New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989–1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

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Therapeutic Use of Intranasal Glucagon: Resolution of Hypoglycemia

International Journal of Molecular Sciences ◽

10.3390/ijms20153646 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3646 ◽

Cited By ~ 3

Author(s):

Antonio E. Pontiroli ◽

Elena Tagliabue

Keyword(s):

Severe Hypoglycemia ◽

Well Being ◽

Glucose Levels ◽

Fear Of Hypoglycemia ◽

Blood Glucose Levels ◽

Increase Blood Glucose ◽

Level Of Consciousness ◽

Patients With Diabetes ◽

Adults And Children ◽

First Time

Episodes of hypoglycemia are frequent in patients with diabetes treated with insulin or sulphonylureas. Hypoglycemia can lead to severe acute complications, and, as such, both prevention and treatment of hypoglycemia are important for the well-being of patients with diabetes. The experience of hypoglycemia also leads to fear of hypoglycemia, that in turn can limit optimal glycemic control in patients, especially with type 1 diabetes. Treatment of hypoglycemia is still based on administration of carbohydrates (oral or parenteral according to the level of consciousness) or of glucagon (intramuscular or subcutaneous injection). In 1983, it was shown for the first time that intranasal (IN) glucagon drops (with sodium glycocholate as a promoter) increase blood glucose levels in healthy volunteers. During the following decade, several authors showed the efficacy of IN glucagon (drops, powders, and sprays) to resolve hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. Only in 2010, based on evaluation of patients’ beliefs and patients’ expectations, a canadian pharmaceutical company (Locemia Solutions, Montreal, Canada) reinitiated efforts to develop glucagon for IN administration. The project has been continued by Eli Lilly, that is seeking to obtain registration in order to make IN glucagon available to insulin users (children and adolescents) worldwide. IN glucagon is as effective as injectable glucagon, and devoid of most of the technical difficulties associated with administration of injectable glucagon. IN glucagon appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both children and adults.

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Abstract 6238: Clarifying the Opportunities to Improve Survival After MI in Diabetic Patients

Circulation ◽

10.1161/circ.118.suppl_18.s_1164-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Lance S Longmore ◽

Kimberly J Reid ◽

Mikhail Kosiborod ◽

Frederick A Masoudi ◽

Verna Welch ◽

...

Keyword(s):

Cardiovascular Disease ◽

Patient Characteristics ◽

Psychosocial Health ◽

Diabetic Patients ◽

Biological Factors ◽

Increased Risk ◽

Wide Range ◽

Patients With Diabetes ◽

Multivariable Models ◽

Adjusted Model

While diabetes is known to be associated with increased mortality after MI, whether these differences in outcome are due to patient characteristics, treatment, or other biological factors is unknown. We analyzed a contemporary cohort of MI survivors to comprehensively adjust for demographics, comorbidities, psychosocial, health status, clinical and treatment factors to determine if residual disparities in outcomes exist. We studied 2481 hospital survivors of MI in the prospective, 19-center PREMIER study (29% with diabetes). Multivariable models with sequential adjustment were employed to identify the extent to which variation in a wide range of patient characteristics (Figure ) accounted for differences in 3-year mortality in patients with and without diabetes. Unadjusted mortality was more than 2.5-fold greater for patients with diabetes (HR 2.55, 95% CI 2.08–3.14). Mortality was most attenuated by diabetes-related comorbidities (Figure ). The fully-adjusted model identified a significant, albeit attenuated, excess 3-year mortality among patients with diabetes (HR 1.57, 95% CI 1.22–1.99). Patients with diabetes experience a substantially increased risk for 3-year mortality after MI, even after accounting for a wide range of patient and treatment characteristics. This suggests that unmeasured, biologic variables associated with diabetes may mediate this difference. Further inquiry into the pathogenesis of diabetic cardiovascular disease is needed to identify new opportunities to improve the prognosis of patients with diabetes.

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Chronic Diseases and Natural Hazards: Impact of Disasters on Diabetic, Renal, and Cardiac Patients

Prehospital and Disaster Medicine ◽

10.1017/s1049023x00005835 ◽

2008 ◽

Vol 23 (2) ◽

pp. 185-194 ◽

Cited By ~ 64

Author(s):

Andrew C. Miller ◽

Bonnie Arquilla

Keyword(s):

Chronic Disease ◽

Chronic Diseases ◽

Natural Hazards ◽

Well Being ◽

Adverse Outcomes ◽

Cardiac Patients ◽

Diabetic Patients ◽

Fluid Restriction ◽

Increased Risk ◽

Relief Efforts

AbstractBackground:Inadequately controlled chronic diseases may present a threat to life and well-being during the emergency response phase of disasters. Chronic disease exacerbations (CDE) account for one of the largest patient populations during disasters, and patients are at increased risk for adverse outcomes.Objective:The objective of this study was to assess the burden of chronic renal failure, diabetes, and cardiovascular disease during disasters due to natural hazards, identify impediments to care, and propose solutions to improve the disaster preparation and management of CDE.Methods:A thorough search of the PubMed, Ovid, and Medline databases was performed. Dr. Miller's personal international experiences treating CDE after disasters due to natural hazards, such as the 2005 Kashmir earthquake, are included.Discussion:Chronic disease exacerbations comprise a sizable disease burden during disasters related to natural hazards. Surveys estimate that 25–40% of those living in the regions affected by hurricanes Katrina and Rita lived with at least one chronic disease. Chronic illness accounted for 33% of visits, peaking 10 days after hurricane landfall. The international nephrology community has responded to dialysis needs by forming a well-organized and effective organization called the Renal Disaster Relief Task Force (RDRTF). The response to the needs of diabetic and cardiac patients has been less vigorous.Patients must be familiar with emergency diet and renal fluid restriction plans, possible modification of dialysis schedules and methods, and rescue treatments such as the administration of kayexalate. Facilities may consider investing in water-independent extracorporeal dialysis techniques as a rescue treatment. In addition to patient databases and medical alert identification, diabetics should maintain an emergency medical kit. Diabetic patients must be taught and practice the carbohydrate counting technique. In addition to improved planning, responding agencies and organizations must bring adequate supplies and medications to care for diabetic, cardiac, and renal patients during relief efforts.Conclusions:By recognizing and addressing impediments to the care of chronic disease exacerbations after natural disasters, the quality, delivery, and effectiveness of the care provided to diabetic patients during relief efforts can be improved.

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Mental Health Risk Among Members of the Millennial Population Cohort: A Concern for Public Health

American Journal of Health Promotion ◽

10.1177/0890117120945089 ◽

2020 ◽

pp. 089011712094508

Author(s):

Julie E. Lucero ◽

Amber D. Emerson ◽

Teysha Bowser ◽

Brandon Koch

Keyword(s):

Mental Health ◽

Psychological Distress ◽

Emerging Adults ◽

American Indians ◽

Well Being ◽

Data Set ◽

Population Cohort ◽

Increased Risk ◽

The Us ◽

Interview Survey

Purpose: Within the millennial population cohort, identify groups reporting increased risk of nonspecific psychological distress. As the largest living population cohort, taking stock of health and well-being early is necessary as substantial national resources may be needed as this cohort ages. Design: The 2017 National Health Interview Survey data, an annual multipurpose survey of the US population, was used. Sample: A sample of 7303 respondents were created by limiting data set to birth years 1980 to 1998. Measures: Outcomes were feeling like everything is an effort, worthlessness, hopelessness, restlessness, nervousness, and sadness. Combined these statements of feeling make up a measure of nonspecific psychological distress, past 30 days. Analysis: A logistic regression was performed on each outcome. All models controlled for demographic variables known to be associated with psychological distress. Results: Females are 1.4 times more likely than males to report nonspecific psychological distress ( P < .001), whereas Hispanics and Blacks are less likely to report nonspecific psychological distress (odds ratio [OR] = 0.49, OR = 0.57, P < .001). American Indians were less likely to report worthlessness (OR = 0.30, P < .05). However, multiple race individuals increasingly reported hopelessness (OR = 1.55, P < .05). Young adults are less likely than emerging adults to report sadness (OR = 0.85, P < .05). Conclusion: In this sample, racial/ethnic groups fared better than referent groups. Health programs need to integrate intersectional identities into promotion of mental health.

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The Challenge of Lipid Management in Patients with Diabetes or Other Endocrine Disorders

European Endocrinology ◽

10.17925/ee.2011.07.02.92 ◽

2010 ◽

Vol 7 (2) ◽

pp. 92

Author(s):

Alberico L Catapano ◽

Liliana Grigore ◽

Angela Pirillo ◽

◽

...

Keyword(s):

Statin Therapy ◽

Meta Analysis ◽

Diabetic Patients ◽

Endocrine Disorders ◽

Lipid Management ◽

Increased Risk ◽

Patients With Diabetes ◽

Associated Risk Factors

Diabetes increases the risk of developing cardiovascular disease (CVD), and several guidelines suggest that subjects with diabetes are at high risk of developing CVD. The increased risk can be attributed, at least in part, to associated risk factors, including hypertension and dyslipidaemia. The role of statins in primary and secondary prevention of CVD is well established, and the positive effect has been clearly demonstrated also in patients with type 2 diabetes. A number of studies have evaluated the effect of statin therapy on incident CVD and shown that statin therapy produces a great reduction in cardiovascular risk, but a recent meta-analysis revealed a slight increase in the risk of developing diabetes. Such risk is, however, low, especially when compared with the reduction in cardiovascular events and should not interfere with the choice of treating diabetic patients with a cholesterol-lowering therapy.

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The Role of Anti-obesity Drugs in Patients with Type 2 Diabetes

US Endocrinology ◽

10.17925/use.2013.09.02.101 ◽

2013 ◽

Vol 09 (02) ◽

pp. 101 ◽

Cited By ~ 1

Author(s):

Priscilla Hollander ◽

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Lifestyle Changes ◽

Important Concern ◽

Increased Risk ◽

The Us ◽

Patients With Diabetes ◽

Obesity Drugs

The prevalence of diabetes continues to rise, following the rising rates of obesity. Obesity is not only associated with an increased risk for developing type 2 diabetes but also an elevated probability of developing long-term complications associated with the disease. Weight gain is also an important concern as a potential side effect of therapies that improve glycemic control in diabetes, including insulin therapy. As a result, patients with type 2 diabetes are at risk for a vicious circle of increasing weight and increasing insulin resistance, thus requiring further intensification of glycemic treatment. It is therefore important to address the problem of obesity in patients with type 2 diabetes. In 2012, the US Food and Drug Administration (FDA) approved two new anti-obesity medications: lorcaserin and phentermine/topiramate extended-release. Both agents have demonstrated clinically meaningful weight reduction as well as significant improvements in glycemic control in obese patients with diabetes. Liraglutide has also shown weight loss and improvements in glycemic control in patients with diabetes. Anti-obesity drugs, in conjunction with lifestyle changes, may play a valuable role in the management of diabetes.

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Implication of Current ASE/EACVI Left Ventricular Diastolic Function Classification in Predicting 2-Year MACE in Asymptomatic Patients with Diabetes and Hypertension

European Heart Journal ◽

10.1093/eurheartj/ehab724.0105 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

D Foo ◽

K H Lam ◽

M Igo ◽

M N A Sulaiman ◽

M Y Ku ◽

...

Keyword(s):

Left Atrial Volume ◽

Left Ventricular ◽

Volume Index ◽

Diabetic Patients ◽

Prognostic Impact ◽

Left Atrial Volume Index ◽

Asymptomatic Patients ◽

Number Of Patients ◽

Increased Risk ◽

Patients With Diabetes

Abstract Background Left ventricular diastolic dysfunction (LVDD) has been shown to be more prevalent in patients with diabetes, and once progress to overt heart failure, carry worse clinical outcomes. Substantial number of patients were classified as indeterminate DF based on the current ASE/EACVI guidelines. The implication of current DF classification in predicting MACE among diabetic patients is not well established. Purpose To assess prognostic impact of current guidelines-based DF classification, and determine predictors of 2-year MACE based on individual LVDD parameters. Methods A total of 111 patients with diabetes and hypertension who attended diabetic clinic follow-up at the primary healthcare settings were enrolled. All patients had no prior cardiovascular events, had preserved left ventricular (LV) ejection fraction on echocardiography and sinus rhythm on ECG at screening. Echocardiography was performed to obtain parameters of LV dimensions, LV volumes and LVDD. The 2016 ASE/EACVI guidelines were applied to classify DF. All patients were followed up until 2 years to assess MACE. Results There were 65 (58.6%) female patients. Mean age was 59.86 (7.45); mean duration of DM was 10.5 (5.41). 80 (72.1%) patients were classified as having normal DF (nDF); 24 (21.6%) patients were classified as indeterminate DF (iDF); 7 patients (6.3%) were classified as LVDD. Patients with LVDD had significantly higher LV mass index (LVMI) (mean 121.72±23.28g/m2 vs 116.62±24.66g/m2 in iDF vs 102.50±22.89g/m2 in nDF); higher left atrial volume index (LAVI) (mean 41.24±10.28ml/m2 vs 30.55±10.07ml/m2 in iDF vs 25.75±6.30ml/m2 in nDF); lower lateral e' velocity (mean 6.35±2.05cm/s vs 7.37±1.73cm/s in iDF vs 8.59±2.13cm/s in nDF); higher septal E/e' ratio (mean 14.89±3.29 vs 12.16±3.99 in iDF vs 9.99±2.35 in nDF); higher average septal-lateral E/e' ratio (mean 14.22±3.77 vs 11.34±3.74 in iDF vs 9.04±2.10 in nDF). Among these 111 patients, 10 patients (9%) reported MACE at 2 years. The risk of 2-year MACE is elevated in both iDF [odds ratio (OR) 3.80, 95% CI 0.87–16.54, p=0.075] and LVDD [OR 7.60, 95% CI 1.11–52.02, p=0.039]. LVMI (OR 1.027, 95% CI 1.004– 1.051, p=0.023), LAVI (OR 1.092, 95% CI 1.017–1.172), and average septal-lateral E/e' ratio (OR 1.276, 95% CI 1.047–1.557, p=0.016) significantly correlated with 2-year MACE. Conclusions LVDD is correlated with increased MACE at 2 years. LVMI, LAVI and average septal-lateral E/e' ratio were predictors of increased risk of MACE at 2 years. Further investigation with larger sample size is warranted. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Malaysia

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Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial

Cardiovascular Diabetology ◽

10.1186/s12933-021-01357-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Job A. J. Verdonschot ◽

João Pedro Ferreira ◽

Pierpaolo Pellicori ◽

Hans-Peter Brunner-La Rocca ◽

Andrew L. Clark ◽

...

Keyword(s):

Heart Failure ◽

At Risk ◽

Plasma Concentrations ◽

Diabetic Patients ◽

Proteomic Profile ◽

Developing Heart ◽

Diabetes Status ◽

Increased Risk ◽

Patients With Diabetes ◽

Patients At Risk

Abstract Background Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The “Heart OMics in AGEing” (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial. Methods Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes. Results Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05). Conclusions Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

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Association of Myocardial Fibrosis Detected by Late Gadolinium-Enhanced MRI with Clinical Outcomes of Patients with Diabetes: A Systematic Review and Meta-Analysis

10.21203/rs.3.rs-30053/v1 ◽

2020 ◽

Author(s):

Zhi Yang ◽

Rong Xu ◽

Jia-rong Wang ◽

Hua-yan Xu ◽

Hang Fu ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Random Effects ◽

Data Extraction ◽

Meta Analysis ◽

Imaging Biomarker ◽

Diabetic Patients ◽

Significant Heterogeneity ◽

Cardiac Events ◽

Increased Risk ◽

Patients With Diabetes

Abstract Background Prior studies demonstrated that myocardial fibrosis assessed by late gadolinium-enhanced (LGE) MRI is associated with an increased risk for major adverse cardiac and cerebrovascular events (MACCE) or major adverse cardiac events (MACE) in patients with diabetes. However, the results of these studies were controversial and limited. Therefore, we performed this meta-analysis assessing the associations of myocardial fibrosis detected by LGE with the risk of MACCE and MACE in patients with diabetes. Methods We selected studies using MEDLINE, EMBASE and Cochrane by Ovid on December 2019. Prospective and retrospective studies that assessed the associations of myocardial fibrosis detected by LGE with the risk of MACCE or MACE in patients with diabetes with a disease duration of at least 12 months. Two independent reviewers performed the data extraction using a standardized form. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated by a random-effects model. Results Eight studies with 1121 patients were included in this meta-analysis, and follow-up of patients ranged from 17 to 70 months. The prevalence of LGE in the total sample was high, occurring in 38.09%. The annualized event rates (AERs) for MACCE was 11.94% in patients with diabetes and LGE. The presence of myocardial fibrosis detected by LGE was associated with an increased risk for MACCE (HR: 2.58; 95%CI 1.42-4.71; P=0.002) and MACE (HR: 5.28; 95%CI 3.20-8.70; P=0.000) in patients with diabetes. In a subgroup meta-analysis, ischemic fibrosis detected by LGE was associated with MACCE/MACE (HR 3.75, 95%CI 2.11-6.69; P=0.000) in patients with diabetes. In diabetic patients with preserved ejection fraction, the association between myocardial fibrosis detected by LGE and MACCE/MACE remained significant (HR: 4.02; 95%CI 2.22-7.25; P=0.000). All of the meta-analyses showed no significant heterogeneity from random effects. Conclusion This study demonstrated that myocardial fibrosis detected by LGE conferred an increase in the risk of MACCE/MACE in patients with diabetes and may be an imaging biomarker for risk stratification.

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Long-term glycemic variability and risk of stroke in patients with diabetes: a meta-analysis

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00770-0 ◽

2022 ◽

Vol 14 (1) ◽

Author(s):

Xiaoli Ren ◽

Zhiyun Wang ◽

Congfang Guo

Keyword(s):

Standard Deviation ◽

Coefficient Of Variation ◽

Meta Analysis ◽

Glycemic Variability ◽

Diabetic Patients ◽

Increased Risk ◽

Follow Up Studies ◽

Patients With Diabetes

Abstract Objectives Long-term glycemic variability has been related to increased risk of vascular complication in patients with diabetes. However, the association between parameters of long-term glycemic variability and risk of stroke remains not fully determined. We performed a meta-analysis to systematically evaluate the above association. Methods Medline, Embase, and Web of Science databases were searched for longitudinal follow-up studies comparing the incidence of stroke in diabetic patients with higher or lower long-term glycemic variability. A random-effect model incorporating the potential heterogeneity among the included studies were used to pool the results. Results Seven follow-up studies with 725,784 diabetic patients were included, and 98% of them were with type 2 diabetes mellitus (T2DM). The mean follow-up duration was 7.7 years. Pooled results showed that compared to those with lowest category of glycemic variability, diabetic patients with the highest patients had significantly increased risk of stroke, as evidenced by glycemic variability analyzed by fasting plasma glucose coefficient of variation (FPG-CV: risk ratio [RR] = 1.24, 95% confidence interval [CI] 1.11 to 1.39, P < 0.001; I2 = 53%), standard deviation of FPG (FPG-SD: RR = 1.16, 95% CI 1.02 to 1.31, P = 0.02; I2 = 74%), HbA1c coefficient of variation (HbA1c-CV: RR = 1.88, 95% CI 1.61 to 2.19 P < 0.001; I2 = 0%), and standard deviation of HbA1c (HbA1c-SD: RR = 1.73, 95% CI 1.49 to 2.00, P < 0.001; I2 = 0%). Conclusions Long-term glycemic variability is associated with higher risk of stroke in T2DM patients.

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