Prior Hypoglycemia Research Articles

Impact of diabetes on the risk of subsequent fractures in 92,600 patients with an incident hip fracture: A Danish nationwide cohort study 2004–2018

PurposeWe investigated the incidence rates of a subsequent hip fracture (HF) and other subsequent fractures than HF after first incident HF, comparing patients with and without diabetes. MethodsUsing Danish medical databases, we identified 92,600 incident HF patients in the period 2004–2018. Diabetes exposure was examined overall, by type of diabetes (T2D and T1D), and by presence of diabetes complications. We estimated cumulative incidence of subsequent HFs and fractures other than HF within two years of the incident HF. Using Cox regression, adjusted hazard ratios (aHRs) with 95 % confidence interval (CI) were calculated. ResultsAmong incident HF patients, 11,469 (12 %) had diabetes, of whom 10,253 (89 %) had T2D and 1216 (11 %) had T1D. The 2-year incidence rates for a new subsequent HF were 4.8 % (95 % CI: 4.6–4.9) for patients without diabetes (reference group), 4.1 % (95 % CI: 3.8–4.6) for T2D, and 4.3 % (95 % CI: 3.3–5.6) for T1D. Corresponding aHRs were 1.01 (95 % CI 0.90–1.14) for T2D and 1.17 (95 % CI 0.87–1.58) for T1D. There was effect modification by sex, as women with T1D had an aHR of 1.52 (95 % CI: 1.09–2.11) for subsequent HF, and by specific diabetes complications (for example, patients with T2D and prior hypoglycemia had an aHR of 1.75 (95 % CI: 1.24–2.42) for subsequent HF, while patients with T1D and neuropathy had an aHR of 1.73 (95 %: 1.09–2.75), when compared with patients without diabetes).For fractures other than HF, the 2-year incidence rates were 7.3 % (95 % CI: 7.2–7.5) for patients without diabetes, 6.6 % (95 % CI: 6.1–7.1) for T2D, and 8.5 % (95 % CI: 7.0–10.1) for T1D, with corresponding aHRs of 1.01 (95 % CI 0.92–1.11) for T2D and 1.43 (95 % CI: 1.16–1.78) for T1D. T2D was only a risk factor for other subsequent fractures among HF patients of high age (age 86–89 years: aHR 1.22 (95 % CI 0.99–1.55), age 90+ years: aHR 1.37 (95 % CI 1.08–1.74)), whereas T1D was robustly associated with increased risk of fractures other than HF in all subgroups. ConclusionAmong HF patients, we found no strong overall association of T2D or T1D with increased risk of subsequent HF, but diabetes patients with prior hypoglycemic events or neuropathy were at increased risk. In contrast, patients with T1D had a clearly increased risk of subsequent fractures other than HF.

Glucagon use by U.S. adults with type 1 and type 2 diabetes.

The American Diabetes Association recommends that all patients at risk for hypoglycemia be prescribed glucagon. Despite this recommendation, there is evidence that prescription rates are lower than expected for patients with type 1 and type 2 diabetes. This study investigated prescription patterns for glucagon among de-identified administrative claims from OptumLabs® Data Warehouse for prescriptions between January 1, 2014 and December 31, 2014 among pharmacologically treated type 1 and 2 diabetes patients. We find that glucagon was rarely filled by patients with type 1 and type 2 diabetes, including fewer than 5% of patients with prior hypoglycemia requiring emergency healthcare utilization. Among patients with type 1 diabetes, glucagon fills were unpredictable and not targeted to highest risk patients.

Impact of Age, Frailty, and Dementia on Prescribing for Type 2 Diabetes at Hospital Discharge 2012-2016

The risks of intensive blood glucose lowering may outweigh the benefits in vulnerable older people. Our primary aim was to determine whether age, frailty, or dementia predict discharge treatment types for patients with type 2 diabetes (T2D) and related complications. Secondly, we aimed to determine the association between prior hypoglycemia and discharge treatment types. We conducted a cohort study involving 3,067 patients aged 65-99 years with T2D and related complications, discharged from Melbourne's Eastern Health Hospital Network between 2012 and 2016. Multinomial logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CI) for the association between age, frailty, dementia and hypoglycemia, and being prescribed insulin-only, non-insulin glucose-lowering drugs (GLDs) or combined insulin and non-insulin GLDs compared to no GLD. International Classification of Diseases-10 codes were used to identify dementia status and prior hypoglycemia; frailty was quantified using the Hospital Frailty Risk Score. Insulin-only, non-insulin GLDs, combined insulin and non-insulin GLDs, and no GLDs were prescribed to 19%, 39%, 20%, and 23% of patients, respectively. Patients >80 years were less likely than patients aged 65-80 to be prescribed any of the GLD therapies, (eg. non-insulin GLDs [OR 0.67; 95%CI 0.55-0.82]), compared to no GLD. Similarly, high vs. low frailty scores were associated with not being prescribed any of the three GLD therapies, (eg. non-insulin GLDs [OR 0.63; 95%CI 0.45-0.87]). However, dementia was not associated with discharge prescribing of GLD therapies. Patients with a hypoglycemia-related admission were more likely than those not hospitalized with hypoglycemia to receive insulin-only (OR 4.28; 95%CI 2.89-6.31). Clinicians consider age and frailty when tailoring diabetes treatment regimens for patients discharged from hospital with T2D and related complications. There is scope to optimize prescribing for patients with dementia and for those admitted with hypoglycemia.

The Safety and Efficacy of Second-Generation Basal Insulin Analogues in Adults with Type 2 Diabetes at Risk of Hypoglycemia and Use in Other Special Populations: A Narrative Review.

Hypoglycemia is a major barrier impeding glycemic control in persons with type 2 diabetes mellitus and creates a substantial burden on the healthcare system. Certain populations that require special attention, such as older adults and individuals with renal impairment, a longer duration of diabetes or those who have experienced prior hypoglycemia, may be at a higher risk of hypoglycemia, particularly with insulin treatment. Second-generation basal insulin analogues (insulin glargine 300 U/mL and degludec) have demonstrated reductions in hypoglycemia compared with insulin glargine 100 U/mL although evidence of this benefit across specific populations is less clear. In this review we summarize the literature with respect to the efficacy and safety data for second-generation basal insulin analogues in adults with type 2 diabetes mellitus who are at risk of hypoglycemia or who require special attention. Randomized controlled trials, meta-analyses and real-world evidence demonstrate that the use of second-generation basal insulin analogues is associated with less hypoglycemia compared with insulin glargine 100 U/mL without compromising glycated hemoglobin control. A reduced risk of hypoglycemia with second-generation basal insulin analogues was evident in older adults and in individuals with obesity, renal impairment, a history of cardiovascular disease or a long duration of insulin use. Further studies are needed in other populations, including those with more severe renal impairment or hepatic dysfunction, the hospitalized population and those with cognitive impairment. Overall, less hypoglycemia associated with second-generation basal insulin analogues may help reduce barriers for insulin use, improve adherence and offset the costs of hypoglycemia-related healthcare resource utilization.

1548-P: Changes in Glucose-Lowering Medication Use in the Era of Cardiovascular Outcomes Trials: Risk/Treatment Paradox Persists

Three new classes of glucose-lowering drugs were introduced into practice over the past 15 years: DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors. These drugs have low hypoglycemia risk, do not cause weight gain, and post-marketing outcomes trials found cardiovascular and renal benefits associated with GLP-1RA and SGLT2i use. Our objective was to determine whether these drugs are being used by patients with type 2 diabetes most likely to benefit from them. Using OptumLabs Data Warehouse, a de-identified dataset of commercially-insured and Medicare Advantage beneficiaries, we identified adults with type 2 diabetes who first started a DPP-4i (n=140,933), GLP-1RA (n=107,331), SGLT2i (n=112,892), or any other diabetes drug (n=1,743,484) between 2013-2018. After adjustment for age, gender, race/ethnicity, insurance type, baseline medications, year, prescriber specialty, and comorbidities, we found that GLP-1RA and SGLT2i, in particular, were less likely to be started by patients most likely to benefit from them. GLP-1RA initiation was less likely among patients with prior hypoglycemia requiring ED/hospital care (OR 0.86 [95% CI 0.79-0.93]), myocardial infarction (MI; OR 0.93 [0.89-0.97], or stroke (OR 0.88 [0.85-0.91]), though more likely with nephropathy (OR 1.20 [1.17-1.23]). SGLT2i initiation was less likely with prior hypoglycemia (OR 0.81 [0.73-0.89]), nephropathy (OR 0.80 [0.78-0.0.82]), or heart failure (HF; OR 0.85 [0.82-0.87]). However, DPP-4i initiation was more likely with prior hypoglycemia (OR 1.49 [1.41-1.57]), MI (OR 1.09 [1.05-1.12]), stroke (OR 1.09 [1.06-1.11), HF (OR 1.12 [1.09-1.14]), and nephropathy (OR 1.40 [1.37-1.43]). Our results do not explain why these drugs are not preferentially used in guideline-recommended contexts, but do highlight missed opportunities to reduce the morbidity and mortality associated with hypoglycemia, cardiovascular disease, and kidney disease in highest risk patients. Disclosure R.G. McCoy: None. H. Van Houten: None. J. Ross: Research Support; Self; Centers for Medicare and Medicaid Services, Janssen Pharmaceuticals, Inc., U.S. Food and Drug Administration. P. Karaca-Mandic: None. V.M. Montori: None. N. Shah: None. Funding National Institutes of Health (K23DK114497); Agency for Healthcare Research and Quality (1U19HS024075, R01HS025164)

379-P: Glucagon Use by U.S. Adults with Type 1 and Type 2 Diabetes

The American Diabetes Association recommends that patients at high risk for hypoglycemia be prescribed glucagon. Using de-identified administrative claims from OptumLabs® Data Warehouse (OLDW) for commercial and Medicare Advantage enrollees, we examined glucagon prescriptions filled between 1/1/2014 and 12/31/2014 among pharmacologically treated type 1 and 2 diabetes patients. We examined association of glucagon fills with demographic, clinical, and laboratory-based factors. HbA1c levels were available for a subsample. Model performance was assessed with AUC and calibration plots. Among 12,338 patients with type 1 and 323,244 with type 2 diabetes, 14.5% and 0.7% filled glucagon in 2014, respectively. Among type 1 diabetes patients, the multivariable model had poor discriminative performance (AUC=0.61). Among patients with type 2 diabetes, the model AUC was 0.89. Factors associated with glucagon use are shown in Figure. HbA1c level was not independently associated with glucagon fills. In this national study, glucagon was rarely filled. Among patients with type 1 diabetes, glucagon fills were unpredictable and not targeted to highest risk patients. Patients with type 2 diabetes were more likely to fill glucagon in the setting of prior hypoglycemia, higher income, and endocrinology care. These findings suggest opportunities to improve care, including better prescribing practices to target high-risk patients. Disclosure P. Kahn: None. S. Liu: None. R.G. McCoy: None. R.A. Gabbay: Advisory Panel; Self; FormHealth, Health Reveal, Lark, Onduo, Vida Health. K.J. Lipska: None. Funding National Institutes of Health (K23AG048359)

Application of Machine Learning Models to Evaluate Hypoglycemia Risk in Type2 Diabetes.

IntroductionTo identify predictors of hypoglycemia and five other clinical and economic outcomes among treated patients with type 2 diabetes (T2D) using machine learning and structured data from a large, geographically diverse administrative claims database.MethodsA retrospective cohort study design was applied to Optum Clinformatics claims data indexed on first antidiabetic prescription date. A hypothesis-free, Bayesian machine learning analytics platform (GNS Healthcare REFS™: Reverse Engineering and Forward Simulation) was used to build ensembles of generalized linear models to predict six outcomes defined in patients’ 1-year post-index claims history, including hypoglycemia, antidiabetic class persistence, glycated hemoglobin (HbA1c) target attainment, HbA1c change, T2D-related inpatient admissions, and T2D-related medical costs. A unified set of 388 variables defined in patients’ 1-year pre-index claims history constituted the set of predictors for all REFS models.ResultsThe derivation cohort comprised 453,487 patients with a T2D diagnosis between 2014 and 2017. Patients with comorbid conditions had the highest risk of hypoglycemia, including those with prior hypoglycemia (odds ratio [OR] = 25.61) and anemia (OR = 1.29). Other identified risk factors included insulin (OR = 2.84) and sulfonylurea use (OR = 1.80). Biguanide use (OR = 0.75), high blood glucose (> 125 mg/dL vs. < 100 mg/dL, OR = 0.47; 100–125 mg/dL vs. < 100 mg/dL, OR = 0.53), and missing blood glucose test (OR = 0.40) were associated with reduced risk of hypoglycemia. Area under the curve (AUC) of the hypoglycemia model in held-out testing data was 0.77. Patients in the top 15% of predicted hypoglycemia risk constituted 50% of observed hypoglycemic events, 26% of T2D-related inpatient admissions, and 24% of all T2D-related medical costs.ConclusionsMachine learning models built within high-dimensional, real-world data can predict patients at risk of clinical outcomes with a high degree of accuracy, while uncovering important factors associated with outcomes that can guide clinical practice. Targeted interventions towards these patients may help reduce hypoglycemia risk and thereby favorably impact associated economic outcomes relevant to key stakeholders.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00759-4) contains supplementary material, which is available to authorized users.

A systematic review of the effect of prior hypoglycaemia on cognitive function in type 1 diabetes.

Background:The effect of prior hypoglycaemia on cognitive function in type 1 diabetes is an important unresolved clinical question. In this systematic review, we aimed to summarize the studies exploring the impact of prior hypoglycaemia on any aspect of cognitive function in type 1 diabetes.Methods:We used a multidatabase search platform Healthcare Database Advanced Search to search Medline, PubMed, EMBASE, EMCARE, CINAHL, PsycINFO, BNI, HMIC, and AMED from inception until 1 May 2019. We included studies on type 1 diabetes of any age. The outcome measure was any aspect of cognitive function.Results:The 62 studies identified were grouped as severe hypoglycaemia (SH) in childhood (⩽18 years) and adult-onset (>18 years) diabetes, nonsevere hypoglycaemia (NSH) and nocturnal hypoglycaemia (NH). SH in early childhood-onset diabetes, especially seizures and coma, was associated with poorer memory (verbal and visuospatial), as well as verbal intelligence. Among adult-onset diabetes, SH was associated with poorer cognitive performance in the older age (>55 years) group only. Early versus late exposure to SH had a significant association with cognitive dysfunction (CD). NSH and NH did not have any significant association with CD, while impaired awareness of hypoglycaemia was associated with poorer memory and cognitive-processing speeds.Conclusion:The effect of SH on cognitive function is age dependent. Exposure to SH in early childhood (<10 years) and older age groups (>55 years) was associated with a moderate effect on the decrease in cognitive function in type 1 diabetes [PROSPERO ID: CRD42019141321].

Adoption of New Glucose-Lowering Medications in the U.S.-The Case of SGLT2 Inhibitors: Nationwide Cohort Study.

Background: High-quality diabetes care is evidence-based, timely, and equitable. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the most recently approved class of glucose-lowering medications with additional cardio- and renal-protective benefits and low risk of hypoglycemia. Cardiovascular and kidney disease are among the most common chronic diabetes complications, whereas hypoglycemia is the most prevalent adverse effect of glucose-lowering therapy. We examine the sociodemographic and clinical factors associated with early SGLT2i initiation and appropriateness of use based on contemporaneous scientific evidence. Materials and Methods: Retrospective analysis of medical and pharmacy claims data from OptumLabs® Data Warehouse for commercially insured and Medicare Advantage adult beneficiaries with diabetes types 1 and 2, who filled any glucose-lowering medication between January 1, 2013 and December 31, 2016. Demographic (age, sex, race, income), clinical (comorbidities), and insurance-related factors affecting first prescription for a SGLT2i were examined using multivariable logistic regression. Results: Among 1,054,727 adults with pharmacologically treated diabetes, 7.2% (n = 75,500) initiated a SGLT2i. Patients with prior myocardial infarction (MI) (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.96), heart failure (HF) (OR: 0.93, 95% CI: 0.91-0.94), kidney disease (OR: 0.80, 95% CI: 0.78-0.81), and severe hypoglycemia (OR: 0.96, 95% CI: 0.94-0.98) were all less likely to start a SGLT2i; P < 0.001 for all. SGLT2i were also less likely to be started by patients ≥75 years (OR: 0.57, 95% CI: 0.55-0.59, vs. 18-44 years), Black patients (OR: 0.93, 95% CI: 0.91-0.95, vs. White), and those with Medicare Advantage insurance (OR: 0.63, 95% CI: 0.62-0.64, vs. commercial). Conclusions: Younger, healthier, non-Black patients with commercial health insurance were most likely to start taking SGLT2i. Patients with MI, HF, kidney disease, and prior hypoglycemia were less likely to use SGLT2i, despite evidence supporting their preferential use in these patients. Efforts to address this treatment-risk paradox may help improve health outcomes among patients with type 2 diabetes.

Diabetic ketoacidosis further increases risk of Alzheimer’s disease in patients with type 2 diabetes

AimDiabetes mellitus (DM) is a known risk factor for dementia. It is unclear whether diabetic ketoacidosis (DKA) further increases the risk of dementia in patients with type 2 DM. MethodsThis retrospective nationwide population-based cohort study was conducted using Taiwan’s National Health Insurance database. We extracted claims data for 4451 patients with type 2 diabetes and DKA and 8902 diabetic controls matched for age, gender, diabetes complication severity index, frequency of clinic visits and baseline comorbidities between 2000 and 2002. Patients with type 1 diabetes or prior hypoglycemia before index date were excluded. All patients were tracked until new dementia diagnosis, death, or end of 2011. ResultsOf the 4451 DKA patients, 211 (4.7%) and 305 (3.4%) of the 8902 diabetic controls were diagnosed as having dementia during the follow-up period. The incidence rate ratio (IRR) for dementia was 1.62 (95% CI 1.35–1.93; P < 0.0001) for patients with DKA versus diabetic patients without DKA. After adjusting for age, baseline comorbidities, geographic area, and income, patients with DKA were found to have 1.86 times the risk of developing dementia, compared to controls (95% CI 1.56–2.22, P < 0.0001). They were found to have a higher risk of Alzheimer’s dementia (HR:1.86; 95% CI 1.52–2.28, P < 0.0001) but not non-Alzheimer’s dementia. ConclusionType 2 diabetes patients with DKA are at increased risk of Alzheimer’s dementia but not non-Alzheimer dementia.

Hospitalization and Emergency Department Visits for Severe Hypoglycemia among U.S. Adults with Diabetes and Serious Comorbid Conditions

Diabetes care guidelines recommend more relaxed glycemic targets for patients with specific chronic conditions because they are thought to have an increased risk of hypoglycemia, limited life expectancy, and/or high clinical complexity. These include dementia, end stage renal disease (ESRD), stages 3-4 chronic kidney disease (CKD), myocardial infarction, heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, cancer, arthritis, urinary incontinence, falls, depression, hypertension, cirrhosis, proliferative retinopathy, and peripheral neuropathy. The rates of severe hypoglycemia among patients with these conditions are unknown. We quantified rates of hospital and emergency department care for hypoglycemia among 216,839 adults (mean 65.5 years old) with diabetes in 2015 using the OptumLabs Data Warehouse (administrative database of &amp;gt;100 million commercially-insured and Medicare Advantage beneficiaries). Hypoglycemia rates varied widely: 10.6/1000 person-years (PY) in patients with hypertension, 26.9/1000 PY with CKD, 26.8/1000 PY with cirrhosis, 37.7/1000 PY with dementia, and 58.3/1000 PY with ESRD. Hypoglycemia was rare among patients with no conditions (2.0/1000 PY). After adjustment for all conditions, prior hypoglycemia, age, sex, race, HbA1c, and diabetes medications, the risk of severe hypoglycemia was significantly increased for all conditions except arthritis, incontinence, and cancer. Hypoglycemia risk increased rapidly with the number of comorbidities: OR 1.8 (95% CI 1.4, 2.2) for 2 conditions, 7.7 (6.2, 9.64) for 5, 16.6 (13.1, 21.1) for 7, and 25.6 (30.4, 32.2) for ?8 conditions compared with ?1 condition. Severe hypoglycemia is common among patients with chronic conditions. Rates vary between conditions but increase dramatically in patients with multiple comorbidities. These data can help inform decisions about glucose-lowering therapy for patients with comorbidities. Disclosure R.G. McCoy: None. H. Van Houten: None. K.J. Lipska: Other Relationship; Self; Centers for Medicare and Medicaid Services. Research Support; Self; National Institutes of Health. N. Shah: None.

Does Initiation of Basal Insulin Analogs in Patients with Type 2 Diabetes Mellitus Confer Advantages over Neutral Protamine Hagedorn (NPH) for Severe Hypoglycemia and Glycemic Control?

In clinical trial populations, long-acting insulin analogs modestly reduce the risk of nocturnal hypoglycemia compared with neutral protamine Hagedorn (NPH) in type 2 diabetes, but cost 2-4 times more. In real-world clinical practice, insulin performance may vary due to greater heterogeneity of patient characteristics and behaviors. To compare rates of severe hypoglycemia and changes in glycemic control associated with insulin analogs vs. NPH, we conducted a propensity-score matched cohort analysis using data from Kaiser Permanente Northern California (20to 2015). We included patients with type 2 diabetes if they started a long-acting insulin analog or NPH, and we censored follow-up at death, loss of health plan coverage, change in type of insulin used, change in sulfonylurea treatment, or end of follow-up. Main outcomes were time to hypoglycemia-related utilization (emergency department visit or hospitalization with a primary or principal discharge diagnosis of hypoglycemia) and change in hemoglobin A1c within 1 year of insulin initiation. Among 1,928 patients with type 2 diabetes who started insulin analogs and 23,561 who started NPH, there were 31 and 319 hypoglycemic events, respectively. After propensity score matching, the hazard ratio for severe hypoglycemia associated with insulin analog use was 0.95 (95% CI, 0.57, 1.46) and did not change significantly after additional adjustment for prior severe hypoglycemia and time-dependent diabetes medication use (HR 0.97, 95% CI 0.58, 1.54). Hemoglobin A1c decreased from 9.4% to 8.1% after initiation of insulin analogs and from 9.4% to 7.9% after initiation of NPH (difference-in-difference -0.19% (95% CI, -0.06, -0.34)). In real-world clinical practice, the use of basal insulin analogs is not associated with a substantial reduction in hypoglycemia-related utilization or improvement in glycemic control compared with NPH insulin. Disclosure K.J. Lipska: Other Relationship; Self; Centers for Medicare and Medicaid Services. Research Support; Self; National Institutes of Health. M.M. Parker: Research Support; Self; Eli Lilly and Company. H.H. Moffet: Research Support; Self; Regeneron Pharmaceuticals, Inc., AstraZeneca. E. Huang: None. A.J. Karter: None.

Development and Validation of a Questionnaire Evaluating Impaired Hypoglycemia Awareness among Adult Filipino Patients with Type 2 Diabetes Mellitus.

IntroductionHazards of hypoglycemia include accidents, cardiovascular events, neurologic damage, and impaired hypoglycemia awareness (IHA) which presents as inability to perceive and respond to hypoglycemic warning symptoms.ObjectiveThis study aimed to develop the first questionnaire evaluating IHA adapted from Clarke Hypoglycemia Index (CHI) and validated among adult Filipino patients with Type 2 Diabetes Mellitus (T2DM).MethodologyA questionnaire development study was conducted involving CHI linguistic translation, its modification through literature review and focus group discussions, panel synthesis, and content validity. A cross-sectional analytic study followed by administration of the questionnaire to 117 adult Filipinos with T2DM, advanced age, long-standing T2DM, insulin or sulfonylurea, polypharmacy, comorbidities and/or prior hypoglycemia. There were 9 participants in pilot testing, 69 in criterion validity against continuous glucose monitoring (CGM), and 108 in construct validity.ResultsIHA domains in the concept map included Elusive Euglycemia Model, Developmental Model, and Cognitive Model. The Filipino-CHI formulated had 8 questions with content validity scores ranging from 87.5-93.75%. Owing to brevity, its internal consistency Cronbach’s alpha was 0.45. Criterion validity against CGM yielded 21 patients with biochemical hypoglycemic events, of which 2 had clinical hypoglycemic events and 19 were positive monitor-identified IHA. A questionnaire IHA cutoff score of ≥4 had sensitivity of 89.47%, and area under the curve of 0.55.ConclusionAn 8-item questionnaire evaluating IHA among adult Filipino T2DM patients was developed and validated.

Impact of recurrent hypoglycemic stress on hindbrain A2 nerve cell energy metabolism and catecholamine biosynthesis: modulation by estradiol.

It is unclear if habituation of hindbrain A2 metabolo‑sensory neurons to recurrent insulin-induced hypoglycemia (RIIH) correlates with estradiol-dependent adjustments in energy metabolism that favor positive energy balance. Laser-microdissected A2 cells from estradiolor oil-implanted ovariectomized female rats were analyzed by Western blot to assess effects of three prior daily insulin injections on basal and hypoglycemic patterns of catecholamine biosynthetic enzyme dopamine-beta-hydroxylase (DβH) and rate-limiting energy pathway enzyme protein expression. Precedent hypoglycemia respectively decreased or increased baseline DβH expression in estradiol- (E) vs. oil (O)-treated rats; this protein profile was further suppressed or augmented in those animals at 2 hr after re-induction of hypoglycemia. These data suggest that estradiol may curtail A2 noradrenergic‑controlled functions both in the midst of and between hypoglycemic bouts. Results also show that prior hypoglycemia exposure upregulated A2 neuron glycolytic enzyme protein levels when E was present, and exerted differential effects on basal and hypoglycemia-associated respiratory chain and fatty acid synthetic pathway enzyme expression. E may thus accordingly amplify glycolysis-derived metabolites/energy, coupled with reduced reliance on oxidative phosphorylation, and activate the fatty acid synthetic pathway during RIIH. E may also be of benefit by preventing maladaptive reductions in A2 neuron Krebs cycle/electron transport enzyme expression during re-exposure to hypoglycemia. Augmentation of negative energy balance during this recurring metabolic stress in the absence of E is a likely impetus for augmented vs. decreased A2 signaling of energy imbalance by DβH in O vs. E rats during RIIH.

Abstract MP76: Severe Hypoglycemia and Prevalence of Cognitive Impairment in Older Adults with Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Hypoglycemia and cognitive impairment are major problems in older adults with diabetes. It is unknown whether persons with prior hypoglycemia have distinct patterns of cognitive impairment compared to persons without hypoglycemia. Hypothesis: Compared to older adults with diabetes and no history of hypoglycemia, persons with prior hypoglycemia will have worse cognitive performance across all domains, but particularly in the executive function domain. Methods: We conducted a cross-sectional analysis of older adults with diagnosed diabetes using data from the ARIC study (2011-2013). Participants completed eight cognitive tests that measured three domains: memory, language, and executive function. Cognitive impairment in each domain was defined as having at least one test score lower than 1.5 standard deviations below age-, race-, and education-specific norms. We identified prior severe hypoglycemic events through 2012 with ICD-9 codes from hospitalizations and emergency department visits. We used Poisson regression with robust standard errors to generate prevalence ratios (PR) adjusted for demographic and clinical characteristics. Results: Among 1,867 adults with diagnosed diabetes: mean age 76 years, 56% female, 32% black, and 3% with prior hypoglycemia. In persons with prior hypoglycemia, 50% had cognitive impairment in at least one domain, compared to 43% in persons without prior hypoglycemia (p=0.24). After adjustment, persons with prior hypoglycemia were more likely to have worse performance in executive function (PR=1.73; 95% CI: 1.14-2.64) and language (PR=1.78; 95% CI: 1.08-2.93) but not memory (PR=1.19; 95% CI: 0.81-1.76) (Figure). Conclusions: Persons with prior severe hypoglycemia are a unique subset of older adults with diabetes with greater cognitive deficits in the domains of executive function and language. Their cognitive impairment presents challenges for the management of their diabetes and the prevention of additional hypoglycemic episodes and cognitive decline.

Effects of Antecedent GABA A Receptor Activation on Counterregulatory Responses to Exercise in Healthy Man.

The aim of this study was to determine whether antecedent stimulation of γ-aminobutyric acid (GABA) A receptors with the benzodiazepine alprazolam can blunt physiologic responses during next-day moderate (90 min) exercise in healthy man. Thirty-one healthy individuals (16 male/15 female aged 28 ± 1 year, BMI 23 ± 3 kg/m2) were studied during separate, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic-euglycemic or hypoglycemic clamps with or without 1 mg alprazolam given 30 min before a clamp. Day 2 consisted of 90-min euglycemic cycling exercise at 50% VO2max. Despite similar euglycemia (5.3 ± 0.1 mmol/L) and insulinemia (46 ± 6 pmol/L) during day 2 exercise studies, GABA A activation with alprazolam during day 1 euglycemia resulted in significant blunting of plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses. Lipolysis (glycerol, nonesterified fatty acids) and endogenous glucose production during exercise were also reduced, and glucose infusion rates were increased following prior euglycemia with alprazolam. Prior hypoglycemia with alprazolam resulted in further reduction of glucagon and cortisol responses during exercise. We conclude that prior activation of GABA A pathways can play a significant role in blunting key autonomous nervous system, neuroendocrine, and metabolic physiologic responses during next-day exercise in healthy man.

Abstract P336: Severe Hypoglycemia as an Independent Coronary Artery Disease Risk Factor in Diabetes Patients of Different Vascular Risk: A Retrospective Longitudinal Cohort Study

Background: Previous studies have suggested an association between severe hypoglycemic events (i.e. requiring external assistance) and coronary artery disease (CAD). However, whether this association varies across patients with different vascular risk remains unclear. We tested the hypothesis that prior severe hypoglycemia was independently associated with incident CAD in diabetes patients cared for in primary care, and that this association was increased for those with elevated vascular risk. Methods: We identified a diabetes cohort within a primary care practice network using electronic health records (EHR, N=9,173). Patients with severe hypoglycemic events at baseline (before 1/1/2006) were identified via ICD-9 codes, including 251.0-251.2, from emergency department, inpatient and outpatient visits. Incident CAD, including myocardial infarction, acute coronary syndrome, percutaneous transluminal coronary angiography and coronary artery bypass grafting, occurring after the hypoglycemic event, were determined through problem and procedure lists. Patients were followed until incident CAD, death, their last visit within the network, or 6/30/2012. We used Cox regression with time interaction to determine the association between hypoglycemia and CAD, with significance set at P &lt;0.05. We also tested this association among high vascular risk patients (age ≥55 years, Hemoglobin A1c [HbA1c] ≥7.5% and ≥2 risk factors [dyslipidemia, hypertension or obesity]), and a subset aged ≥65 years. Results: A total of 285 (3%) patients had a history of severe hypoglycemia at baseline and 1,098 (12%) developed CAD during follow-up. Severe hypoglycemia was associated with a twofold increase in CAD risk [HR 1.90 (95%CI 1.09-3.31)], adjusting for time interaction, vascular risk factors, diabetes duration and HbA1c; the hypoglycemia-CAD association weakened over time (time interaction P=0.06). Further adjustment for microvascular complications and medication exposures attenuated the association [HR 1.67 (0.96-2.92)]. Among 1,823 (20% of the cohort) high vascular risk patients aged ≥55 years, CAD risk was elevated threefold [HR 3.01 (1.15-7.91)], and in those aged ≥65 years (N=996, 11%), fourfold [HR 4.62 (1.65-12.90)]. The association was not significant among lower vascular risk patients [HR 1.61 (0.97-3.75), N=7,350]. Conclusions: Prior severe hypoglycemic episodes were strongly associated with incident CAD, especially among high vascular risk patients who were similar to those studied in the ACCORD trial. Whereas severe hypoglycemia was not as strongly associated with CAD in patients with fewer vascular risk factors. Results of studies like ACCORD only apply to a fifth of diabetes patients in this primary care cohort. Careful evaluation of diabetes treatment and close monitoring for CAD are especially needed in older high vascular risk patients with severe hypoglycemia.

Severe hypoglycemia and mortality after cardiovascular events for type 1 diabetic patients in Sweden.

To examine whether previous severe hypoglycemic events were associated with the risk of all-cause mortality after major cardiovascular events (myocardial infarction [MI] or stroke) in patients with type 1 diabetes. This study is based on data from the Swedish National Diabetes Register linked to patient-level hospital records, prescription data, and death records. We selected patients with type 1 diabetes who visited a clinic during 2002-2010 and experienced a major cardiovascular complication after their clinic visit. We estimated a two-part model for all-cause mortality after a major cardiovascular event: logistic regression for death within the first month and a Cox proportional hazards model conditional on 1-month survival. At age 60 years, 5-year cumulative mortality risk was estimated from the models for patients with and without prior diabetes complications. A total of 1,839 patients experienced major cardiovascular events, of whom 403 had previously experienced severe hypoglycemic events and 703 died within our study period. A prior hypoglycemic event was associated with a significant increase in mortality after a cardiovascular event, with hazard ratios estimated at 1.79 (95% CI 1.37-2.35) within the first month and 1.25 (95% CI 1.02-1.53) after 1 month. Patients with prior hypoglycemia had an estimated 5-year cumulative mortality risk of 52.4% (95% CI 45.3-59.5) and 39.8% (95% CI 33.4-46.3) for MI and stroke, respectively. We have found evidence that patients with type 1 diabetes in Sweden with prior severe hypoglycemic events have increased risk of mortality after a cardiovascular event.

Antecedent hypoglycaemia does not diminish the glycaemia-increasing effect and glucoregulatory responses of a 10 s sprint in people with type 1 diabetes

A 10 s sprint has been reported to provide a means to prevent acute post-exercise hypoglycaemia in young adults with type 1 diabetes because of its glycaemia-raising effect, but it is unclear whether this effect is impaired by antecedent hypoglycaemia. The purpose of this study was to investigate whether antecedent hypoglycaemia impairs the glycaemia-raising effect of a 10 s sprint in individuals with type 1 diabetes. Eight individuals underwent a hyperinsulinaemic-hypoglycaemic or hyperinsulinaemic-euglycaemic clamp on two separate mornings. Thereafter, the participants underwent a basal insulin-euglycaemic clamp before performing a 10 s sprint on a cycle ergometer. The levels of blood glucose and glucoregulatory hormones and rates of glucose appearance (Ra) and disappearance (Rd) were compared between conditions. During the morning clamps, blood glucose levels were significantly different between conditions of hypoglycaemia (2.8 ± 0.1 mmol/l) and euglycaemia (5.4 ± 0.2 mmol/l; p < 0.001). Mean glycaemia prior to sprinting was similar (5.6 ± 0.4 and 5.5 ± 0.3 mmol/l for hypoglycaemic and euglycaemic conditions, respectively; p = 0.83). In response to the afternoon sprint, the pattern of increase in blood glucose levels did not differ between conditions, reaching similar maximal levels 45 min after exercise (6.5 ± 0.4 and 6.6 ± 0.3 mmol/l, respectively; p = 0.43). The early post-exercise patterns in glucose Ra and Rd and increases in plasma adrenaline (epinephrine), growth hormone and cortisol levels did not differ between conditions. Hypoglycaemia in the morning does not diminish the glycaemia-raising effect of an afternoon 10 s sprint in young adults with type 1 diabetes, suggesting that sprinting is a useful strategy for opposing hypoglycaemia, regardless of prior hypoglycaemia.

Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7‐year follow‐up study

We investigated the risk of dementia in patients with type 2 diabetes with or without prior hypoglycaemic episodes. One million subjects randomly selected from the National Health Insurance Research Database, Taiwan. A total of 15 404 diabetic subjects without prior dementia and a mean age of 64.2 years were enrolled in the study. About 2% (n = 289) of participants had at least one episode of hypoglycaemia in a 3-year period; these subjects were older and more likely to be women and also had higher rates of insulin use and comorbidities compared to those without hypoglycaemia. During a total of 7 years of follow-up (mean and median follow-up, 3.8 and 4.8 years, respectively), 1106 patients with diabetes (7.2%) developed dementia. The incidence rate of dementia was higher in diabetic subjects with [29.9 per 1000 person-years (95% CI 22.1-39.2)] compared to those without [11.1 per 1000 person-years (95% CI 10.3-11.8)] hypoglycaemic episodes. The crude rate ratio (RR) and age- and gender-adjusted RR values for dementia were 2.76 (95% CI 2.06-3.70, P < 0.001) and 1.60 (95% CI 1.19-2.14, P = 0.002), respectively, in diabetic subjects with hypoglycaemia compared to those without hypoglycaemia. Results of Cox proportional hazards analysis revealed that hypoglycaemia, older age, female gender and insulin use were independent predictors of dementia. Adult diabetic patients with prior hypoglycaemia had a significantly increased risk of dementia. The influence of hypoglycaemic episodes on brain function warrants further investigation.