In This Issue of Diabetes Care

Prescription fill rates for glucagon are “concerningly” low in high-risk groups in the U.S., according to Herges et al. (p. 620). Additionally, the cost of glucagon appears to have steadily risen in the study period examined. This was despite new types of easier-to-use glucagon preparations being introduced in recent years. According to the authors, the worrying pattern should spur on efforts to increase glucagon use in high-risk groups, and efforts should be made with legislation and insurance to control costs overall. The findings come from a retrospective cohort study that examined glucagon prescription fill rates and patient out-of-pocket and health plan costs per filled dose. This was specifically done for U.S. adults with diabetes in the OptumLabs Data Warehouse covering the period 2011–2021. Overall prescription fill rates for glucagon decreased from 2.91 to 2.28 per 1,000 person-years during the study period. This was a drop of 22%. Conversely, fill rates increased in patients with type 1 diabetes (64% increase), patients treated with short-acting insulin (43% increase), and patients with a history of severe hypoglycemia (25% increase). Factors that appeared to explain higher fill rates included White ethnic background, female sex, higher income, and commercial health insurance. Commercially insured patients saw costs per dose increase from just under $160 in 2011 to ∼$275 in 2021—a 75% increase. Medicare Advantage beneficiaries saw total cost of about $150 per dose in 2011 and just under $295 in 2021, an increase of 95%. “We hope this research brings awareness to the issue of glucagon underutilization for patients living with diabetes,” said author Joseph R. Herges. “The gap in glucagon access is profound, even in populations that are at the highest risk of the dangerous outcomes of untreated hypoglycemia. It is also critical to recognize the disparities in glucagon access in minority patients and those with low income and find solutions to barriers such as high cost.”

Youth-onset type 2 diabetes is increasing in the U.S. and will require multilevel interventions to stem its increasing incidence and prevalence, according to Perng et al. (p. 490). Using a narrative review, the authors describe the rising incidence and prevalence of type 2 diabetes among youth and the often more severe clinical outcomes of this disease, compared with type 1 diabetes, in youth. In terms of causes, they note the outsized contribution of childhood and maternal obesity, but they also highlight the significant effects of the social determinants of health—the conditions and environment into which individuals are born, live, work, and play. While the authors quite rightly note that individual- and family-level interventions (e.g., diabetes prevention programs) can bring results, the approach can be particularly burdensome for some. Alternatively, they suggest that community-level improvements should be considered to encourage healthier lifestyles. In their exploration of future directions, the authors highlight how there are, in fact, limited data on youth-onset type 2 diabetes, particularly compared with what is known about diabetes in adulthood. There is also evidence that distinct subgroups of characteristics exist that make diagnosis and treatment difficult right now but, at the same time, might also make diagnosis and treatment easier in the future if these characteristics are better understood. They go on to highlight the issue of the intergenerational cycle of obesity and type 2 diabetes and propose a dual approach to tackling youth-onset diabetes that involves a better understanding of the disease and that an overarching approach to chronic disease prevention on political, public health, and clinical levels is needed. Commenting more widely, author Wei Perng said, “In the words of Dana Dabelea [senior author of the article], even one case of youth-onset type 2 diabetes is one too many given its aggressive clinical course and low responsiveness to pharmaceutical treatments. Accordingly, there needs to be a shifting focus toward multipronged prevention rather than treatment of this chronic metabolic condition.”

Women who had a prior Roux-en-Y gastric bypass (RYGB) experienced greater exposure to hypoglycemia and hyperglycemia both during and after pregnancy, according to Stentebjerg et al. (p. 502). Specifically, they experienced reduced time in range, measured with continuous glucose monitoring, owing to greater periods both above and below the target. The findings raise important questions about gestational diabetes mellitus risk and postbariatric hypoglycemia during pregnancy and whether it is suitable for women of childbearing age, even though the procedure can deliver substantial weight loss and an increase in fertility. The findings come from a prospective study of 23 pregnant women with prior RYGB and 23 BMI- and parity-matched pregnant women who had interstitial continuous glucose monitoring both during and 4 weeks after pregnancy. Women with prior RYGB spent less time in range (∼88%; defined as interstitial glucose in the range 3.5–7.8 mmol/L) than control participants (∼95%), even though there were no significant differences between the groups in terms of mean measured glucose levels. The group that received the surgery experienced twofold increased time above range and increased time below range compared with the control group. Indeed, nearly half of the surgically treated women had time below range, with most experiencing very low glucose levels at some point. The authors also note that glycemic variability was significantly higher in the women who received surgery, while active continuous glucose monitoring use was significantly lower. Modeling suggested that women with RYGB had significantly increased risks for hypoglycemia in pregnancy, with a variety of factors explaining associations in univariate but not multivariate analysis. “Future studies should investigate the screening of gestational diabetes mellitus in these women, given that they had twofold increased time in hyperglycemia and that we cannot use the standard oral glucose tolerance test,” said author Louise L. Stentebjerg. “Furthermore, larger studies should investigate whether postbariatric hypoglycemia during pregnancy in women with RYGB is associated with decreased fetal growth.”

Poorer glycemic management among adults with type 2 diabetes appears to be associated with increased deficits in health relating to aging and particularly frailty, according to Simpson et al. (p. 519). Conversely, weight loss and metformin treatment (intriguingly) led to slower frailty progression, which the authors suggest reflects slower biological aging. The findings come from further analysis of the Action for Health in Diabetes (Look AHEAD) trial, which originally compared the effectiveness of intensive lifestyle intervention with that of diabetes support and education. This exploratory analysis included just under 4,200 participants in the original trial and looked at the relationship between baseline and 8-year levels of HbA_1c and frailty index scores. The authors also looked at associations between 8-year changes in frailty index and classes of diabetes medication use and assessed weight changes while controlling for HbA_1c levels. Crucially, they also used inverse probability weighting to deal with bias associated with different rates of follow-up. They found that levels of HbA_1c below 7% were associated with less increase in frailty scores than higher (i.e., >8%) HbA_1c levels. Metformin use and weight loss of >5% were independent factors associated with slower increases in frailty. The authors conclude that better diabetes management and weight loss is a key approach to slowing biological aging in the overall context of diabetes. However, they warn that it is still not clear whether higher levels of frailty at younger ages can be tackled with such interventions. “People age at different rates,” said author Mark A. Espeland. “We see individuals who appear younger than their age and others who do not. Our research suggests that older adults with type 2 diabetes who can control their HbA_1c, especially with weight loss or metformin, may slow their aging processes compared with other individuals with diabetes.”