A single-site feasibility randomised controlled trial comparing 'my hypo compass' short pyscho-educational intervention with standard care alone in individuals with type 1 diabetes and impaired awareness of hypoglycaemia.

AIMS: The HypoCOMPaSS multi-centre trial achieved improvement in hypoglycaemia awareness and 20-fold reduction in severe hypoglycaemia (SH) in a cohort with long-standing type 1 diabetes (T1D). All participants received 'my hypo compass' (MHC) brief structured psycho-educational intervention in addition to optimisation of insulin delivery/glucose monitoring. In this 24-week, prospective, single-centre feasibility RCT, we piloted MHC as a sole intervention in comparison to standard clinical care alone (CON). METHODS: Participants with T1D and impaired hypoglycaemia awareness (IAH) (Clarke score ≥4) were recruited. MHC comprised a group/individual 1-2 h face-to-face session followed by a telephone call and second face-to-face session at 4 weeks. Outcome measures at 24 weeks were compared with baseline. RESULTS: Fifty-two individuals provided consent for screening with 39 fulfilling eligibility criteria. Fifteen withdrew before any study intervention. Twenty-four adults with (mean ± SD) T1D duration 41.0 ± 15.1 years commenced/completed the study (100% visit attendance); 12 randomised to MHC and 12 to CON. All had IAH at baseline and at 24 weeks. Annualised SH rate following MHC was 3.8 ± 19.0 (24 weeks) versus 12.6 ± 3.5 (Baseline) and in CON group 2.0 ± 19.0 (24 weeks) versus 4.6 ± 11.5 (Baseline). 'Immediate Action' for and 'Worry' about hyperglycaemia measured by the Hyperglycaemia Avoidance Scale appeared lower following MHC. Participants attended all study visits and reflected positively on the MHC intervention. CONCLUSIONS: Feasibility of MHC implementation without additional intervention has been demonstrated. MHC education was associated with positive changes in attitudes and behaviours with the potential to reduce SH risk. MHC provides a validated, simple, well-received programme to fulfil the educational component within RCTs targeting problematic hypoglycaemia and as part of holistic clinical care.

Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry.

AIMS/HYPOTHESIS: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR). METHODS: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs). RESULTS: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA1c <53 mmol/mol (7.0%), 73% had HbA1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups. CONCLUSIONS/INTERPRETATION: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.

A real-life comparison of hypoglycaemia symptomatology between insulin-treated type 2 diabetes participants with and without impaired awareness of hypoglycaemia.

AIMS: We aim to compare and correlate Gold and Clarke questionnaire scores with hypoglycaemic symptomatic responses between insulin-treated type 2 diabetes participants with and without IAH in a real-life study. METHODS: Insulin-treated type 2 diabetes participants attending an outpatient diabetes clinic in Singapore were asked to complete the Gold and Clarke questionnaires, record capillary blood glucose (CBG) and hypoglycaemic symptoms for 4 weeks. RESULTS: Data were collected from 153 participants (M:F = 98:55) with mean age 61.0 ± 9.4 years, duration of diabetes 19.5 ± 8.8 years and HbA1c 68 ± 17 mmol/mol (8.4 ± 1.5%). Gold and Clarke methods classified 19.6% and 26.8% of participants with IAH, respectively. Using CBG threshold of <3 mmol/L, significantly greater proportion of participants with intact awareness were experiencing autonomic symptoms than those with IAH with either method (Gold: 69% vs. 18%, p = 0.006; Clarke: 85% vs. 46%, p = 0.010). Significantly greater proportion of participants with IAH experienced no hypoglycaemia symptoms than those with intact awareness (Gold: 3.4% vs. 36%, p = 0.015; Clarke: 3.7% vs. 31%, p = 0.031). Participants with IAH had significantly higher rates of severe hypoglycaemia in the preceding year compared to those without (Gold: 17% vs. 3.3%; Clarke: 15% vs. 2.7%, p = 0.012). CONCLUSIONS: Gold and Clarke questionnaires are appropriate tools in ascertaining IAH status in insulin-treated type 2 diabetes participants. This is the first time whereby the hypoglycaemia symptomology has robustly validated the Gold and Clarke questionnaire in insulin-treated type 2 diabetes participants.

Fall in prevalence of impaired awareness of hypoglycaemia in individuals with type 1 diabetes.

AIMS: Impaired awareness of hypoglycaemia (IAH) has been reported to affect up to a third of people with type 1 diabetes. Whether the increased use of sensor technology has changed its prevalence remains unknown. The aim of this study was to investigate the current prevalence of IAH and its change over time in a cohort of individuals with type 1 diabetes. METHODS: IAH was assessed using the modified Clarke questionnaire in adults with type 1 diabetes. Participants were recruited from the diabetes outpatient clinic from February 2020 through April 2021. The scores were compared to similar data collected during previous assessments in 2006, 2010 and 2016 respectively. RESULTS: A total of 488 individuals (51.2% male) with a mean (±SD) age of 51.3 ± 15.9 years, median [Q1-Q3] diabetes duration of 30 [16-40] years and mean HbA1c of 60 ± 12 mmol/mol (7.7 ± 1.1%) were included. Sensors were used by 85% of the study population. IAH was present among 78 (16.0%) participants, whereas 86 (17.6%) participants had a history of severe hypoglycaemia. By comparison, the prevalence of IAH equalled 32.5% in 2006, 32.3% in 2010 and 30.1% in 2016 (p for trend <0.001), while the proportion of individuals reporting severe hypoglycaemia equalled 21.2%, 46.7% and 49.8% respectively (p for trend 0.010). Comparing sequential assessments over time, the proportion of individuals with persistent IAH decreased from 74.0% and 63.6% between 2006 and 2016 to 32.5% in 2020. CONCLUSIONS: Among individuals with type 1 diabetes and high use of sensor technology, the current prevalence of IAH was 16%, about 50% lower as compared to previous years.

Impact of severe hypoglycaemia requiring hospitalization on mortality in people with type 1 diabetes: A national retrospective observational cohort study.

AIMS: To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization. MATERIALS AND METHODS: We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model. RESULTS: A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951]). CONCLUSIONS: The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization.

Severe hypoglycaemia in adults presenting to a hospital emergency department: Clinical characteristics, comorbidities, and mortality outcomes.

AIMS: To determine the clinical characteristics, risk factors and mortality outcomes associated with severe hypoglycaemia (SH) treated at a hospital emergency department. MATERIALS AND METHODS: Adult patients presenting with SH to the Northern General Hospital, Sheffield, UK over a 44-month period were assessed for clinical characteristics, coexisting comorbidities and mortality outcomes, including cause of death, and analysed by age of diabetes onset, below and above age 40 years. Factors that predicted mortality were determined. RESULTS: A total of 619 episodes of SH occurred in 506 individuals. Most had type 1 (T1D; n = 172 [34.0%]) or type 2 diabetes (T2D; n = 216 [42.7%]), but several attendees did not have diabetes (non-DM; n = 110 [21.7%]). Irrespective of age of diabetes onset, patients with T2D had more socioeconomic deprivation and comorbidities (P < 0.005). SH was uncommon in those with young-onset T2D, who constituted 7.2% of all episodes in diabetes. Hospital admission was high (60%-75%). The T2D cohort had the longest inpatient stay (median 5 days, vs. 2 and 3 days for the T1D and non-DM cohorts, respectively). Survival after the index SH episode was lower and mortality was higher in the non-DM (39.1%) and T2D (38.0%) cohorts than the T1D cohort (13.3%; all P < 0.05), with a median time to death of 13, 113 and 465 days, respectively. Most deaths (78%-86%) were from non-cardiovascular causes. Charlson index predicted mortality and poor survival in T1D and T2D (both P < 0.05). CONCLUSIONS: Severe hypoglycaemia requiring emergency hospital treatment is associated with non-cardiovascular deaths and exerts a disproportionately greater impact on mortality in people with T2D and those without diabetes. Multimorbidity is an important risk factor for SH and increases mortality risk.

Non-adjunctive continuous glucose monitoring for control of hypoglycaemia (COACH): Results of a post-approval observational study.

OBJECTIVE: Prior to the Continuous Monitoring and Control of Hypoglycaemia (COACH) study described herein, no study had been powered to evaluate the impact of non-adjunctive RT-CGM use on the rate of debilitating moderate or severe hypoglycaemic events. RESEARCH DESIGN AND METHODS: In this 12-month observational study, adults with insulin-requiring diabetes who were new to RT-CGM participated in a 6-month control phase where insulin dosing decisions were based on self monitoring of blood glucose values, followed by a 6-month phase where decisions were based on RT-CGM data (i.e. non-adjunctive RT-CGM use); recommendations for RT-CGM use were made according to sites' usual care. The primary outcome was change in debilitating moderate (requiring second-party assistance) and severe (resulting in seizures or loss of consciousness) hypoglycaemic event frequency. Secondary outcomes included changes in HbA1c and diabetic ketoacidosis (DKA) frequency. RESULTS: A total of 519 participants with mean (SD) age 50.3 (16.1) years and baseline HbA1c 8.0% (1.4%) completed the study, of whom 32.8% had impaired hypoglycaemia awareness and 33.5% had type 2 diabetes (T2D). The mean (SE) per-patient frequency of hypoglycaemic events decreased by 63% from 0.08 (0.016) during the SMBG phase to 0.03 (0.010) during the RT-CGM phase (p = 0.005). HbA1c decreased during the RT-CGM phase both for participants with type 1 diabetes (T1D) and T2D and there was a trend towards larger reductions among individuals with higher baseline HbA1c. CONCLUSIONS: Among adults with insulin-requiring diabetes, non-adjunctive use of RT-CGM data is safe, resulting in significantly fewer debilitating hypoglycaemic events than management using SMBG.

Impaired awareness of hypoglycaemia in women with type 1 diabetes in pregnancy: Hypoglycaemia fear, glycaemic and pregnancy outcomes.

AIMS: To examine maternal fear of hypoglycaemia, glycaemia and pregnancy outcomes in women with impaired and normal awareness of hypoglycaemia. METHODS: A pre-planned sub-study of 214 pregnant women with type 1 diabetes who participated in the CONCEPTT trial. Participants completed hypoglycaemia fear surveys (HFS-II) at baseline. Logistic regression and Poisson regression analyses were used to obtain an adjusted estimate for the rate ratio relating awareness to the number of severe hypoglycaemic episodes, and for several neonatal outcomes in relation to the total HFS-II score. The role of continuous glucose monitoring (CGM) use was examined. RESULTS: Overall, 30% of participants reported impaired awareness of hypoglycaemia (n = 64). Women with impaired awareness of hypoglycaemia had more episodes of severe hypoglycaemia (mean 0.44 vs. 0.08, p < 0.001) (12-34 weeks gestation) and scored higher on the HFS-II scale (43.7 vs. 36.0, p 0.008), indicating more fear of hypoglycaemia. They spent more time below range (CGM <3.5 mmol/L) and exhibited more glycaemic variability at 12 weeks gestation. Higher overall HFS-II scores were associated with a higher risk of maternal severe hypoglycaemia episodes (Rate Ratio 1.78, 95% CI 1.39-2.27). Women with impaired awareness of hypoglycaemia had less maternal weight gain but there were no differences in neonatal outcomes between women with impaired awareness of hypoglycaemia and normal hypoglycaemia awareness. Higher HFS-II scores were associated with more nephropathy (Odds Ratio 1.91, 95% CI 1.06-3.4). CGM use after 12 weeks was not associated with the number of episodes of severe hypoglycaemia (RR 0.75, 95% CI 0.49-1.15; p = 0.18). CONCLUSIONS: In pregnant women with type 1 diabetes, impaired awareness of hypoglycaemia is associated with more maternal severe hypoglycaemia episodes and more fear of hypoglycaemia. Having impaired awareness of hypoglycaemia and/or fear of hypoglycaemia should alert clinicians to this increased risk. Reassuringly, there was no increase in adverse neonatal outcomes.

Previously unrecognized risk factors for severe hypoglycaemia requiring emergency medical care in insulin-treated type 2 diabetes: Results from a real-world nested case-control study.

AIM: Several risk factors for severe hypoglycaemia (SH) are associated with insulin-treated diabetes. This study explored potential risk factors in adults with insulin-treated type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this case-control study, adults with T2DM initiating insulin were identified in the IQVIA PharMetrics® Plus database. The index date was the date of the first SH event (cases). Using incidence-density sampling, controls were selected from those who had been exposed 'at risk' of SH for the same amount of time as each case. After exact-matching on the well-established factors, previously unreported risk factors were evaluated through conditional logistic regression. RESULTS: In 3153 case-control pairs, pregnancy [odds ratios (OR) = 3.20, p = .0003], alcohol abuse (OR = 2.43, p < .0001), short-/rapid-acting insulin (OR = 2.22/1.47, p < .0001), cancer (OR = 1.87, p < .0001), dementia/Alzheimer's disease (OR = 1.73, p = .0175), peripheral vascular disease (OR = 1.59, p < .0001), antipsychotics (OR = 1.59; p = .0059), anxiolytics (OR = 1.51, p = .0012), paralysis/hemiplegia/paraplegia (OR = 1.51, p = .0416), hepatitis (OR = 1.50, p = .0303), congestive heart failure (OR = 1.47, p = .0002), adrenergic-corticosteroid combinations (OR = 1.45, p = .0165), ß-adrenoceptor agonists (OR = 1.40, p = .0225), opioids (OR = 1.38, p < .0001), corticosteroids (OR = 1.35, p = .0159), cardiac arrhythmia (OR = 1.29. p = .0065), smoking (OR = 1.28, p = .005), Charlson Comorbidity Index score 2 (OR = 1.28, p = .0026), 3 (OR = 1.41, p = .0016) or ≥4 (OR = 1.57, p = .0002), liver/gallbladder/pancreatic disease (OR = 1.26, p = .0182) and hypertension (OR = 1.19, p = .0164) were independently associated with SH. CONCLUSIONS: Although all people with insulin-treated diabetes are at risk of SH, these results have identified some previously unrecognized risk factors and sub-groups of insulin-treated adults with T2DM at greater risk. Scrutiny of current therapies and comorbidities are advised as well as additional glucose monitoring and education, when identifying and managing SH in vulnerable populations.

Effects of bariatric surgery on kidney diseases, cardiovascular diseases, mortality and severe hypoglycaemia among patients with Type 2 diabetes mellitus.

BACKGROUND: Bariatric surgery has been widely indicated for the management of obesity and related comorbidities. However, there are uncertainties pertaining to the risks of post-bariatric severe hypoglycaemia (SH), cardiovascular diseases (CVDs), end-stage kidney diseases (ESKDs) and all-cause mortality in obese patients with Type 2 diabetes mellitus (T2DM), especially among Asian populations. METHODS: A retrospective population-based cohort of 1702 obese T2DM patients who were free of CVD and ESKD were assembled based on the 2006-17 Hospital Authority database. One-to-five propensity-score matching was used to balance baseline covariates between patients in bariatric surgery and control groups. Incidence rates (IRs) of SH, CVD, Stage 4/5 chronic kidney diseases (CKD), ESKD and all-cause mortality events for two groups were calculated. Hazard ratios (HR) for SH, CVD and Stage 4/5 CKD events were assessed using Cox-proportional hazard models. Changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) were measured up to 60 months. RESULTS: Over a mean follow-up period of 32 months with 5725 person-years, cumulative incidences of mortality, CVD, Stage 4/5 CKD, ESKD and SH were 0, 0.036, 0.050, 0.017 and 0.020, respectively. The surgery group had a significant reduction in risk of CVD events (HR = 0.464, P = 0.015) and no occurrence of mortality events. However, there were no significant differences in risks of SH [HR = 0.469, 95% confidence interval (CI): 0.204-1.081], Stage 4/5 CKD (HR =0.896, 95% CI: 0.519-1.545) and ESKD (HR = 0.666, 95% CI: 0.264-1.683) between two groups, although IRs were lower in the surgery group. Surgical patients had significantly higher eGFR within 12 months and had significantly lower UACR until 48 months. CONCLUSIONS: Among obese T2DM patients, bariatric surgery lowered the risk of CVD and mortality, and was beneficial towards the kidney outcomes.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies.

AIM: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. RESULTS: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. CONCLUSIONS: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.

Patients with highly unstable type 1 diabetes eligible for islet transplantation can be managed with a closed-loop insulin delivery system: A series of N-of-1 randomized controlled trials.

AIM: To compare the efficacy of the closed-loop Diabeloop for highly unstable diabetes (DBLHU) system with the open-loop predictive low glucose suspend (PLGS) system in patients with highly unstable type 1 diabetes (T1D) who experience acute metabolic events. METHODS: DBLHU-WP10 was an interventional, controlled, randomized, open-label study that comprised two cycles of N-of-1 trials (2-of-1 trials). Each trial consisted of two crossover 4-week periods of treatment with either DBLHU or PLGS in randomized order. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (time in range [TIR]). RESULTS: Five out of seven randomized patients completed the aggregated 2-of-1 trials. TIR was significantly higher with DBLHU (73.3% ± 1.7%) compared with PLGS (43.5% ± 1.7%; P < .0001). The percentage of time below 70 mg/dL was significantly lower with DBLHU (0.9% ± 0.4%) versus PLGS (3.7% ± 0.4%; P < .0001). DBLHU was also significantly superior to PLGS in reducing hyperglycaemic excursions and improving almost all other secondary outcomes, including glucose variability and satisfaction score. No adverse event could be related to the experimental treatment. CONCLUSIONS: DBLHU was superior to PLGS in improving the metabolic control of patients with highly unstable T1D who require an islet or pancreas transplant but who either have a contraindication or refuse to consent.

Risk of major cardiovascular events, severe hypoglycaemia, and all-cause mortality for users of insulin degludec versus insulin glargine U100-A Danish cohort study.

AIMS: Real-world evidence of the safety of insulin degludec compared with insulin glargine U100 is sparse. This study sought to investigate the risk of major cardiovascular events, severe hypoglycaemia, and all-cause mortality after initiation of degludec or glargine U100 in the population of Denmark. MATERIALS AND METHODS: All Danish people with diabetes initiating treatment on degludec (n=5159) or glargine (n=4041) in 2016 to 2017 were included in the study. The effect of insulin treatment on the endpoints of major cardiovascular events, severe hypoglycaemia, and all-cause mortality was analysed with Cox proportional hazard models. The models were adjusted for age, sex, diabetes duration, diabetes type, highest completed education, and annual income. The model of severe hypoglycaemia was also adjusted for severe hypoglycaemia prior to baseline. The model of mortality was also adjusted for history of alcohol abuse, use of antidepressants, use of opioids, and use of anxiolytics. Lastly, the models of major cardiovascular events and mortality were also adjusted for Charlson comorbidity index. RESULTS: Use of degludec resulted in an almost twofold decrease in risk of death (hazard rate [HR]: 0.54, 95% CI: 0.44-0.65) compared with use of glargine. No statistically significant risk changes were found for major cardiovascular events (HR: 0.86, 95% CI: 0.62-1.19) and severe hypoglycaemia (HR: 1.13, 95% CI: 0.66-1.93). The proportion of cause of death due to malignant neoplasm of pancreas was almost doubled for glargine compared with degludec. CONCLUSIONS: These results indicate that insulin degludec has a safer profile with respect to all-cause mortality as compared with insulin glargine U100.

Development of a hypoglycaemia risk score to identify high-risk individuals with advanced type 2 diabetes in DEVOTE.

AIMS: The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2-year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. MATERIALS AND METHODS: Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data-driven machine-learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data-driven model, included: insulin treatment regimen; diabetes duration; sex; age; and glycated haemoglobin, all at baseline. Both the data-driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE, and were validated against the external LEADER cardiovascular outcomes trial dataset. RESULTS: Both the data-driven model and the simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time-dependent area under the curve index (0.63 and 0.66, respectively) over a 2-year time horizon. CONCLUSIONS: Both the data-driven model and the simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care.

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE.

AIMS: To undertake a post-hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes. MATERIALS AND METHODS: The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all-cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all-cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all-cause mortality were investigated. RESULTS: Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all-cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all-cause mortality). CONCLUSIONS: The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all-cause mortality and that, in this high-risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

Treatment and prevention of severe hypoglycaemia in people with diabetes: Current and new formulations of glucagon.

Some therapies for diabetes increase the risk of hypoglycaemia, in particular all insulins and insulin secretagogues, including the glinides and sulfonylureas. Hypoglycaemia remains a major limiting factor to successful glycaemic management, despite the availability of prevention options such as insulin analogues, continuous glucose monitoring, insulin pumps, and dogs that have been trained to detect hypoglycaemia. Non-severe (self-treated) and severe (requiring assistance for recovery) hypoglycaemia rates are higher in people with type 1 diabetes, but those with insulin-treated type 2 diabetes are also at risk. Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention and treatment. Awareness of the potential dangers of hypoglycaemia is fundamental to the optimal management of diabetes. When therapy is intensified to achieve glycaemic targets, it is important that people at risk of severe hypoglycaemia, and particularly their caregivers, have ready access to effective treatment for hypoglycaemia emergencies. The current and potential formulations of glucagon available for treatment of severe hypoglycaemia are reviewed.

Association of insulin regimens with severe hypoglycaemia in patients with type 1 diabetes: A Danish case-control study.

AIMS: To evaluate the risk of severe hypoglycaemia for patients with Type 1 diabetes (T1D) when exposed to insulin regimens including human insulin only or insulin analogues. METHODS: A total of 19 896 patients with T1D were extracted from the Danish National Patient Register. Of these, 6379 T1D patients experiencing 1 of more severe hypoglycaemic episodes (total of 17 242 episodes) were matched 1:1 with T1D patients without severe hypoglycaemia. A logistic regression model with last insulin regimen used as exposure was constructed to analyse the effect on severe hypoglycaemia. RESULTS: People on a basal-bolus regimen with insulin analogues had a reduced risk of severe hypoglycaemia of 39% (odds ratio: 0.61, 95% confidence interval: 0.54-0.68) compared to patients on a basal-bolus human insulin only regimen. Furthermore, patients on a premixed regimen containing an insulin analogue had a 58% (odds ratio: 0.42, 95% confidence interval: 0.36-0.49) reduced risk of severe hypoglycaemia compared to patients on premixed human insulin only. CONCLUSION: This study indicates that use of a basal-bolus insulin regimen with an insulin analogue is safer with respect to severe hypoglycaemia in patients with T1D than the use of a basal-bolus human insulin only regimen.

Outcomes of people with severe hypoglycaemia requiring prehospital emergency medical services management: a prospective study.

AIMS/HYPOTHESIS: The aim of this work was to investigate clinical outcomes following severe hypoglycaemia requiring prehospital emergency medical services (EMS) management. METHODS: We carried out a prospective, observational study of adults with diabetes attended by prehospital EMS for management of severe hypoglycaemia between April 2016 and July 2017. Information on precipitants, hospitalisation, length of hospital stay and recurrence was collected at 1 and 3 months following the episode of severe hypoglycaemia. Median and logistic regression models examined predictive factors. RESULTS: Five hundred and five adults (61% male, median age 67 years) participated in the study. Fifty-two per cent had type 1 diabetes, 43% type 2 diabetes and 5% were unsure of their diabetes type. Following EMS management of the index episode of severe hypoglycaemia, 50.3% were transported to hospital. Of those transported, 41.3% were admitted to hospital for ongoing management (20.8% of all participants). The following factors predicted hospital admission: older age (OR 1.28 [95% CI 1.02, 1.60] per 10 years), greater number of comorbidities (OR 1.27 [95% CI 1.08, 1.48] per morbidity), moderate-severe injury accompanying the hypoglycaemia (OR 5.24 [95% CI 1.07, 25.8] compared with nil-mild injury) and unknown cause of hypoglycaemia (OR 2.21 [95% CI 1.24, 3.94] compared with known cause). The median (interquartile range) length of hospital stay was 4 (2-7) days. During follow-up, recurrent severe hypoglycaemia attended by prehospital EMS was experienced by 10.7% of participants. Predictive factors of recurrent severe hypoglycaemia in 3 months were decreased HbA1c (OR 1.97 [95% CI 1.27, 3.06] per 10 mmol/mol decrease) and a greater number of antecedent severe hypoglycaemia episodes (OR 1.12 [95% CI 1.03, 1.23] per episode). CONCLUSIONS/INTERPRETATION: Following an episode of severe hypoglycaemia managed by EMS, one-fifth of participants required hospital admission, more likely in those with advancing age, increasing comorbidities and injury and one-tenth required EMS again for severe hypoglycaemia in a 3 month period, more likely in those with a greater number of antecedent episodes and lower HbA1c. Knowledge of these factors associated with admission and recurrence provides an opportunity for development of targeted strategies aimed at prevention of severe hypoglycaemia in those most vulnerable.

Early cardiovascular risk and all-cause mortality following an incident of severe hypoglycaemia: A population-based cohort study.

AIMS: Severe hypoglycaemia is associated with a high risk of cardiovascular events in patient with diabetes. The aim of this study was to clarify the temporal relationship between hypoglycaemia and cardiovascular events. MATERIALS AND METHODS: This observational cohort study was conducted using Taiwan's Longitudinal Cohort of Diabetes Patients Database, which included 360 000 patients with newly diagnosed diabetes during the period 1999 to 2001. Patients with the first severe hypoglycaemia after 2002 served as the study cohort. Each patient in the study cohort was matched with two control patients without severe hypoglycaemia, based on a propensity score. A joinpoint regression model was used to determine trends in all-cause mortality and incidence of cardiovascular disease (CVD) events in both cohorts. RESULTS: A total of 10 157 patients with severe hypoglycaemia and 20 314 matched controls were recruited. Patients with severe hypoglycaemia had a significantly higher risk of CVD (HR, 7.28; 95% CI, 5.19-10.20) and all-cause mortality (HR, 19.92; 95% CI, 13.42-29.56) during the first month compared with those without. In patients with severe hypoglycaemia, the incidence of CVDs dropped by 17.29% monthly during the first 4 months and slowly decreased (-0.67%) during subsequent months. All-cause mortality decreased by 16.55% and 3.24% monthly during months 0-6 and months 6-17, respectively. CONCLUSIONS: Severe hypoglycaemia is associated with a greater risk of cardiovascular events and death, especially during the first month following a hypoglycaemic episode. Patients prone to severe hypoglycaemia should be made aware of the elevated risk of subsequent cardiovascular events.

Direct medical costs in the preceding, event and subsequent years of a first severe hypoglycaemia episode requiring hospitalization: A population-based cohort study.

AIMS: We aimed to estimate the use of healthcare services and the direct medical costs accrued by patients with diabetes mellitus (DM) during the year of the first severe hypoglycaemia (SH) event, as well as during the years before and after the event year. MATERIALS AND METHODS: We analysed a population-based, retrospective cohort including all adults with DM managed in the primary care setting from the Hong Kong Hospital Authority between 2006 and 2013. DM patients for whom SH was first recorded during the designated period were identified and matched to a control group of patients who had not experienced an SH event using the propensity score method. Direct medical costs in the years before, during and after the first SH event were determined by totalling the costs of health services utilized within respective years. RESULTS: After matching, a total of 22 694 DM patients were divided into the first recorded-SH group (n = 11 347) and the non-SH control group (n = 11 347). Patients for whom SH was first recorded, on average, made 7.85 outpatient clinic visits, made 1.89 emergency visits and spent 17.75 nights hospitalized during the event year. Mean direct medical costs during the event year were 11 751 US$, more than 2-fold that during the preceding year (4846 US$; P < 0.001) and subsequent years (4198-4700 US$; P < 0.001) and was 4.5 times that 2 years before the event (2481 US$; P < 0.001). Incremental costs of SH patients vs matched controls during the event year and the preceding year were 10 873 US$ (P < 0.001) and 3974 US$ (P < 0.001), respectively. CONCLUSIONS: SH is associated with excessive hospital admission rates and direct medical costs during the event year and, in particular, during the year before as compared to patients who had not experienced an SH event.