Adrenal gland response to adrenocorticotropic hormone is intact in patients with postural orthostatic tachycardia syndrome.

BACKGROUND: Many patients with postural orthostatic tachycardia syndrome (POTS) are hypovolemic with plasma volume deficits of 10-30 %. Some also have low levels of aldosterone and diminished aldosterone-renin ratios despite elevations in angiotensin II, pointing to potential adrenal dysfunction. To assess adrenal gland responsiveness in POTS, we measured circulating levels of aldosterone and cortisol following adrenocorticotropin hormone (ACTH) stimulation. METHODS: While on a low Na+ diet (∼10 mEq/day), 8 female patients with POTS and 5 female healthy controls (HC) received a low dose (1 µg) ACTH bolus following a baseline blood sample. After 60 min, a high dose (249 µg) infusion of ACTH was administered to ensure maximal adrenal response. Venous aldosterone and cortisol levels were sampled every 30 min for 2 h. RESULTS: Aldosterone increased in both groups in response to ACTH but was not different between POTS vs. HC at 60 min (53.5 ng/dL [37.8-61.8 ng/dL] vs. 46.1 ng/dL [36.7-84.9 ng/dL]; P = 1.000) or maximally (56.4 ng/dL [49.2-67.1 ng/dL] vs. 49.5 ng/dL [39.1-82.8 ng/dL]; P = 0.524). Cortisol increased in both groups in response to ACTH but was not different in patients with POTS vs. HC at 60 min (39.9 µg/dL [36.1-47.7 µg/dL] vs. 39.3 µg/dL [35.4-46.6 µg/dL]; P = 0.724) or maximally (39.9 µg/dL [33.9-45.4 µg/dL] vs. 42.0 µg/dL [37.6-49.7 µg/dL]; P = 0.354). CONCLUSIONS: ACTH appropriately increased the aldosterone and cortisol levels in patients with POTS. These findings suggest that the response of the adrenal cortex to hormonal stimulation is intact in patients with POTS.

Slow breathing for reducing stress: The effect of extending exhale.

INTRODUCTION: Slow breathing techniques are commonly used to reduce stress. While it is believed by mind-body practitioners that extending the exhale time relative to inhale increases relaxation, this has not been demonstrated. METHODS: We conducted a 12-week randomized, single-blinded trial among 100 participants to compare if yoga-based slow breathing with an exhale greater inhale versus an exhale equals inhale produces measurable differences in physiological and psychological stress among healthy adults. RESULTS: Participants mean individual instruction attendance was 10.7 ± 1.5 sessions out of 12 offered sessions. The mean weekly home practice was 4.8 ± 1.2 practices per week. There was no statistical difference between treatment groups for frequency of class attendance, home practice, or achieved slow breathing respiratory rate. Participants demonstrated fidelity to assigned breath ratios with home practice as measured by remote biometric assessments through smart garments (HEXOSKIN). Regular slow breathing practice for 12 weeks significantly reduced psychological stress as measured by PROMIS Anxiety (-4.85 S.D. ± 5.53, confidence interval [-5.60, -3.00], but not physiological stress as measured by heart rate variability. Group comparisons showed small effect size differences (d = 0.2) with further reductions in psychological stress and physiological stress from baseline to 12 weeks for exhale greater than inhale versus exhale equals inhale, however these differences were not statistically significant. CONCLUSION: While slow breathing significantly reduces psychological stress, breath ratios do not have a significant differential effect on stress reduction among healthy adults.

Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure.

BACKGROUND: Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. METHODS: In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H2O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8-12 cm H2O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. RESULTS: In Protocol 1, acute CPAP (4-16 cm H2O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (-16+3%) and cardiac output (-14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). CONCLUSIONS: CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03312556.

Worsening Postural Tachycardia Syndrome Is Associated With Increased Glucose-Dependent Insulinotropic Polypeptide Secretion.

BACKGROUND: Postural tachycardia syndrome (POTS) is characterized by excessive upright tachycardia and disabling presyncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal; it is unknown, however, what is the precise underlying mechanism. We seek to investigate the effect of glucose intake on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. METHODS: Prospective, case-control study, 12 women with POTS who reported a postprandial worsening of their POTS symptoms and 13 age-matched female controls received 75-g oral glucose and 20 mg/kg acetaminophen to assess nutrient absorption. Hemodynamic, gastrointestinal hormone and acetaminophen levels were measured for up to 120 minutes postingestion while supine and standing. RESULTS: Patients with POTS had significant orthostatic tachycardia, 48.7±11.2 versus 23.3±8.1 bpm, P=0.012 and elevated upright norepinephrine levels, 835.2±368.4 versus 356.9±156.7 pg/mL, P=0.004. After oral glucose, upright heart rate significantly increased in POTS, 21.2±11.9% versus 6.0±19.9%, P=0.033 with a concomitant decline in upright stroke volume, -10.3±11.90% versus 3.3±13.7%, P=0.027; total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707), indicating comparable nutrient absorption rates. POTS had increased plasma levels of C-peptide (P=0.001), GIP (glucose-dependent insulinotropic polypeptide; P=0.001), peptide YY (P=0.016), and pancreatic polypeptide (P=0.04) following glucose consumption, but only GIP had a time-dependent association with the worsening upright tachycardia and stroke volume fall. CONCLUSIONS: The glucose-induced worsening orthostatic tachycardia in POTS was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, was maximally elevated.

Ganglionic Acetylcholine Receptor Antibodies in Postural Tachycardia Syndrome.

OBJECTIVE: Postural tachycardia syndrome (POTS), the most common form of dysautonomia, may be associated with autoimmunity in some cases. Autoantibodies against the ganglionic acetylcholine receptor (gAChR) have been reported in a minority of patients with POTS, but the prevalence and clinical relevance is unclear. METHODS: Clinical information and serum samples were systematically collected from participants with POTS and healthy control volunteers (n = 294). The level of positive gAChR antibodies was classified as very low (0.02-0.05 nmol/L), low (0.05-0.2 nmol/L), and high (>0.2 nmol/L). RESULTS: Fifteen of 217 patients with POTS (7%) had gAChR antibodies (8 very low and 7 low). Six of the 77 healthy controls (8%) were positive (3 very low and 3 low). There were no clinical differences between seropositive and seronegative patients with POTS. CONCLUSIONS: Prevalence of gAChR antibody did not differ between POTS and healthy controls, and none had high antibody levels. Patients with POTS were not clinically different based on seropositivity. Low levels of gAChR antibodies are not clinically important in POTS.

Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome.

BACKGROUND: High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES: This study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS: A total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. RESULTS: In POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. CONCLUSIONS: In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117).

Elevated cerebral blood flow in patients with pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. METHODS: Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. RESULTS: Gray matter CBF was higher in PAF (51.1 ± 13.4 mL/100 g/min) compared to controls (42.9 ± 6.5 mL/100 g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). CONCLUSIONS: Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure.

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

High-sodium diet does not worsen endothelial function in female patients with postural tachycardia syndrome.

PURPOSE: Postural tachycardia syndrome (POTS), a syndrome characterized by orthostatic symptoms and a heart rate increase of at least 30 beats per minute in the absence of hypotension upon standing, is often accompanied by increased sympathetic activity and low blood volume. A common non-pharmacologic recommendation for patients with POTS is a high-sodium (HS) diet with the goal of bolstering circulating blood volume. The objective of this study is to assess the effects of 6 days of a HS diet on endothelial function in POTS. METHODS: A total of 14 patients with POTS and 13 age-matched healthy controls, all females, were studied following 6 days on a low-sodium (LS) diet (10 mEq/day) and 6 days on a HS diet (300 mEq/day) in a crossover design. We measured endothelial function following reactive hyperemia in the brachial artery using flow-mediated dilation (FMD), leg blood flow (LBF) using strain gauge plethysmography in the calf, and reactive hyperemic index (RHI) in the microcirculation of the hand using pulsatile arterial tonometry. RESULTS: On the LS diet, FMD% did not differ between patients with POTS and the healthy controls although peak brachial artery diameter was lower for the patient group. RHI was higher for the patient group than for the controls, but there were no differences in post-ischemic LBF increase. On the HS diet, there were no between-group differences in FMD%, LBF increase, or RHI. CONCLUSION: In summary, a HS diet for 6 days did not induce endothelial dysfunction. This non-pharmacologic treatment used for patients with POTS does not negatively affect endothelial function when used for a sub-acute duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT01550315; March 9, 2012.

A comparison of health-related quality of life in autonomic disorders: postural tachycardia syndrome versus vasovagal syncope.

PURPOSE: Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS. METHODS: POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18 years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey. RESULTS: POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p < 0.001), role limitations due to physical health (11.4 ± 1.9 vs. 33.0 ± 5.0, p < 0.001), energy and fatigue (27.2 ± 1.3 vs. 50.7 ± 2.6, p < 0.001), social functioning (45.2 ± 1.8 vs. 71.2 ± 2.9, p < 0.001), pain (48.8 ± 1.9 vs. 67.7 ± 2.9, p < 0.001), and general health (31.2 ± 1.5 vs. 60.5 ± 2.6, p < 0.001) domains. Scores did not differ significantly in the role limitations due to emotional health (p = 0.052) and emotional well-being (p = 0.271) domains. Physical and general health composite scores were lower in the POTS population, while mental health composite scores were not different. CONCLUSION: Differences in HRQoL exist between these patient populations. POTS patients report lower scores in physical and general health domains than VVS patients, but emotional health domains do not differ significantly. Targeting physical functioning in these patients may help improve quality of life.

Assessment of dynamic cardiac repolarization and contractility in patients with hypertrophic cardiomyopathy.

AIMS: Arrhythmia mechanisms in hypertrophic cardiomyopathy remain uncertain. Preclinical models suggest hypertrophic cardiomyopathy-linked mutations perturb sarcomere length-dependent activation, alter cardiac repolarization in rate-dependent fashion and potentiate triggered electrical activity. This study was designed to assess rate-dependence of clinical surrogates of contractility and repolarization in humans with hypertrophic cardiomyopathy. METHODS: All participants had a cardiac implantable device capable of atrial pacing. Cases had clinical diagnosis of hypertrophic cardiomyopathy, controls were age-matched. Continuous electrocardiogram and blood pressure were recorded during and immediately after 30 second pacing trains delivered at increasing rates. RESULTS: Nine hypertrophic cardiomyopathy patients and 10 controls were enrolled (47% female, median 55 years), with similar baseline QRS duration, QT interval and blood pressure. Median septal thickness in hypertrophic cardiomyopathy patients was 18mm; 33% of hypertrophic cardiomyopathy patients had peak sub-aortic velocity >50mmHg. Ventricular ectopy occurred during or immediately after pacing trains in 4/9 hypertrophic cardiomyopathy patients and 0/10 controls (P = 0.03). During delivery of steady rate pacing across a range of cycle lengths, the QT-RR relationship was not statistically different between HCM and control groups; no differences were seen in subgroup analysis of patients with or without intact AV node conduction. Similarly, there was no difference between groups in the QT interval of the first post-pause recovery beat after pacing trains. No statistically significant differences were seen in surrogate measures for cardiac contractility. CONCLUSION: Rapid pacing trains triggered ventricular ectopy in hypertrophic cardiomyopathy patients, but not controls. This finding aligns with pre-clinical descriptions of excessive cardiomyocyte calcium loading during rapid pacing, increased post-pause sarcoplasmic reticulum calcium release, and subsequent calcium-triggered activity. Normal contractility at all diastolic intervals argues against clinical significance of altered length-dependent myofilament activation.

Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome.

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01308099.

Increased vascular α1-adrenergic receptor sensitivity in older adults with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is an independent risk factor for the development of hypertension and cardiovascular disease. Patients with PTSD have heightened blood pressure and sympathetic nervous system reactivity; however, it is unclear if patients with PTSD have exaggerated vasoconstriction in response to sympathetic nerve activation that could also contribute to increased blood pressure reactivity. Therefore, we hypothesized that patients with PTSD have increased sensitivity of vascular α1-adrenergic receptors (α1ARs), the major mediators of vasoconstriction in response to release of norepinephrine at sympathetic nerve terminals. To assess vascular α1AR sensitivity, we measured the degree of venoconstriction in a dorsal hand vein in response to exponentially increasing doses of the selective α1AR agonist, phenylephrine (PE), in 9 patients with PTSD (age = 59 ± 2 yr) and 10 age-matched controls (age = 60 ± 1 yr). Individual dose-response curves were generated to determine the dose of PE that induces 50% of maximal venoconstriction (i.e., PE ED50) reflective of vascular α1AR sensitivity. In support of our hypothesis, PE ED50 values were lower in PTSD compared with controls (245 ± 54 ng/min vs. 1,995 ± 459 ng/min, P = 0.012), indicating increased vascular α1AR sensitivity in PTSD. The PTSD group also had an increase in slope of rise in venoconstriction, indicative of an altered venoconstrictive reactivity to PE compared with controls (19.8% ± 1.2% vs. 15.1% ± 1.2%, P = 0.009). Heightened vascular α1AR sensitivity in PTSD may contribute to augmented vasoconstriction and blood pressure reactivity to sympathoexcitation and to increased cardiovascular disease risk in this patient population.

Splanchnic Venous Compression Enhances the Effects of ß-Blockade in the Treatment of Postural Tachycardia Syndrome.

Background Splanchnic venous pooling induced by upright posture triggers a compensatory increase in heart rate (HR), a response that is exaggerated in patients with postural tachycardia syndrome. To assess whether abdominal compression attenuates orthostatic tachycardia and improves symptoms, 18 postural tachycardia syndrome patients (32±2 years) were randomized to receive either abdominal compression (40 mm Hg applied with an inflatable binder ≈2 minutes before standing) or propranolol (20 mg) in a placebo-controlled, crossover study. Methods and Results Systolic blood pressure, HR, and symptoms were assessed while seated and standing, before and 2 hours postdrug. As expected, propranolol decreased standing HR compared with placebo (81±2 versus 98±4 beats per minute; P<0.001) and was associated with lower standing systolic blood pressure (93±2 versus 100±2 mm Hg for placebo; P=0.002). Compression had no effect on standing HR (96±4 beats per minute) but increased standing systolic blood pressure compared with placebo and propranolol (106±2 mm Hg; P<0.01). Neither propranolol nor compression improved symptoms compared with placebo. In 16 patients we compared the combination of abdominal compression and propranolol with propranolol alone. The combination had no additional effect on standing HR (81±2 beats per minute for both interventions) but prevented the decrease in standing systolic blood pressure produced by propranolol (98±2 versus 93±2 mm Hg for propranolol; P=0.029), and significantly improved total symptom burden (-6±2 versus -1±2 for propranolol; P=0.041). Conclusions Splanchnic venous compression alone did not improve HR or symptoms but prevented the blood pressure decrease produced by propranolol. The combination was more effective in improving symptoms than either alone. Splanchnic venous compression can be a useful adjuvant therapy to propranolol in postural tachycardia syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00262470.

Estimation of Annual Health Care Costs for Adults with Type 1 Diabetes in the United States.

BACKGROUND: Diabetes health care resource utilization (HCRU) studies tend to focus on patients with type 2 diabetes (T2D) or pool patients with T2D and type 1 diabetes (T1D). There is a paucity of recent data on the cost of treating patients with T1D in the United States. OBJECTIVES: To (a) estimate the per-patient per-year (PPPY) HCRU and costs, from a payer perspective, associated with treating U.S. adults with T1D and (b) compare these with the HCRU and costs for patients with T2D. METHODS: This retrospective cohort study used claims data from the Optum Clinformatics database between January 2015 and December 2017. Adults (aged ≥ 18 years) with a diagnosis of T1D were propensity score-matched to adults with T2D. Overall and nondiabetes-related HCRU and costs were assessed for T1D and T2D and compared between the 2 groups. RESULTS: Propensity scores were used to match 10,103 patient pairs from T1D and T2D cohorts (mean ages 54.4 and 56.9 years, respectively). In the T1D cohort, inpatient, emergency department (ED), outpatient, and prescription claims occurred in 14.0%, 17.3%, 85.5%, and 100% of patients, respectively, resulting in a mean total cost of U.S. $18,817 PPPY (diabetes-related = $11,002; nondiabetes-related = $7,816). The T1D cohort had significantly higher mean total costs than the T2D cohort ($18,817 vs. $14,148 PPPY; P < 0.001). When extrapolating these findings to a commercial health plan with 1 million covered lives, the estimated total direct medical costs of T1D would be $103.4 million. CONCLUSIONS: This study showed that the total annual cost of managing an adult with T1D is significantly higher than that of an adult with T2D. Nondiabetes costs accounted for 40% of the total per-patient cost, similar to patients with T2D, confirming that as patients with T1D live longer lives, they may also be at greater risk for cardiometabolic complications. DISCLOSURES: This study was funded by Sanofi U.S. and Lexicon Pharmaceuticals as part of a business partnership in a diabetes program at the time this study was conducted. Joish and Davies are employees and stockholders of Lexicon Pharmaceuticals. Zhou, Preblick, and Paranjape are employees and stockholders of Sanofi. Lin was a postdoctoral fellow at Sanofi through Rutgers University during this project. Deshpande provided consulting services through Communication Symmetry. Verma is an employee of Evidera, which was contracted by Sanofi for work on this study. Pettus is a consultant for Diasome, Insulet, Lexicon, Lilly, Mannkind, Novo Nordisk, Sanofi, and Senseonics.

Burden of Cardiovascular Disease in Adult Patients with Type 1 Diabetes in the US.

BACKGROUND AND OBJECTIVES: The burden imposed by cardiovascular disease (CVD) on patients with type 1 diabetes (T1D) in the US has not been thoroughly addressed. In a retrospective observational analysis of the Optum® Clinformatics™ Data Mart database, the prevalence of CVD and cardiovascular risk factors (CVRF) as well as health economic outcomes were evaluated in adults with T1D. METHODS: Patients with at least one T1D medical claim between January 1, 2016, and December 31, 2016, were divided into cohorts based on the presence of CVD and/or CVRF. Descriptive and multivariate analyses enabled comparisons of healthcare resource utilization and costs between the cohorts. RESULTS: The analysis included 12,687 patients: CVD, 2871; CVRF, 5371; and no CVD/CVRF, 4445. The period prevalence of CVD and CVRF in the combined baseline and follow-up periods was 27% and 44%, respectively. Fewer patients in the no-CVD/CVRF cohort had a claim of a diabetes-related inpatient admission compared with the CVD cohort (8% vs. 26%, respectively; P < 0.001, standardized mean difference [SMD] > 0.1). Likewise, fewer patients with no CVD/CVRF visited the emergency department vs. those with CVRF or CVD (diabetes-related: 4% vs. 7% and 18%, respectively; P < 0.001, SMD > 0.1). Higher overall costs were observed for the CVD and CVRF vs. the no-CVD/CVRF cohort ($30,241 and $16,220, respectively, vs. $11,761; P < 0.05 and SMD ≥ 0.1 for both). CONCLUSIONS: Cardiovascular comorbidities are common among US adults with T1D. Considering their significant economic burden, optimal management is of the utmost importance to improve patient outcomes and reduce healthcare costs.

Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data.

BACKGROUND: To examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose. METHODS: A post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658). RESULTS: Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of < 10 mmol/L (< 180 mg/dL) than placebo-treated patients (P < 0.001), regardless of baseline fasting plasma glucose (FPG) levels. More importantly, those who reached the PPG target experienced a significantly greater reduction in mean HbA1c, were more likely to achieve HbA1c target of < 53 mmol/mol (< 7.0%), and experienced weight loss. Those outcomes were achieved with no significant differences in the risk of symptomatic hypoglycemia compared with placebo. CONCLUSION: Compared with placebo, addition of lixisenatide to basal insulin improved HbA1c and reduced PPG, without increasing hypoglycemia risk. These findings highlight the importance of PPG control in the management of T2D, and provide evidence that adding an agent to basal insulin therapy that also impacts PPG has therapeutic value for patients who are not meeting glycemic targets. TRIAL REGISTRATION: NCT00715624. Registered 15 July 2008, NCT00975286. Registered 11 September 2009, NCT00866658. Registered 20 March 2009.

Differences between patients with type 1 diabetes with optimal and suboptimal glycaemic control: A real-world study of more than 30 000 patients in a US electronic health record database.

AIMS: To use electronic health record data from real-world clinical practice to assess demographics, clinical characteristics and disease burden of adults with type 1 diabetes (T1D) in the United States. MATERIALS AND METHODS: Retrospective observational study of adults with T1D for ≥24 months at their first visit with a T1D diagnosis code ("index date") between July 2014 and June 2016 in the Optum Humedica database. Demographic characteristics, acute complications (severe hypoglycaemia [SH], diabetic ketoacidosis [DKA]), microvascular complications, cardiovascular (CV) events and health care resource utilization during the 12 months before the index date ("baseline period") were compared between patients with optimal versus suboptimal glycaemic control (glycated haemoglobin [HbA1c] <7.0% vs. ≥7.0% [53 mmol/mol]) at the closest measurement to the index date. RESULTS: Of 31 430 adults with T1D, 79.9% had suboptimal glycaemic control (mean HbA1c 8.8% [73 mmol/mol]). These patients were more likely to be younger, African American, uninsured or on Medicaid, obese, smokers, have uncontrolled hypertension and have depression. Despite worse glycaemic control and increased CV risk factors of uncontrolled hypertension, obesity and smoking, rates of coronary heart disease and stroke were not higher in these patients. Patients with suboptimal glycaemic control also experienced more diabetes complications (including SH, DKA and microvascular disease) and utilized more emergency care, with more emergency department visits and inpatient stays. CONCLUSION: This real-world study of >30 000 adults with T1D showed that individuals with suboptimal versus optimal glycaemic control differed significantly in terms of health care coverage, comorbidities, diabetes-related complications, health care utilization and CV risk factors. However, suboptimal control was not associated with increased risk of CV outcomes.

Incidences of Severe Hypoglycemia and Diabetic Ketoacidosis and Prevalence of Microvascular Complications Stratified by Age and Glycemic Control in U.S. Adult Patients With Type 1 Diabetes: A Real-World Study.

OBJECTIVE: To assess the burden of disease for adults with type 1 diabetes in a U.S. electronic health record database by evaluating acute and microvascular complications stratified by age and glycemic control. RESEARCH DESIGN AND METHODS: This is a retrospective observational study of adults with type 1 diabetes (1 July 2014-30 June 2016) classified using a validated algorithm, with disease duration ≥24 months and, during a 12-month baseline period, not pregnant and having one or more insulin prescriptions and one or more HbA1c measurements. Demographic characteristics, acute complications (severe hypoglycemia [SH], diabetic ketoacidosis [DKA]), and microvascular complications (neuropathy, nephropathy, retinopathy) were stratified by age (18-25, 26-49, 50-64, ≥65 years) and glycemic control (HbA1c <7%, 7% to <9%, ≥9%). RESULTS: Of 31,430 patients, ∼20% had HbA1c <7%. Older patients had lower HbA1c values than younger patients (P < 0.001). Patients with poor glycemic control had the highest annual incidence of SH (4.2%, 4.0%, and 8.3%) and DKA (1.3%, 2.8%, and 15.8%) for HbA1c <7%, 7% to <9%, and ≥9% cohorts, respectively (both P < 0.001), and a higher prevalence of neuropathy and nephropathy (both P < 0.001). CONCLUSIONS: For adults with type 1 diabetes, glycemic control appears worse than previously estimated. Rates of all complications increased with increasing HbA1c. Compared with HbA1c <7%, HbA1c ≥9% was associated with twofold and 12-fold higher incidences of SH and DKA, respectively. Younger adults had more pronounced higher risks of SH and DKA associated with poor glycemic control than older adults.