. Using a mix of follow-up data, they report a study of a cohort of patients with type 1 diabetes (n = 97) and comparative control participants (n = 138). In particular, they followed up on a group of patients with type 1 diabetes more than 30 years after they had been diagnosed during childhood. The report suggests that cognitive impairment is much more likely to occur in later years following a diagnosis of type 1 diabetes at age <18 years and that this status is likely to be independent of education levels, current age, or blood pressure status. The battery of cognitive tests applied to compare impairment revealed much lower scores in patients with type 1 diabetes than in individuals without diabetes. This included measures of psychomotor speed, executive function, visuoconstruction ability, and verbal intelligence. Particular aspects of type 1 diabetes that were linked to cognitive impairment included an average HbA1c >7.5% (>58 mmol/mol) over 14 years, proliferative retinopathy, and distal polyneuropathy. The authors pinpoint chronic hyperglycemia and microvascular issues as the likely primary causes of this cognitive impairment in middle age. They suggest that such microvascular issues may extend to the brain and particularly its exposure to hyperglycemia during developmental growth periods during youth and so, future cognitive performance. Touching on the wider implications of the study, the authors conclude that “the effects of cognitive impairment on these individuals—diabetes self-management, health service utilization, disability, and quality of life issues—deserve further investigation. Future studies with larger sample sizes and a wider range of ages at diagnosis are needed to improve our understanding of the development and progression of [type 1 diabetes]-related cognitive impairment.” They also suggest that combining neuroimaging and more extensive measures of metabolism and vascular health in studies might help to uncover the mechanisms behind such cognitive impairment.
Bone Marrow–Derived Stem Cells Appear to Be Safe for Treatment of Type 2 Diabetes With Early Signs of Efficacy
Stem cells in the form of bone marrow–derived mesenchymal precursor cells (MPCs) (rexlemestrocel-L) are starting to show promise for treatment of type 2 diabetes according to new trial data published in this issue of Diabetes Care (p. 1742). In a small short-term dose-escalating, randomized, placebo- controlled trial, Skyler et al. investigated safety and tolerability of single intravenous doses of MPCs and found no particular safety issues associated with the treatment. The infusion of cells was also well tolerated by all patients. Previous studies have shown that adult bone marrow MPCs affect a pathway involved in inflammation, and such cells have shown promise in terms of modifying hyperglycemia in preclinical models of diabetes and pilot clinical studies. According to the authors, this is the first report of such a cell therapy in type 2 diabetes in humans. Of notable interest, however, will be the more exploratory data on biological activity and efficacy. Although only modest effects are reported (and the authors stress that the study was not powered to adequately test any hypotheses relating to efficacy), a third of patients receiving MPCs did manage to reduce HbA1c to <7% (<53 mmol/mol). Overall reductions in HbA1c in comparison with placebo are also reported, although it is not clear at this stage whether they would be considered clinically relevant, particularly due to the study design. The authors stress in their conclusions that “despite these limitations, the safety and feasibility results of this study support further investigations to evaluate the use of MPCs in type 2 diabetes and its complications in appropriately sized and powered studies of longer duration, possibly including multiple or periodic cell administrations.”
