Glucose Drink With Ketone Substrate Eases Hypoglycemia Recovery in Type 1 Diabetes Trial

Adults with type 1 diabetes who treated low blood sugar with a recovery drink combining glucose and beta-hydroxybutyrate reported a better recovery experience than when they used standard glucose gel, according to a randomized, open-label crossover study published in Diabetes Therapy. The drink, known as FLO23011, was rated more favorably than glucose gel in 13 of 14 patient-reported domains, and structured exit interviews converged on three themes: faster perceived cognitive recovery, less disruption to daily activities, and greater confidence in self-managing hypoglycemia.

The study enrolled 12 adults with type 1 diabetes, eight male and four female, with a mean age of 49.3 years and a mean HbA1c of 6.8 percent. Participants were randomized in a 1:1 ratio to use either FLO23011 first or standard-of-care glucose gel first, each for a six-week period, with no washout between periods. Both products delivered 15 grams of fast-acting carbohydrate; the drink additionally contained 10 grams of beta-hydroxybutyrate, an energy substrate that can enter oxidative metabolism downstream of glycolysis. Participants treated naturally occurring hypoglycemic episodes during normal daily life while wearing continuous glucose monitors throughout the full 12-week study. A total of 1,032 hypoglycemic episodes were identified from 232,607 CGM readings.

The rationale for the drink rests on a proposed mechanism rather than a demonstrated one. Although conventional glucose treatment restores plasma glucose, it may be followed by glycemic oscillations and prolonged neuroglycopenic symptoms such as fatigue, impaired cognition, and reduced functional capacity. Experimental evidence suggests these symptoms can persist after blood glucose normalizes because cerebral energy metabolism remains transiently impaired. One proposed explanation is a hypoglycemia-related energy bottleneck: activation of the enzyme poly(ADP-ribose) polymerase 1 depletes cytosolic NAD+, constraining neuronal glycolytic flux. This bottleneck has been proposed as a contributor to the so-called hypoglycemia hangover, the post-episode fatigue, cognitive fog, and functional impairment that can linger after glucose has returned to range. Beta-hydroxybutyrate is proposed to bypass this constraint by feeding oxidative metabolism directly, potentially supporting neuronal ATP production during the recovery window.

At the end of the study, participants compared the two treatments across 14 domains using a single 10-point anchored scale, where scores above 5 indicated preference for the drink and scores below 5 indicated preference for the gel. Because two participants had impaired awareness of hypoglycemia and did not experience post-hypoglycemic symptoms, symptom-experience and functional-recovery domains were analyzed in the remaining 10 participants; all other domains included all 12. Among those contributing to recovery-related analyses, 70 percent reported less severe aftereffects such as fatigue or weakness, and 80 percent reported faster return to daily activities. Rebound hypoglycemia management favored the drink in 58 percent of participants. Ease of use was preferred by 75 percent, while portability favored the gel, with only 33 percent preferring the drink. Psychological benefits were also reported, including increased sense of control at 82 percent, greater dosing confidence at 73 percent, and reduced worry at 55 percent. Overall, 64 percent preferred the drink for hypoglycemia management.

Closed-response exit interview items reinforced these preferences. Ninety-two percent of participants rated the drink very or extremely effective, compared with 50 percent for the gel. The same proportion, 92 percent, reported never or rarely experiencing post-hypoglycemia hangover symptoms with the drink, versus 33 percent for the gel. More than half described rapid cognitive restoration with the drink, and 75 percent reported perceived reductions in glucose spikes, which they attributed to more precise dosing and reduced overtreatment. In the qualitative analysis, participants described the drink as producing faster and clearer mental recovery after hypoglycemia, in contrast to the gel, which some associated with residual brain fog and disorientation. Others said the gel left them feeling written off for the day, whereas the drink allowed a quicker return to work, social activities, and usual tasks. Participants also described greater confidence that an episode would resolve without repeated treatment or major disruption.

The study also explored how continuous glucose monitoring data related to these patient-reported outcomes, though the authors emphasize these were hypothesis-generating analyses conducted in small subsets. Among the five participants with both usable CGM data and corresponding questionnaire data, reductions in exposure to Level 1 hypoglycemia, defined as glucose between 3.0 and 3.8 mmol/L, were associated with higher ratings for reduced worry about hypoglycemia and overall management ability, with a Spearman correlation of 0.90 and a P value of 0.037. This association was not observed with the gel, and changes in time spent in the low-normal glucose band of 3.9 to 5.0 mmol/L were not associated with the psychological scores. The authors suggest this pattern points to a specific link between psychological benefit and reduced exposure to clinically meaningful low-glucose episodes rather than a nonspecific effect of broader glucose changes.

A second exploratory analysis examined whether baseline glycemic characteristics could predict objective treatment response. Among nine participants with adequate paired CGM data after quality control, higher coefficient of variation during the gel period was associated with greater improvement in time in range when using the drink, with a Spearman correlation of 0.917 and a P value of 0.0005. Four baseline metrics were examined, and all showed directionally consistent associations, with coefficient of variation showing the strongest. If confirmed prospectively, the authors write, baseline CGM characteristics could support more targeted use of treatments designed to improve post-hypoglycemia stability and recovery.

These patient-experience findings complement previously reported results from the same trial. The earlier report showed that the drink improved post-hypoglycemia time in range by 5.5 percentage points and reduced recurrent hypoglycemia within two hours by 27 percent relative to the gel, both statistically significant. The present analysis adds domain-level preference data, a structured analysis of exit interviews, and the exploratory CGM correlations. The authors also connect the findings to a behavioral dimension of hypoglycemia care: in practice, hypoglycemia is often overtreated, and impaired judgment and delayed cognitive recovery after glucose restoration may make it harder to stop consuming carbohydrate once blood glucose is already recovering. By improving perceived cognitive recovery and increasing confidence that an episode has been adequately treated, the drink may plausibly help reduce symptom-driven overtreatment, a concern that may grow as hybrid closed-loop systems alter carbohydrate requirements during insulin suspension.

The study has substantial limitations that the authors address directly. Because the drink and the gel differ in format, volume, and taste, blinding was not feasible, and participants knew which product they were using when rating it. Expectancy, novelty, and preference effects may therefore have contributed to the ratings, and differences in format and taste may have influenced perceptions of effectiveness and speed of recovery independently of any physiological effect. The consistency of the patient-reported findings with objective glycemic outcomes from the same trial suggests the preference signal is unlikely to be explained by expectancy alone, although comparator-matched designs would be needed to separate these effects. The CGM analyses were exploratory, selected post hoc, not powered for definitive inference, and not corrected for multiple comparisons. The PRO questionnaire was study-specific and has not been formally psychometrically validated. The end-of-study comparison was a single rating made after both treatment periods without a washout, and may have been influenced by recall or the more recent treatment experience. Exit interviews were conducted by diabetes experts aware of treatment allocation, and no formal qualitative methodology was applied.

Further constraints shape how broadly the results apply. The predominantly male sample of CGM users, in which 67 percent were men, may not represent the full type 1 diabetes population, and the single-center UK sample may limit generalizability across ethnic groups and healthcare settings. Participants with impaired hypoglycemia awareness or absent post-hypoglycemic symptoms were excluded from symptom- and recovery-related analyses, so those findings apply most directly to individuals who perceive hypoglycemia and recovery symptoms. Correlation analyses were conducted in subsets of only five and nine participants. The authors call for independent evaluation by investigators without a commercial interest, study designs that reduce expectancy effects such as comparator-matched formats, and more diverse populations including hybrid closed-loop users and people with impaired hypoglycemia awareness, using validated PRO instruments. No cognitive, neurophysiological, or metabolic measures were included to test the proposed energy-bottleneck mechanism, and the study was not designed to test it. The trial was retrospectively registered with the ISRCTN Registry on 11 June 2026.

Subject of Research: Patient-reported outcomes and exploratory CGM correlates of a glucose and beta-hydroxybutyrate hypoglycemia recovery drink in adults with type 1 diabetes

Article Title: Reducing the Burden of Hypoglycemia in Type 1 Diabetes: The Impact of FLO23011 on Patient-Reported Outcomes and Glycemic Correlates of Treatment Response

Article References: Russell-Jones, D., Meehan, E. G., Smout, V., Roy, S., Frost, W., Young, T. M., & Bartlett, D. B. (2026). Reducing the Burden of Hypoglycemia in Type 1 Diabetes: The Impact of FLO23011 on Patient-Reported Outcomes and Glycemic Correlates of Treatment Response. Diabetes Therapy. https://doi.org/10.1007/s13300-026-01929-6

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01929-6

Keywords: type 1 diabetes, hypoglycemia, FLO23011, beta-hydroxybutyrate, continuous glucose monitoring, patient-reported outcomes, crossover trial, time in range, glycemic variability, hypoglycemia hangover, glucose gel, open-label study