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Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial
research-article
Author(s):
Thomas R. Pieber
1 ,
Ronnie Aronson
2 ,
Ulrike Hövelmann
3 ,
Julie Willard
4 ,
Leona Plum-Mörschel
5 ,
Kim M. Knudsen
6 ,
Benedikte Bandak
6 ,
Ramin Tehranchi
6
Publication date (Electronic):
21 April 2021
Journal:
Diabetes Care
Publisher:
American Diabetes Association
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Abstract
OBJECTIVE
To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes.
RESEARCH DESIGN AND METHODS
This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.
RESULTS
Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo ( P < 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment.
CONCLUSIONS
Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.
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Most cited references11
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Standards of Medical Care in Diabetes—2020 Abridged for Primary Care Providers
(2020)
The American Diabetes Association’s (ADA’s) Standards of Medical Care in Diabetes is updated and published annually in a supplement to the January issue of Diabetes Care. The Standards are developed by the ADA’s multidisciplinary Professional Practice Committee, which comprises physicians, diabetes educators, and other expert diabetes health care professionals. The Standards include the most current evidence-based recommendations for diagnosing and treating adults and children with all forms of diabetes. ADA’s grading system uses A, B, C, or E to show the evidence level that supports each recommendation. A—Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered B—Supportive evidence from well-conducted cohort studies C—Supportive evidence from poorly controlled or uncontrolled studies E—Expert consensus or clinical experience This is an abridged version of the current Standards containing the evidence-based recommendations most pertinent to primary care. The recommendations, tables, and figures included here retain the same numbering used in the complete 2020 Standards and so are not numbered sequentially in this abridged version. All of the recommendations included here are substantively the same as in the complete Standards. The abridged version does not include references. The complete 2020 Standards of Care, including all supporting references, is available at professional.diabetes.org/standards. 1. IMPROVING CARE AND PROMOTING HEALTH IN POPULATIONS Diabetes and Population Health Population health is defined as “the health outcomes of a group of individuals, including the distribution of health outcomes within the group”; these outcomes can be measured in terms of health outcomes (mortality, morbidity, health, and functional status), disease burden (incidence and prevalence), and behavioral and metabolic factors (exercise, diet, A1C, etc.). Recommendations 1.1 Ensure treatment decisions are timely, rely on evidence-based guidelines, and are made collaboratively with patients based on individual preferences, prognoses, and comorbidities. B 1.2 Align approaches to diabetes management with the Chronic Care Model (CCM). This model emphasizes person-centered team care, integrated long-term treatment approaches to diabetes and comorbidities, and ongoing collaborative communication and goal setting between all team members. A 1.3 Care systems should facilitate team-based care and utilization of patient registries, decision support tools, and community involvement to meet patient needs. B 1.4 Assess diabetes health care maintenance using reliable and relevant data metrics to improve processes of care and health outcomes, with simultaneous emphasis on care costs. B Six Core Elements The CCM includes six core elements to optimize the care of patients with chronic disease: 1. Delivery system design (moving from a reactive to a proactive care delivery system where planned visits are coordinated through a team-based approach) 2. Self-management support 3. Decision support (basing care on evidence-based, effective care guidelines) 4. Clinical information systems (using registries that can provide patient-specific and population-based support to the care team) 5. Community resources and policies (identifying or developing resources to support healthy lifestyles) 6. Health systems (to create a quality-oriented culture) A 5-year effectiveness study of the CCM in 53,436 primary care patients with type 2 diabetes suggested that the use of this model of care delivery reduced the cumulative incidence of diabetes-related complications and all-cause mortality. Patients who were enrolled in the CCM experienced a reduction in cardiovascular disease (CVD) risk by 56.6%, microvascular complications by 11.9%, and mortality by 66.1%. The same study suggested that health care utilization was lower in the CCM group, resulting in health care savings of $7,294 per individual over the study period. Strategies for System-Level Improvement 1. Care teams 2. Telemedicine 3. Behaviors and well-being 4. Cost considerations 5. Access to care and quality improvement Tailoring Treatment for Social Context Recommendations 1.5 Providers should assess social context, including potential food insecurity, housing stability, and financial barriers, and apply that information to treatment decisions. A 1.6 Refer patients to local community resources when available. B 1.7 Provide patients with self-management support from lay health coaches, navigators, or community health workers when available. A Health inequities related to diabetes and its complications are well documented and are heavily influenced by social determinants of health (SDoH). SDoH are defined as the economic, environmental, political, and social conditions in which people live and are responsible for a major part of health inequality worldwide. The ADA recognizes the association between social and environmental factors and the prevention and treatment of diabetes and has issued a call for research that seeks to better understand how these SDoH influence behaviors and how the relationships between these variables might be modified for the prevention and management of diabetes. The complete 2020 Standards of Care include a discussion of assessment and treatment considerations in the context of food insecurity, homelessness, seasonal agricultural work, and language barriers. 2. CLASSIFICATION AND DIAGNOSIS OF DIABETES Classification Diabetes can be classified into the following general categories: 1. Type 1 diabetes (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of β-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM; diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation) It is important for providers to realize that classification of diabetes type is not always straightforward at presentation, and misdiagnosis may occur. The diagnosis may become more obvious over time and should be reevaluated if there is concern. Screening and Diagnostic Tests for Prediabetes and Type 2 Diabetes The diagnostic criteria for diabetes and prediabetes are shown in Table 2.2/2.5. TABLE 2.2/2.5 Criteria for the screening and diagnosis of prediabetes and diabetes Prediabetes Diabetes A1C 5.7–6.4% (39–47 mmol/mol)* ≥6.5% (48 mmol/mol)† Fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L)* ≥126 mg/dL (7.0 mmol/L)† Oral glucose tolerance test 140–199 mg/dL (7.8–11.0 mmol/L)* ≥200 mg/dL (11.1 mmol/L)† Random plasma glucose ≥200 mg/dL (11.1 mmol/L)‡ Adapted from Tables 2.2 and 2.5 in the complete Standards of Care. *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range. †In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate samples. ‡Only diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. Recommendations 2.6 Screening for prediabetes and type 2 diabetes with an informal assessment of risk factors or validated tools should be considered in asymptomatic adults. B 2.7 Testing for prediabetes and/or type 2 diabetes in asymptomatic people should be considered in adults of any age with overweight or obesity (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) and who have one or more additional risk factors for diabetes (Table 2.3). B 2.8 Testing for prediabetes and/or type 2 diabetes should be considered in women planning pregnancy with overweight or obesity and/or who have one or more additional risk factor for diabetes (Table 2.3). C 2.9 For all people, testing should begin at age 45 years. B 2.10 If tests are normal, repeat testing carried out at a minimum of 3-year intervals is reasonable. C 2.12 In patients with prediabetes and type 2 diabetes, identify and treat other CVD risk factors. B 2.13 Risk-based screening for prediabetes and/or type 2 diabetes should be considered after the onset of puberty or after 10 years of age, whichever occurs earlier, in children and adolescents with overweight (BMI ≥85th percentile) or obesity (BMI ≥95th percentile) and who have additional risk factors for diabetes. (See Table 2.4 for evidence grading of risk factors.) TABLE 2.3 Criteria for testing for diabetes or prediabetes in asymptomatic adults 1. Testing should be considered in adults with overweight or obesity (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) who have one or more of the following risk factors: • First-degree relative with diabetes • High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) • History of CVD • Hypertension (≥140/90 mmHg or on therapy for hypertension) • HDL cholesterol level 250 mg/dL (2.82 mmol/L) • Women with polycystic ovary syndrome • Physical inactivity • Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) 2. Patients with prediabetes (A1C ≥5.7% [39 mmol/mol], impaired glucose tolerance, or impaired fasting glucose) should be tested yearly. 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. 4. For all other patients, testing should begin at age 45 years. 5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results and risk status. TABLE 2.4 Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting Testing should be considered in youth* with overweight (≥85th percentile) or obesity (≥95th percentile) A who have one or more additional risk factors based on the strength of their association with diabetes: • Maternal history of diabetes or GDM during the child’s gestation A • Family history of type 2 diabetes in first- or second-degree relative A • Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A • Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B * After the onset of puberty or after 10 years of age, whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, or more frequently if BMI is increasing, is recommended. Reports of type 2 diabetes before age 10 years exist, and this can be considered with numerous risk factors. Marked discrepancies between measured A1C and plasma glucose levels should prompt consideration that the A1C assay may not be reliable for that individual, and one should consider using an assay without interference or plasma blood glucose criteria for diagnosis. (See “6. Glycemic Targets” in the complete 2020 Standards of Care for conditions causing discrepancies.) Unless there is a clear clinical diagnosis based on overt signs of hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples. If using two separate test samples, it is recommended that the second test, which may either be a repeat of the initial test or a different test, be performed without delay. If the patient has a test result near the margins of the diagnostic threshold, the provider should follow the patient closely and repeat the test in 3–6 months. 3. PREVENTION OR DELAY OF TYPE 2 DIABETES Recommendation 3.1 At least annual monitoring for the development of type 2 diabetes in those with prediabetes is suggested. E Screening for prediabetes and type 2 diabetes risk through an informal assessment of risk factors (Table 2.3) or with an assessment tool such as the ADA risk test (diabetes.org/socrisktest) is recommended to guide providers on whether performing a diagnostic test for prediabetes and previously undiagnosed type 2 diabetes (Table 2.2/2.5) is appropriate. Those who are determined to be at high risk for type 2 diabetes, including people with an A1C of 5.7–6.4% (39–47 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. Lifestyle Interventions Recommendations 3.2 Refer patients with prediabetes to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program (DPP) to achieve and maintain 7% loss of initial body weight and increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A 3.3 A variety of eating patterns are acceptable for persons with prediabetes. B 3.4 Based on patient preference, technology-assisted diabetes prevention interventions may be effective in preventing type 2 diabetes and should be considered. B 3.5 Given the cost-effectiveness of diabetes prevention, such intervention programs should be covered by third-party payers. B The DPP trial demonstrated that an intensive lifestyle intervention could reduce the incidence of type 2 diabetes by 58% over 3 years. Follow-up of three large studies of lifestyle intervention for diabetes prevention has shown sustained reduction in the rate of conversion to type 2 diabetes: 39% reduction at 30 years in the Da Qing Diabetes Prevention Study, 43% reduction at 7 years in the Finnish Diabetes Prevention Study, and 34% reduction at 10 years and 27% reduction at 15 years in the U.S. Diabetes Prevention Program Outcomes Study. Pharmacologic Interventions Recommendation 3.6 Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m2, those aged 180 mg/dL [10.0 mmol/L]) are useful parameters for reevaluation of the treatment regimen. E Glucose monitoring is key for the achievement of glycemic targets for many people with diabetes. SMBG is an integral component of effective therapy for patients taking insulin. CGM has emerged as a complementary method for the assessment of glucose levels. The patient’s specific needs and goals should dictate SMBG frequency and timing or the consideration of CGM use. Glucose Assessment Using CGM CGM has evolved rapidly in both accuracy and affordability. To make CGM metrics more actionable, standardized reports with visual cues such as the AGP (Figure 6.1) are recommended and may help patients and providers interpret the data and use it to guide treatment decisions. FIGURE 6.1 Sample AGP report. Adapted from Battelino T, Danne T, Bergenstal RM, et al. Diabetes Care 2019;42:1593–1603. A1C Goals Recommendations 6.6 An A1C goal for many nonpregnant adults of 5%, short-term (3-month) interventions that use very low-calorie diets (≤800 kcal/day) and meal replacements may be prescribed for carefully selected patients by trained practitioners in medical care settings with close medical monitoring. To maintain weight loss, such programs must incorporate long-term comprehensive weight-maintenance counseling. B Pharmacotherapy Recommendations 8.11 When choosing glucose-lowering medications for patients with type 2 diabetes and overweight or obesity, consider a medication’s effect on weight. B 8.12 Whenever possible, minimize medications for comorbid conditions that are associated with weight gain. E 8.13 Weight-loss medications are effective as adjuncts to diet, physical activity, and behavioral counseling for selected patients with type 2 diabetes and BMI ≥27 kg/m2. Potential benefits must be weighed against potential risks of medications. A 8.14 If a patient’s response to weight-loss medications is 10% [86 mmol/mol]) or blood glucose levels (≥300 mg/dL [16.7 mmol/L]) are very high. E 9.8 A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include CV comorbidities, hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences (Figure 9.1). E 9.9 Among patients with type 2 diabetes who have established ASCVD or indicators of high-risk, established kidney disease, or HF, a sodium–glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like peptide 1 (GLP-1) receptor agonist with demonstrated CVD benefit (Table 9.1) is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors (Figure 9.1). A 9.10 In patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents, GLP-1 receptor agonists are preferred to insulin when possible. B 9.11 Intensification of treatment for patients with type 2 diabetes not meeting treatment goals should not be delayed. B 9.12 The medication regimen and medication-taking behavior should be reevaluated at regular intervals (every 3–6 months) and adjusted as needed to incorporate specific factors that impact choice of treatment (Figure 4.1 and Table 9.1). E CV Outcomes Trials See “10. CVD and Risk Management” below for details. 10. CVD AND RISK MANAGEMENT This section has received endorsement from the American College of Cardiology. ASCVD—defined as coronary heart disease, cerebrovascular disease, or peripheral arterial disease (PAD) presumed to be of atherosclerotic origin—is the leading cause of morbidity and mortality for individuals with diabetes. HF is another major cause of morbidity and mortality from CVD. For prevention and management of both ASCVD and HF, CV risk factors should be systematically assessed at least annually in all patients with diabetes. These risk factors include obesity/overweight, hypertension, dyslipidemia, smoking, a family history of premature coronary disease, chronic kidney disease (CKD), and the presence of albuminuria. The Risk Calculator The American College of Cardiology/American Heart Association ASCVD risk calculator (Risk Estimator Plus) is a useful tool to estimate 10-year ASCVD risk (http://tools.acc.org/ASCVD-Risk-Estimator-Plus). This calculator includes diabetes as a risk factor because diabetes itself confers increased risk for ASCVD. It should be acknowledged that this risk calculator does not account for duration of diabetes or the presence of diabetes complications such as albuminuria. Hypertension/Blood Pressure Control Screening and Diagnosis Recommendations 10.1 Blood pressure should be measured at every routine clinical visit. Patients found to have elevated blood pressure (≥140/90 mmHg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension. B 10.2 All hypertensive patients with diabetes should monitor their blood pressure at home. B Treatment Goals Recommendations 10.3 For patients with diabetes and hypertension, blood pressure targets should be individualized through a shared decision-making process that addresses CV risk, potential adverse effects of antihypertensive medications, and patient preferences. C 10.4 For individuals with diabetes and hypertension at higher CV risk (existing ASCVD or 10-year ASCVD risk ≥15%), a blood pressure target of 120/80 mmHg, lifestyle intervention consists of weight loss if they have overweight or obesity, a Dietary Approaches to Stop Hypertension (DASH)-style eating pattern including reducing sodium and increasing potassium intake, moderation of alcohol intake, and increased physical activity. A Pharmacologic Interventions Recommendations 10.8 Patients with confirmed office-based blood pressure ≥140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of pharmacologic therapy to achieve blood pressure goals. A 10.9 Patients with confirmed office-based blood pressure ≥160/100 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single-pill combination of drugs demonstrated to reduce CV events in patients with diabetes. A 10.10 Treatment for hypertension should include drug classes demonstrated to reduce CV events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers [ARBs], thiazide-like diuretics, or dihydropyridine calcium channel blockers [CCBs]). A 10.11 Multiple-drug therapy is generally required to achieve blood pressure targets. However, combinations of ACE inhibitors and ARBs and combinations of ACE inhibitors or ARBs with direct renin inhibitors should not be used. A 10.12 An ACE inhibitor or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio (UACR) ≥300 mg/g creatinine (Cr) A or 30–299 mg/g Cr. B If one class is not tolerated, the other should be substituted. B 10.13 For patients treated with an ACE inhibitor, ARB, or diuretic, serum Cr/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored at least annually. B Resistant Hypertension Recommendation 10.14 Patients with hypertension who are not meeting blood pressure targets on three classes of antihypertensive medications (including a diuretic) should be considered for mineralocorticoid receptor antagonist therapy. B Prior to diagnosing resistant hypertension, a number of other conditions should be excluded, including medication nonadherence, white coat hypertension, and secondary hypertension. Mineralocorticoid receptor antagonists are effective for management of resistant hypertension in patients with type 2 diabetes when added to existing treatment with an ACE inhibitor or ARB, thiazide-like diuretic, or dihydropyridine CCB. Lipid Management Lifestyle Intervention Recommendations 10.15 Lifestyle modification focusing on weight loss (if indicated); application of a Mediterranean-style or DASH eating pattern; reduction of saturated fat and trans fat; increase of dietary n-3 fatty acids, viscous fiber, and plant stanols/sterols intake; and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing ASCVD in patients with diabetes. A 10.16 Intensify lifestyle therapy and optimize glycemic control for patients with elevated triglyceride levels (≥150 mg/dL [1.7 mmol/L]) and/or low HDL cholesterol ( 75 years already on statin therapy, it is reasonable to continue statin treatment. B 10.27 In adults with diabetes aged >75 years, it may be reasonable to initiate statin therapy after discussion of potential benefits and risks. C 10.28 Statin therapy is contraindicated in pregnancy. B Treatment of Other Lipoprotein Fractions or Targets Recommendations 10.29 For patients with fasting triglyceride levels ≥500 mg/dL, evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. C 10.30 In adults with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175–499 mg/dL), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that raise triglycerides. C 10.31 In patients with ASCVD or other CV risk factors on a statin with controlled LDL cholesterol but elevated triglycerides (135–499 mg/dL), the addition of icosapent ethyl can be considered to reduce CV risk. A Other Combination Therapy Recommendations 10.32 Statin plus fibrate combination therapy has not been shown to improve ASCVD outcomes and is generally not recommended. A 10.33 Statin plus niacin combination therapy has not been shown to provide additional CV benefit above statin therapy alone, may increase the risk of stroke with additional side effects, and is generally not recommended. A Diabetes Risk With Statin Use Several studies have reported a modestly increased risk of incident diabetes with statin use, which may be limited to those with diabetes risk factors. A meta-analysis of 13 randomized statin trials showed an odds ratio of 1.09 for a new diagnosis of diabetes, so that (on average) treatment of 255 patients with statins for 4 years resulted in one additional case of diabetes while simultaneously preventing 5.4 vascular events among those 255 patients. Lipid-Lowering Agents and Cognitive Function A concern that statins or other lipid-lowering agents might cause cognitive dysfunction or dementia is not currently supported by evidence and should not deter their use in individuals with diabetes at high risk for ASCVD. Antiplatelet Agents Recommendations 10.34 Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes and a history of ASCVD. A 10.35 For patients with ASCVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used. B 10.36 Dual antiplatelet therapy (with low-dose aspirin and a P2Y12 inhibitor) is reasonable for a year after an acute coronary syndrome A and may have benefits beyond this period. B 10.37 Aspirin therapy (75–162 mg/day) may be considered as a primary prevention strategy in those with diabetes who are at increased CV risk, after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding. A Risk Reduction Aspirin has been shown to be effective in reducing CV morbidity and mortality in high-risk patients with previous myocardial infarction or stroke (secondary prevention) and is strongly recommended. In primary prevention, however, among patients with no previous CV events, its net benefit is more controversial. Recommendations for using aspirin as primary prevention include both men and women aged ≥50 years with diabetes and at least one additional major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, or CKD/albuminuria) who are not at increased risk of bleeding (e.g., older age, anemia, renal disease). The main adverse effect is an increased risk of gastrointestinal bleeding. CVD Recommendations Screening 10.38 In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as ASCVD risk factors are treated. A 10.39 Consider investigations for coronary artery disease in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs or symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or PAD; or electrocardiogram abnormalities (e.g., Q waves). E Treatment 10.40 In patients with known ASCVD, consider ACE inhibitor or ARB therapy to reduce the risk of CV events. B 10.41 In patients with prior myocardial infarction, β-blockers should be continued for at least 2 years after the event. B 10.42 In patients with type 2 diabetes with stable HF, metformin may be continued for glucose lowering if eGFR remains >30 mL/min but should be avoided in unstable or hospitalized patients with HF. B 10.43 Among patients with type 2 diabetes who have established ASCVD or established kidney disease, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated CVD benefit is recommended as part of the glucose-lowering regimen. A 10.43a In patients with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or DKD, an SGLT2 inhibitor with demonstrated CV benefit is recommended to reduce the risk of major adverse CV events and HF hospitalization. A 10.43b In patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, a GLP-1 receptor agonist with demonstrated CV benefit is recommended to reduce the risk of major adverse CV events. A 10.43c In patients with type 2 diabetes and established HF, an SGLT2 inhibitor may be considered to reduce risk of HF hospitalization. C Numerous large, randomized controlled trials have reported statistically significant reductions in CV events for three of the FDA-approved SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) and four FDA-approved GLP-1 receptor agonists (liraglutide, albiglutide [although that agent was removed from the market for business reasons], semaglutide [lower risk of CV events in a moderate-sized clinical trial but one not powered as a CV outcomes trial], and dulaglutide). SGLT2 inhibitors also appear to reduce risk of HF hospitalization and progression of kidney disease in patients with established ASCVD, multiple risk factors for ASCVD, or DKD. 11. MICROVASCULAR COMPLICATIONS AND FOOT CARE CKD Recommendations Screening 11.1 At least once a year, assess urinary albumin (e.g., spot UACR) and eGFR in patients with type 1 diabetes with duration of ≥5 years and in all patients with type 2 diabetes regardless of treatment. B Patients with urinary albumin >30 mg/g Cr and/or an eGFR 30 mg/g Cr, particularly in those with urinary albumin >300 mg/g Cr, to reduce risk of CKD progression, CV events, or both. A In patients with CKD who are at increased risk for CV events, use of a GLP-1 receptor agonist may reduce risk of progression of albuminuria, CV events, or both (Table 9.1). C 11.4 Optimize blood pressure control to reduce the risk or slow the progression of CKD. A 11.5 Do not discontinue renin-angiotensin system blockade for minor increases in serum Cr ( 65 years of age is growing. This population has unique challenges and requires distinct treatment considerations. DSME and ongoing support are vital components of diabetes care for older adults and their caregivers. Older adults with diabetes are likely to benefit from control of other CV risk factors, with treatment of hypertension to individualized target levels indicated in most. There is less evidence for lipid-lowering and aspirin therapy, although the benefits of these interventions are likely to apply to older adults whose life expectancies equal or exceed the time frames of clinical prevention trials. Lifestyle Management Recommendation 12.10 Optimal nutrition and protein intake is recommended for older adults; regular exercise, including aerobic activity and resistance training, should be encouraged in all older adults who can safely engage in such activities. B Pharmacologic Therapy Recommendations 12.11 In older adults with type 2 diabetes at increased risk of hypoglycemia, medication classes with low risk of hypoglycemia are preferred. B 12.12 Overtreatment of diabetes is common in older adults and should be avoided. B 12.13 Deintensification (or simplification) of complex regimens is recommended to reduce the risk of hypoglycemia and polypharmacy, if it can be achieved within the individualized A1C target. B 12.14 Consider costs of care and insurance coverage rules when developing treatment plans in order to reduce risk of cost-related nonadherence. B Special care is required in prescribing and monitoring pharmacologic therapies in older adults. See Figure 9.1 for general recommendations regarding glucose-lowering treatment for adults with type 2 diabetes and Table 9.1 for patient- and drug-specific factors to consider when selecting glucose-lowering agents. Metformin is the first-line agent for older adults with type 2 diabetes. Tight glycemic control in older adults with multiple medical conditions is considered overtreatment and is associated with an increased risk of hypoglycemia; unfortunately, overtreatment is common in clinical practice. Deintensification of regimens in patients taking noninsulin glucose-lowering medications can be achieved by either lowering the dose or discontinuing some medications, so long as the individualized glycemic target is maintained. Simplification of insulin regimens may also be appropriate. The needs of older adults with diabetes and their caregivers should be evaluated to construct a tailored care plan. Treatment in Skilled Nursing Facilities and Nursing Homes Recommendations 12.15 Consider diabetes education for the staff of long-term care (LTC) and rehabilitation facilities to improve the management of older adults with diabetes. E 12.16 Patients with diabetes residing in long-term care facilities need careful assessment to establish individualized glycemic goals and to make appropriate choices of glucose-lowering agents based on their clinical and functional status. E Management of diabetes is unique in the LTC setting. Practical guidance is needed for medical providers as well as LTC staff and caregivers. Treatments for each patient should be individualized. Special management considerations include the need to avoid both hypoglycemia and the complications of hyperglycemia. The ADA position statement “Management of Diabetes in Long-term Care and Skilled Nursing Facilities” provide more information on this topic. End-of-Life Care Recommendations 12.17 When palliative care is needed in older adults with diabetes, providers should initiate conversations regarding the goals and intensity of care. Strict glucose and blood pressure control may not be necessary E, and reduction of therapy may be appropriate. Similarly, the intensity of lipid management can be relaxed, and withdrawal of lipid-lowering therapy may be appropriate. A Overall, palliative medicine promotes comfort, symptom control and prevention (pain, hypoglycemia, hyperglycemia, and dehydration), and preservation of dignity and quality of life in patients with limited life expectancy. Different patient categories have been proposed for diabetes management in those with advanced disease. These include stable patients, patients with organ failure, and dying patients. 13. CHILDREN AND ADOLESCENTS The management of diabetes in children and adolescents cannot simply be derived from care routinely provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric-onset diabetes are different from adult diabetes. Type 1 Diabetes Type 1 diabetes is the most common form of diabetes in youth. A multidisciplinary team of specialists trained in pediatric diabetes management and sensitive to the challenges of children and adolescents with type 1 diabetes and their families should provide care for this population. See “13. Children and Adolescents” in the complete 2020 Standards of Care for specific recommendations. The ADA position statements “Type 1 Diabetes in Children and Adolescents” and “Evaluation and Management of Youth-Onset Type 2 Diabetes” offer additional information. Type 2 Diabetes Management Recommendations Glycemic Targets 13.59 A reasonable A1C target for most children and adolescents with type 2 diabetes treated with oral agents alone is 135/85 mmHg should be treated in the interest of optimizing long-term maternal health. Blood pressure targets should range no lower than 120/80 mmHg, as lower blood pressure targets may impair fetal growth. C 14.20 Potentially harmful medications in pregnancy (i.e., ACE inhibitors, ARBs, statins) should be stopped at conception and avoided in sexually active women of childbearing age who are not using reliable contraception. B Postpartum Care Recommendations 14.21 Insulin resistance decreases dramatically immediately postpartum, and insulin requirements need to be evaluated and adjusted as they are often roughly half the prepregnancy requirements for the initial few days postpartum. C 14.22 A contraceptive plan should be discussed and implemented with all women with diabetes of reproductive potential. C 14.23 Screen women with a recent history of GDM at 4–12 weeks postpartum, using the 75-g oral glucose tolerance test and clinically appropriate nonpregnancy diagnostic criteria. B 14.24 Women with a history of GDM found to have prediabetes should receive intensive lifestyle interventions and/or metformin to prevent diabetes. A 14.25 Women with a history of GDM should have lifelong screening for the development of type 2 diabetes or prediabetes at least every 3 years. B 14.26 Women with a history of GDM should seek preconception screening for diabetes and preconception care to identify and treat hyperglycemia and prevent congenital malformations. E 14.27 Postpartum care should include psychosocial assessment and support for self-care. E 15. DIABETES CARE IN THE HOSPITAL Among hospitalized patients, both hyperglycemia and hypoglycemia are associated with adverse outcomes, including death. Therefore, careful management of inpatients with diabetes has direct and immediate benefits. When caring for hospitalized patients with diabetes, consult with a specialized diabetes or glucose management team when possible. Hospital Care Delivery Standards Recommendations 15.1 Perform an A1C on all patients with diabetes or hyperglycemia (blood glucose >140 mg/dL [7.8 mmol/L]) admitted to the hospital if not performed in the prior 3 months. B 15.2 Insulin should be administered using validated written or computerized protocols that allow for predefined adjustments in the insulin dosage based on glycemic fluctuations. C Considerations on Admission Initial orders should state the type of diabetes. Because inpatient treatment and discharge planning are more effective if based on preadmission glycemia, an A1C should be measured on all patients with diabetes or hyperglycemia. Glycemic Targets in Hospitalized Patients Recommendations 15.4 Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold ≥ 180 mg/dL (10.0 mmol/L). Once insulin therapy is started, a target glucose range of 140–180 mg/dL (7.8–10.0 mmol/L) is recommended for the majority of critically ill patients and noncritically ill patients. A 15.5 More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L), may be appropriate for selected patients if they can be achieved without significant hypoglycemia. C Hyperglycemia in hospitalized patients is defined as blood glucose levels >140 mg/dL (7.8 mmol/L). An admission A1C value ≥6.5% (48 mmol/mol) suggests that diabetes preceded hospitalization. Hypoglycemia in the hospital is classified the same as in any setting. (See “6. Glycemic Targets” above.) Bedside Blood Glucose Monitoring In patients who are eating, glucose monitoring should be performed before meals; in those not eating, glucose monitoring is advised every 4–6 h. Testing every 30 min to every 2 h is required for intravenous insulin infusion. Several inpatient studies have shown that CGM use did not improve glucose control but detected a greater number of hypoglycemic events than point-of-care glucose testing. However, there are insufficient data on clinical outcomes, safety, and cost-effectiveness to recommend using CGM in hospitalized patients. Glucose-Lowering Treatment in Hospitalized Patients Recommendations 15.6 Basal insulin or a basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill hospitalized patients with poor oral intake or those who are taking nothing by mouth. A An insulin regimen with basal, prandial, and correction components is the preferred treatment for noncritically ill hospitalized patients with good nutritional intake. A 15.7 Use of only a sliding scale insulin regimen in the inpatient hospital setting is strongly discouraged. A In most instances in the hospital setting, insulin is the preferred treatment for glycemic control. In certain circumstances, it may be appropriate to continue home regimens including oral glucose-lowering medications. If oral medications are held in the hospital, there should be a protocol for resuming them 1–2 days before discharge. Insulin Therapy In the critical care setting, continuous intravenous insulin infusion is the best method for achieving glycemic targets. Outside of critical care units, scheduled insulin regimens as described above are recommended. For patients who are eating, insulin injections should align with meals. In such instances, point-of-care glucose testing should be performed immediately before meals. An insulin regimen with basal and correction components is necessary for all hospitalized patients with type 1 diabetes, with the addition of prandial insulin if patients are eating. A transition protocol from insulin infusion to subcutaneous insulin is recommended. Noninsulin Therapies The safety and efficacy of noninsulin glucose-lowering therapies in the hospital setting is an area of active research. See “15. Diabetes Care in the Hospital” in the complete 2020 Standards of Care for a comprehensive review of the inpatient use of these medications. Hypoglycemia Recommendations 15.8 A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system. A plan for preventing and treating hypoglycemia should be established for each patient. Episodes of hypoglycemia in the hospital should be documented in the medical record and tracked. E 15.9 The treatment regimen should be reviewed and changed as necessary to prevent further hypoglycemia when a blood glucose value of <70 mg/dL (3.9 mmol/L) is documented. C Patients with or without diabetes may experience hypoglycemia in the hospital setting. While hypoglycemia is associated with increased mortality, it may be a marker of underlying disease rather than the cause of fatality. Recently, several groups have developed algorithms to predict episodes of hypoglycemia among inpatients. Models such as these are potentially important and, once validated for general use, could provide a valuable tool to reduce rates of hypoglycemia in hospitalized patients. MNT in the Hospital The goals of MNT in the hospital are to provide adequate calories to meet metabolic demands, optimize glycemic control, and address personal food preferences, and facilitate creation of a discharge plan. The ADA does not endorse any single meal plan. When nutritional issues in the hospital are complex, the involvement of an RD/RDN can contribute to patient care. Self-Management in the Hospital Diabetes self-management in the hospital may be appropriate for selected patients. Sufficient cognitive and physical skills, adequate oral intake, proficiency in carbohydrate estimation, and knowledge of sick-day management are some of the requirements. Self-administered insulin with a stable MDI regimen or insulin pump therapy may be considered. A protocol should exist for these situations. Standards for Special Situations See “15. Diabetes Care in the Hospital” in the complete 2020 Standards of Care for guidance on enteral/parenteral feedings, glucocorticoid therapy, perioperative care, and diabetic ketoacidosis and hyperosmolar hyperglycemic state. Transition From the Acute Care Setting Recommendation 15.10 There should be a structured discharge plan tailored to the individual patient with diabetes. B Transition from the acute care setting presents risk for all patients. A structured discharge plan may reduce length of hospital stay and readmission rates and increase patient satisfaction. Medication Reconciliation The patient’s medications must be cross-checked to ensure that no chronic medications were stopped and to ensure the safety of new prescriptions. Prescriptions for new or changed medication should be filled and reviewed with the patient and family at or before discharge. Discharge planning should begin at admission and be updated as patient needs change. An outpatient follow-up visit 1 month after discharge is recommended. An earlier appointment (in 1–2 weeks) is preferred, and frequent contact may be needed. 16. DIABETES ADVOCACY For a list of ADA advocacy position statements, including “Diabetes and Driving” and “Diabetes and Employment,” see “16. Diabetes Advocacy” in the complete 2020 Standards of Care.
- Record: found
- Abstract: found
- Article: not found
Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach
Nitil Kedia (2011)
Tight glycemic control is important in reducing and delaying vascular complications in type 1 and 2 diabetes patients; however, the benefits achieved through strict metabolic control are counterbalanced by an increased risk of hypoglycemia. Glucagon is an effective therapy for treating severe hypoglycemia. Available as an emergency kit, glucagon is an essential tool for rapid response, but remains underappreciated and underused. This article reviews the role of glucagon in treating severe hypoglycemia and discusses the need for better education on glucagon for people with diabetes and their caregivers in order to alleviate fears of hypoglycemia and of administering glucagon in the event of an emergency.
- Record: found
- Abstract: found
- Article: not found
Economic impact of severe and non-severe hypoglycemia in patients with Type 1 and Type 2 diabetes in the United States.
Volker Foos, Nebibe Varol, Bradley H Curtis … (2015)
To identify the direct and indirect costs of hypoglycemia in patients with Type 1 or Type 2 diabetes mellitus (DM) in the US setting.
Author and article information
Journal
Journal ID (nlm-ta): Diabetes Care
Journal ID (iso-abbrev): Diabetes Care
Journal ID (hwp): diacare
Journal ID (publisher-id): Diabetes Care
Title:
Diabetes Care
Publisher:
American Diabetes Association
ISSN
(Print):
0149-5992
ISSN
(Electronic):
1935-5548
Publication date
(Print):
June
2021
Publication date
(Electronic):
21
April
2021
Publication date PMC-release: 21
April
2021
Volume: 44
Issue: 6
Pages: 1361-1367
Affiliations
Author notes
Corresponding author: Thomas R. Pieber,
thomas.pieber@
123456medunigraz.at
Author information
Thomas R. Pieber
https://orcid.org/0000-0003-3554-0405
Ronnie Aronson
https://orcid.org/0000-0002-8976-2321
Ulrike Hövelmann
https://orcid.org/0000-0002-0940-8972
Article
Publisher ID: 202995DOI: 10.2337/dc20-2995
PMC ID: 8247529
PubMed ID: 33883196
SO-VID: 6d191e91-6efb-4b49-85bf-5c11ac68c97f
Copyright © © 2021 by the American Diabetes Association
License:
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
History
Date
received
: 9
December
2020
Date
accepted
: 11
March
2021
Page count
Figures: 2,
Tables: 3,
Equations: 0,
References: 13,
Pages: 7
Categories
Subject:
Emerging Therapies: Drugs and Regimens
ScienceOpen disciplines: Endocrinology & Diabetes
Data availability:
ScienceOpen disciplines: Endocrinology & Diabetes