Insulins General Statement (Monograph)

Drug class: Insulins
ATC class: A10A
VA class: HS501

Introduction

Insulin is a hormone secreted by the beta cells of the pancreatic islets of Langerhans. Commercially available insulin preparations are classified as rapid-acting (insulin aspart, insulin glulisine, insulin lispro), short-acting (insulin human), intermediate-acting (insulin human isophane), or long-acting (insulin degludec, insulin detemir, insulin glargine).

Uses for Insulins General Statement

Diabetes Mellitus

Overview

The American Diabetes Association (ADA) generally classifies diabetes mellitus as type 1 (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency); type 2 (due to a progressive loss of β-cell insulin secretion frequently on the background of insulin resistance); gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation); or specific types of diabetes due to other causes, such as monogenic diabetes syndromes (e.g., neonatal diabetes or maturity-onset diabetes of the young [MODY], diseases of the exocrine pancreas (e.g., cystic fibrosis, pancreatitis), or drug- or chemical-induced diabetes (e.g., that associated with glucocorticoid use, treatment of human immunodeficiency virus [HIV] /acquired immunodeficiency syndrome [AIDS], organ transplantation).

According to ADA and other experts, a diagnosis of diabetes mellitus currently is established by a fasting plasma glucose concentration of 126 mg/dL or greater, a 2-hour plasma glucose concentration of 200 mg/dL or greater during an oral glucose tolerance test, or a glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) concentration of 6.5% or greater; results should be confirmed by repeat testing in the absence of unequivocal hyperglycemia. Alternatively, a random plasma glucose concentration of 200 mg/dL or greater in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis is considered confirmation of the diagnosis of diabetes mellitus.

Type 1 diabetes mellitus was previously described as juvenile-onset diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus was previously described as adult-onset diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on the age of onset. In both type 1 and type 2 diabetes mellitus, various genetic and environmental factors can result in the progressive loss of β-cell mass and/or function that manifests clinically as hyperglycemia. Many patients’ diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents.

Patients with type 2 diabetes mellitus (approximately 90–95% of all patients with diabetes mellitus) have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Considerations in Initiating Antidiabetic Therapy

Lifestyle modifications (e.g., self-management of diabetes mellitus, medical nutrition therapy [promoting healthy eating to achieve and maintain body weight goals], increased physical activity, smoking cessation, psychosocial care) are an important aspect of diabetes mellitus care in patients of all ages. Such lifestyle/behavioral modifications decrease cardiovascular risk and microvascular complications, improve glycemic control, and remain an indispensable part of the management of diabetes mellitus. Lipid management aimed at lowering low-density lipoprotein (LDL)-cholesterol, raising high-density lipoprotein (HDL)-cholesterol, and lowering triglycerides in patients with type 2 diabetes mellitus has been shown to reduce macrovascular disease and mortality. Although data on risk reduction are not as definitive in patients with type 1 diabetes mellitus, lipid-lowering therapy also should be considered in patients with type 1 diabetes. Efforts also should be aimed at blood pressure control in both adults and children, as reduction in blood pressure in uncomplicated mild to moderately hypertensive patients with diabetes mellitus has reduced the incidence of virtually all macrovascular (stroke, heart failure) and microvascular (retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality. For information on the treatment of hypertension in patients with diabetes mellitus, see Uses: Hypertension, in Captopril 24:24.

Treatment with insulin is essential in all patients with type 1 diabetes mellitus. (See Insulin Monotherapy under Uses: Diabetes Mellitus.) Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications because of its well-established safety and efficacy (e.g., beneficial effects on HbA_1c, weight, and cardiovascular mortality) in patients with recent-onset or newly diagnosed type 2 diabetes mellitus or mild hyperglycemia. However, insulin therapy should be considered in patients with type 2 diabetes mellitus when hyperglycemia is severe (e.g., blood glucose concentration of 300 mg/dL or higher, HbA_1c of at least 10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis), or if symptoms of hyperglycemia are present. When the greater glucose-lowering effect of an injectable drug is needed, some experts currently suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may be preferred over insulin because of a lower risk of hypoglycemia and beneficial effects on body weight, although they are associated with a greater risk of adverse GI effects. Because of the progressive nature of the disease, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control. (See Combination Therapy with Other Antidiabetic Agents under Uses: Diabetes Mellitus.)

Insulin Monotherapy

Insulin is used as replacement therapy in the management of diabetes mellitus. It supplements deficient concentrations of endogenous insulin and temporarily restores the ability of the body to properly utilize carbohydrates, fats, and proteins.

Insulin therapy is indicated in all cases of type 1 diabetes mellitus and is mandatory in the treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin also is indicated in patients with type 2 diabetes mellitus when weight reduction, proper dietary regulation, and/or oral antidiabetic agents have failed to maintain satisfactory concentrations of blood glucose in both the fasting and postprandial state. In addition, insulin is indicated in otherwise stable, type 2 diabetic patients in the presence of major surgery, fever, severe trauma, infections, serious renal or hepatic dysfunction, hyperthyroidism or other endocrine dysfunction, gangrene, Raynaud’s disease, or pregnancy.

In general, goals of insulin therapy in all patients should include maintenance of blood glucose as close as possible to euglycemia without an undue risk of hypoglycemia; avoidance of symptoms attributable to hyperglycemia, glycosuria, or ketonuria; and maintenance of ideal body weight and of normal growth and development in children.

Both conventional and intensive insulin treatment regimens have been used in patients with type 1 or severe type 2 diabetes mellitus. Conventional insulin therapy generally has consisted of 1 or 2 subcutaneous injections of insulin per day (e.g., before breakfast and/or dinner) using a mixture of an intermediate-acting insulin such as isophane (neutral protamine Hagedorn [NPH]) insulin and a short-acting (e.g., insulin human) or rapid-acting insulin (e.g., insulin lispro, insulin glulisine, insulin aspart). However, in most patients with type 1 diabetes mellitus who are able to understand and carry out the treatment regimen, who are not at increased risk for hypoglycemic episodes, and who do not have other characteristics that increase risk or decrease benefit, ADA and many clinicians currently recommend the use of physiologically based, intensive insulin regimens (i.e., 3 or more insulin injections daily of basal [intermediate- or long-acting] and prandial [short- or rapid-acting] insulin or continuous subcutaneous insulin infusion with dosage adjusted according to the results of multiple daily blood glucose determinations [e.g., 3 or 4 times daily], dietary intake, and anticipated exercise). (See Cautions: Precautions and Contraindications.)

The goal of intensive insulin therapy is to achieve near-normal glycemic control (some experts currently recommend a HbA_1c target of less than 7% as a reasonable goal for nonpregnant adults); however, some clinicians recommend more stringent goals (i.e., HbA_1c target of 6.5% or less), especially if this can be achieved without substantial hypoglycemia or other adverse effects. Because HbA_1c is slightly lower in normal pregnancy than in normal nonpregnant women due to increased red blood cell turnover, ADA states that the ideal HbA_1c in pregnant women is less than 6% but that target HbA_1c may be relaxed to less than 7% to prevent hypoglycemia. ADA recommends a HbA_1c target of less than 7.5% for older adults and even less stringent glycemic goals (i.e., HbA_1c target of less than 8–8.5%) in older adults with multiple comorbidities, cognitive impairment, or functional dependence. In children and adolescents, ADA recommends an HbA_1c target of less than 7.5% in those with type 1 diabetes mellitus (with individualization according to the needs of the patient and family), although a target less than 7% is reasonable if it can be achieved without excessive hypoglycemia. In children and adolescents with type 2 diabetes mellitus, ADA recommends an HbA_1c target of less than 7% (or less than 6.5% if it can be achieved without substantial hypoglycemia or other adverse effects). (See Glycemic Control and Microvascular Complications under Uses: Diabetes Mellitus.)

Insulin regimens should be tailored to the specific clinical circumstances in individual patients. In patients without acute illness who are eating discrete meals, physiologic insulin requirements are composed of basal insulin (the amount of exogenous insulin per unit of time required to prevent unchecked gluconeogenesis and ketogenesis), meal-related (prandial or “bolus”) insulin, and supplemental (correction-dose) insulin to cover premeal or between-meal hyperglycemia. Correction-dose insulin should not be confused with “sliding-scale” insulin regimens, which generally consist of set amounts of short-acting insulin given several times daily based on capillary blood glucose measurements without regard to timing of food, presence or absence of other insulin requirements, or consideration of individual patient sensitivity to insulin; such regimens have been ineffective in hospitalized diabetic patients and are not recommended. Use of such sliding-scale regimens treats existing hyperglycemia rather than preventing its occurrence and may lead to rapid changes in blood glucose concentrations, which exacerbates both hyperglycemia and hypoglycemia. In addition, studies have found that sliding-scale insulin regimens prescribed upon hospital admission are likely to be used throughout the hospital stay without modifications for risk factors for hypoglycemia or hyperglycemia, prehospital insulin treatment regimens, or patient’s sensitivity to insulin.

In hospitalized patients, nutritional intake may not be provided principally as discrete meals, and insulin requirements should be considered to comprise basal and nutritional needs (e.g., IV dextrose, parenteral nutrition, enteral feedings, nutritional supplements, discrete meals). Determination of insulin requirements in hospitalized patients also must take into account counterregulatory responses to stress and/or illness and use of diabetogenic drugs (e.g., corticosteroids, vasopressors).

Subcutaneous insulin may be used to achieve glucose control in most noncritically ill hospitalized patients with diabetes mellitus, and various types of insulin may be used to achieve the daily insulin dose requirements. Subcutaneous insulin regimens in hospitalized patients generally consist of regularly scheduled injections of intermediate- or long-acting insulin to fulfill basal insulin requirements, with supplemental injections of rapid- or short-acting insulin as prandial and correction-dose insulin.

IV administration of regular insulin provides the greatest flexibility in dosing and is used in preference to subcutaneous administration in hospitalized patients with established diabetes mellitus or hyperglycemia (e.g., unrecognized diabetes mellitus, hospital-related hyperglycemia) for diabetic ketoacidosis, nonketotic hyperosmolar states, poorly controlled diabetes mellitus and widely fluctuating blood glucose concentrations, or severe insulin resistance. In critically ill patients, continuous IV insulin infusion has been demonstrated to be the most effective method for achieving glycemic control. Other situations that may require IV infusion of regular insulin include diabetic or hyperglycemic hospitalized patients who are not eating, have cardiogenic shock, or are experiencing exacerbated hyperglycemia during high-dose corticosteroid therapy. IV infusion of regular insulin also is used in general preoperative, intraoperative, and postoperative care, including heart or solid organ transplantation or surgery, or surgical patients requiring mechanical ventilation. IV regular insulin is also used as a dose-finding strategy in anticipation of initiation or reinitiation of subcutaneous insulin therapy in diabetic patients.

Combination Therapy with Other Antidiabetic Agents

Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of oral agent(s) and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested. Some experts currently state that GLP-1 receptor agonists may be preferred over insulin in most patients who require the addition of a more potent glucose-lowering drug to achieve glycemic control. In clinical studies in patients receiving oral antidiabetic agents who required further blood glucose lowering, the efficacy of add-on therapy with a GLP-1 receptor agonist or insulin was similar. Additionally, use of GLP-1 receptor agonists was associated with beneficial effects on body weight and a lower risk of hypoglycemia compared with insulin, at the cost of a greater incidence of adverse GI effects.

Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin prior to meals) and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy. In addition, oral antidiabetic therapy combined with insulin therapy may delay progression to either more intensive insulin monotherapy or to a second daytime injection of insulin with oral antidiabetic agents. However, combined therapy may increase the risk of hypoglycemic reactions.

Patients who have inadequate glycemic control with basal insulin (with or without metformin) may benefit from the addition of a GLP-1 receptor agonist, a sodium glucose cotransporter-2 (SGLT2) inhibitor, or a dipeptidyl peptidase-4 (DPP-4) inhibitor (if not already receiving one of these agents). The combination of insulin and a DPP-4 inhibitor, GLP-1 receptor agonist, or SGLT2 inhibitor enhances blood glucose reductions and may minimize weight gain without increasing the risk of hypoglycemia. DPP-4 inhibitors and GLP-1 receptor agonists also increase endogenous insulin secretion in response to food, which may reduce postprandial hyperglycemia. Patients whose blood glucose concentrations remain uncontrolled despite treatment with basal insulin (e.g., given as intermediate-acting or long-acting insulin at bedtime or in the morning) in combination with oral antidiabetic agents or a GLP-1 receptor may require intensification of their insulin regimens through the addition of short-acting or rapid-acting insulin injections at mealtimes to control postprandial hyperglycemia.

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., neuropathy, retinopathy, nephropathy) complications associated with the disease. HbA_1c concentration reflects the nonenzymatic glycosylation of other proteins throughout the body as a result of hyperglycemia over the previous 6–8 weeks and is used as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy). Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.

In the Diabetes Control and Complications Trial (DCCT), a reduction of approximately 50–75% in the risk of development or progression of retinopathy, nephropathy, and neuropathy was demonstrated during an average 6.5 years of follow-up in patients with type 1 diabetes mellitus receiving intensive insulin treatment (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) compared with that in patients receiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring of blood or urine glucose values, education about diet and exercise). However, the incidence of severe hypoglycemia, including multiple episodes in some patients, was 3 times higher in the intensive-treatment group than in the conventional-treatment group. The reduction in risk of microvascular complications in the DCCT correlated continuously with the reduction in HbA_1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in hemoglobin A_1c concentration). These data imply that any reduction in HbA_1c concentrations is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.

The DCCT was terminated prematurely because of the pronounced benefits of intensive insulin regimens, and all treatment groups were encouraged to institute or continue such intensive insulin therapy. In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term, open-label continuation phase of the DCCT, the reduction in the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has been maintained throughout 7 years of follow-up. In addition, the prevalence of hypertension (an important consequence of diabetic nephropathy) in those receiving conventional therapy has exceeded that of those receiving intensive therapy. Patients receiving conventional insulin therapy in the DCCT were able to achieve a lower HbA_1c concentration when switched to intensive therapy in the continuation study, although the average HbA_1c concentrations achieved during the continuation study were higher (i.e., worse) than those achieved during the DCCT with intensive insulin therapy. Patients who remained on intensive insulin therapy during the EDIC continuation study were not able to maintain the degree of glycemic control achieved during the DCCT; by 5 years of follow-up in the EDIC study, HbA_1c concentrations were similar in both intensive and conventional therapy groups. The EDIC study demonstrated that the greater the duration of chronically elevated plasma glucose concentrations (as determined by HbA_1c concentrations), the greater the risk of microvascular complications. Conversely, the longer patients can maintain a target HbA_1c concentration of 7% or less, the greater the delay in the onset of these complications.

In another randomized, controlled study (Stockholm Diabetes Intervention Study) in patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood glucose control (as determined by HbA_1c concentrations) was improved, and the incidence of microvascular complications (e.g., decreased visual acuity, retinopathy, nephropathy, decreased nerve conduction velocity) was reduced, with intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by intensive educational efforts) compared with that in patients receiving standard treatment (e.g., generally 2 insulin injections daily without intensive educational efforts).

Evidence from the United Kingdom Prospective Diabetes Study (UKPDS) and the Action in Diabetes and VAscular disease: preterax and diamicroN modified release Controlled Evaluation (ADVANCE) study in patients with type 2 diabetes mellitus generally is consistent with the same benefits of therapy with insulin and/or oral hypoglycemic agents on microvascular complications as those observed in type 1 diabetics receiving insulin therapy in the DCCT.

The UKPDS evaluated middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received conventional or intensive treatment regimens with an oral antidiabetic agent and/or insulin. Intensive insulin (i.e., long-acting [UltraLente, no longer commercially available in the US] or insulin human isophane [NPH] given once daily) therapy was initiated with a stepwise approach, in which the dosage of insulin is gradually increased, followed by addition of short-acting regular insulin at meals, and substitution of mixtures of short-acting and isophane (NPH) insulins given several times daily if preprandial or bedtime plasma glucose concentrations were above 126 mg/dL. Conventional treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 270 mg/dL without symptoms of hyperglycemia. Results of the UKPDS indicate greater beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive glucose-lowering therapy (median achieved HbA_1c concentration: 7%) in type 2 diabetics compared with that in the conventional treatment group (median achieved HbA_1c concentration: 7.9%). The overall incidence of microvascular complications was reduced by 25% with intensive therapy. Epidemiologic analysis of the UKPDS results indicates a continuous relationship between the risks of microvascular complications and glycemia, with a 35% reduction in risk for each 1% reduction in HbA_1c concentrations, and no evidence of a glycemic threshold.

The ADVANCE study also evaluated the relatively short-term effects (median follow-up: 5 years) of conventional or intensive therapy on the development of major vascular complications. The primary end point was the composite of major macrovascular (death from cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular (new or worsening nephropathy or retinopathy) events. While the incidence of the primary composite end point was reduced by approximately 10% in the ADVANCE study, the beneficial effect was due principally to a 21% reduction in microvascular events (nephropathy); there was no appreciable reduction in macrovascular outcomes. Intensive antidiabetic therapy (mean achieved HbA_1c concentration: 6.5%) was associated with a reduction in new or worsening nephropathy compared with conventional treatment (mean achieved HbA_1c concentration of 7.3%), but there was no effect on the development of new or worsening retinopathy. Results of the Veterans Affairs Diabetes Trial (VADT), another study similar in design to the ADVANCE study, also indicated that intensive therapy in patients with poorly controlled type 2 diabetes mellitus (median baseline HbA_1c concentration of 9.4%) did not lessen the rate of microvascular complications compared with standard antidiabetic therapy.

In the UKPDS, fasting plasma glucose and HbA_1c concentrations steadily increased over 10 years in the patients receiving conventional therapy, and more than 80% of these patients eventually required antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations within the desired goal of less than 270 mg/dL. In patients receiving intensive therapy initiated with insulin, chlorpropamide, or glyburide, fasting plasma glucose concentrations and HbA_1c concentrations decreased during the first year of the study. Subsequent increases in these indices of glycemic control after the first year paralleled that in the conventional therapy group for the remainder of the study, indicating slow decline of pancreatic β-cell function and loss of glycemic control regardless of intensity of therapy. In contrast to UKPDS, no diminution in the effect on HbA_1c or fasting blood glucose concentrations with either intensive or conventional therapy was observed in ADVANCE or VADT over a median follow-up of 5 or 5.6 years, respectively.

Macrovascular Outcomes and Cardiovascular Risk Reduction

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus. In contrast to the demonstrated benefits of intensive glycemic control on microvascular complications, antidiabetic therapy titrated with the goal of reducing HbA_1c to near-normal concentrations (6–6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes. Data from recent, relatively short-term (median duration: 3.5–5.6 years) clinical trials (ADVANCE, VADT, Action to Control Cardiovascular Risk in Diabetes [ACCORD]) in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease (e.g., mean age 60–66 years, 8–12 years older than patients in UKPDS, disease duration of 8–11.5 years, known cardiovascular disease or multiple risk factors suggestive of atherosclerosis present in approximately one-third of patients) and were receiving intensive antidiabetic therapy (median achieved HbA_1c concentrations of 6.3, 6.4, and 6.9% in ADVANCE, ACCORD, and VADT studies, respectively) have not demonstrated substantial reductions in the incidence of cardiovascular events beyond that associated with aggressive management of known cardiovascular risk factors (e.g., blood pressure control, dyslipidemia, smoking cessation).

However, results of long-term follow-up (10–11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus. Data from the DCCT-EDIC study, which reported the results of 11 years of follow-up from DCCT, have shown that patients with type 1 diabetes mellitus and without cardiovascular disease who were randomized to intensive insulin therapy at a relatively young age (13–40 years of age at time of randomization) had a 42% reduction in the risk of any cardiovascular event (i.e., myocardial infarction, stroke, angina, need for revascularization, cardiovascular death) and a 57% reduction in the risk of first nonfatal myocardial infarction, stroke, or cardiovascular death compared with those outcomes in patients randomized at baseline to conventional insulin therapy. Similarly, 10-year follow-up data from the UKPDS indicate that intensive therapy with sulfonylurea/insulin or metformin reduced the risk of myocardial infarction by 15 or 33%, respectively.

In middle-aged patients with well-established type 2 diabetes mellitus, some evidence of a cardiovascular benefit with intensive antidiabetic therapy also has been observed in certain subsets of patients with characteristics similar to those in the DCCT and UKPDS, such as those with a shorter duration of diabetes, lower baseline HbA_1c concentrations, and/or absence of known cardiovascular disease. In the ACCORD study, prespecified subgroup analyses suggested that patients with no cardiovascular events at study entry and those with a baseline HbA_1c concentration of 8% or less had a reduction in primary cardiovascular outcome (myocardial infarction, stroke, cardiovascular death). Posthoc subgroup analyses of the VADT suggested that patients with a duration of diabetes of less than 12 years appeared to have a cardiovascular benefit with intensive antidiabetic therapy while such therapy had a neutral or adverse effect on the development of cardiovascular disease in those with a longer duration of diabetes.

A relationship between glycemia (as determined by fasting glucose or HbA_1c concentration) and vascular intima-media thickness, a surrogate marker for coronary and cerebrovascular disease, has been demonstrated in patients with and without diabetes mellitus. The delayed benefits of intensive antidiabetic therapy on risk of cardiovascular events in patients with diabetes mellitus in whom such therapy was initiated relatively early in the course of the disease may relate to reduction in the accumulation of advanced glycosylation end products that lead to the development of atherosclerosis over a period of years. Clinical data from long-term follow-up studies and subgroup analyses of relatively short-term studies suggest that intensive therapy may delay or prevent the progression of cardiovascular disease optimally in those without substantial atherosclerosis while providing minimal protection from cardiovascular events when the disease is well established. Subset analyses from EDIC and VADT examining carotid intima-media thickness and vascular calcification also suggest that intensive therapy reduces the progression of atherosclerosis in those with minimal or less advanced atherosclerosis. Data from the EDIC follow-up study to DCCT suggest that patients receiving intensive insulin therapy during DCCT had less progression of carotid intima-media thickness 6 years after completion of the DCCT than patients receiving conventional therapy. The lower HbA_1c concentration attained in the intensive therapy group during DCCT was associated with a decrease in the progression of carotid-intima media thickness at the end of the EDIC follow-up study. Limited data from VADT suggest that middle-aged patients with less coronary arterial calcification at baseline (coronary artery calcification Agatson scores of less than 100) had a reduction in cardiovascular events with intensive treatment. In contrast, patients in VADT with higher coronary arterial calcification at baseline (coronary artery calcification Agatson scores exceeding 100) did not have a reduction in cardiovascular events with intensive treatment.

Current strategies for intensive treatment of hyperglycemia and the associated increased risk of severe hypoglycemia in patients with advanced type 2 diabetes mellitus may have counterbalancing consequences for cardiovascular disease (e.g., myocardial ischemia/infarction, increased cardiovascular morbidity and mortality, weight gain, other metabolic changes). Potential risks of very intensive therapy may outweigh benefits in patients with a very long duration of diabetes; known history of severe hypoglycemia; advanced atherosclerosis or other cardiovascular disease; positive risk factors for cardiovascular disease; or advanced age or frailty. In the ACCORD study, patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease and received intensive antidiabetic therapy had a 22 or 35% increase in the relative risk of all-cause or cardiovascular death, respectively, compared with that in patients receiving conventional antidiabetic therapy. Differences in mortality in patients receiving intensive therapy became apparent after 1 year and continued throughout follow-up until premature discontinuance of the intensive-therapy regimen after a mean of 3.5 years of follow-up. Exploratory analyses of episodes of severe hypoglycemia, differences in the use of ancillary drug therapy between those receiving conventional and intensive therapy, weight changes, achieved HbA_1c concentrations and rate of achievement of target HbA_1c concentrations, drug interactions, and other factors did not provide an explanation for the increased mortality observed in the ACCORD study. However, intensive therapy was not associated with an increase in mortality in the ADVANCE trial, another trial of similar design, despite achievement of a target HbA_1c concentration (median of 6.3%) that was similar to that achieved in the ACCORD trial (median of 6.4%). Differences in patient characteristics and study design between the ADVANCE and ACCORD trials may provide additional hypotheses regarding discrepancies between the effects of intensive therapy on mortality in these trials. Patients in the ADVANCE trial had less-advanced diabetes (disease duration 2–3 years shorter than in ACCORD) and had lower baseline HbA_1c despite use of insulin in only a small proportion of patients (1.5% of patients in the ADVANCE study were receiving insulin at baseline versus 35% of those in the ACCORD study). HbA_1c concentration was lowered more gradually to the target goal in the ADVANCE trial (several years versus 1 year to achieve maximum separation between HbA_1c in the ADVANCE or ACCORD trial, respectively); the target goal was achieved in the ADVANCE trial without appreciable weight gain and with fewer episodes of severe hypoglycemia than in ACCORD or VADT. Severe hypoglycemia occurred in less than 3%, approximately 16%, or 21% of patients receiving intensive therapy in ADVANCE, ACCORD, or VADT, respectively. Future combined analyses of the ADVANCE, ACCORD, and other trials should provide further insight into the effects of intensive antidiabetic therapy on the development of macrovascular events.

Data from clinical trials also support the use of certain oral antidiabetic agents (e.g., some SGLT2 inhibitors [canagliflozin, empagliflozin] or GLP-1 receptor agonists [liraglutide, semaglutide]) to reduce the risk of cardiovascular events in patients with type 2 diabetes mellitus and established cardiovascular disease. For further discussion on the use of certain SGLT2 inhibitors or GLP-1 receptor agonists for cardiovascular risk reduction, see the individual drug monographs in 68:20.

Treatment Goals

ADA generally recommends the same blood glucose and HbA_1c concentration goals for all nonpregnant adults with type 1 or type 2 diabetes mellitus but states that less stringent treatment goals may be appropriate for certain patients. ADA currently recommends target preprandial and peak postprandial (1–2 hours after the beginning of a meal) plasma glucose concentrations of 80–130 and less than 180 mg/dL, respectively, and HbA_1c concentrations of less than 7% (based on a nondiabetic range of 4–6%) in general in adults with type 1 or 2 diabetes mellitus who are not pregnant. HbA_1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA_1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA_1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1–2 hours after the start of a meal.

More stringent treatment goals (i.e., HbA_1c concentrations even lower than the general goal of less than 7 or less than 6% in nonpregnant or pregnant patients, respectively, can be considered in selected patients. An individualized HbA_1c concentration goal that is closer to normal without risking severe hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. ADA recommends target preprandial and 2-hour postprandial blood glucose concentrations less than 95 and 120 mg/dL, respectively, in women with gestational diabetes mellitus. (See Cautions: Pregnancy and see Uses: Gestational Diabetes Mellitus.)

In hospitalized patients, ADA recommends a target blood glucose concentration of 140–180 mg/dL for the majority of critically ill and noncritically ill patients. Higher target glucose concentrations may be appropriate in terminally ill patients, those with severe comorbidities, and in patient care settings where frequent glucose monitoring is not feasible. An HbA_1c concentration should be obtained in all hospitalized diabetic patients if a current (previous 3 months) test is not available. Hospitalized patients who have hyperglycemia (random blood glucose concentration exceeding 140 mg/dL) should have a follow-up appointment with a clinician within 1 month of hospital discharge.

Treatment goals should be individualized, and specific target values for blood glucose and HbA_1c concentration appropriately adjusted, based on the patient’s capacity to understand and adhere to the treatment regimen, the risk of severe hypoglycemia, and other patient factors that may increase risk or decrease benefit (e.g., young children [less than 6 years of age]; advanced age or frailty; cognitive or functional impairment; advanced microvascular or macrovascular complications or extensive comorbid conditions; other diseases that materially shorten life expectancy). Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA_1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin. Achievement of HbA_1c concentrations less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy. Higher target blood glucose concentrations are advisable in patients with a history of recurrent, severe hypoglycemia and in patients with hypoglycemic unawareness, after they have been advised of the risks of intensive insulin therapy. Some clinicians consider it inappropriate to institute intensive therapy in these patients because they may have defective glucose counterregulatory responses. Severe or frequent hypoglycemia is an absolute indication for modification of treatment regimens, including setting higher glycemic goals. Clinicians should be vigilant in the prevention of severe hypoglycemia in patients with advanced diabetes mellitus and should not aggressively attempt to achieve near-normal HbA_1c concentrations in patients in whom such a target cannot be achieved with reasonable ease and safety.

Data from a decision model based on extrapolated benefits of intensive glycemic control in type 1 diabetic patients (i.e., as demonstrated in the Diabetes Control and Complications Trial [DCCT]) suggest substantial benefits (i.e., in terms of reduction in years of blindness or end-stage renal disease) of reducing HbA_1c to near-normal concentrations (e.g., from 9 to 7%) in patients with early-onset (i.e., at 40–50 years of age) type 2 diabetes mellitus. Geriatric patients with a life expectancy long enough to reap the benefits of long-term intensive diabetes management who are active, cognitively intact, and willing to self-manage diabetes mellitus should be treated using the same goals for younger adults with diabetes mellitus. For frail geriatric patients, patients with an intermediate remaining life expectancy, and those in whom the risks of intensive glycemic control appears to outweigh the benefits, a less stringent target HbA_1c concentration such as 8% is appropriate. An even less stringent target HbA_1c concentration (i.e., less than 8.5%) may be considered in geriatric patients in very poor health and with a limited life expectancy. Hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all geriatric patients.

In children and adolescents with type 1 diabetes mellitus, ADA recommends target preprandial and bedtime/overnight plasma glucose concentrations of 90–130 and 90–150 mg/dL, respectively, and HbA_1c concentrations of less than 7.5% (a lower goal of less than 7% may be reasonable if it can be achieved without excessive hypoglycemia). Special consideration should be given to the risk of hypoglycemia in young children (younger than 6 years of age) who may be unable to recognize, articulate, and/or manage hypoglycemia. However, some data indicate that young children can achieve target HbA_1c concentrations without increased risk of severe hypoglycemia. In children and adolescents with type 2 diabetes mellitus, ADA recommends a target HbA_1c concentration of less than 7% in those patients treated with oral antidiabetic agents alone; more stringent targets (i.e., less than 6.5%) may be appropriate for certain individuals who can achieve this concentration without substantial hypoglycemia or other adverse effects. Treatment goals should be individualized and the benefits of achieving a lower HbA_1c concentration should be weighed against the risks of hypoglycemia and the developmental burdens of intensive antidiabetic regimens in children and adolescents.

Gestational Diabetes Mellitus

Gestational diabetes mellitus is a condition in which a woman without clearly overt diabetes mellitus prior to pregnancy develops glucose intolerance (i.e., elevated blood glucose concentrations) during pregnancy. (See Insulin Use during Pregnancy under Dosage and Administration: Dosage.) Gestational diabetes mellitus may be associated with macrosomia, birth complications, and an increased risk of maternal type 2 diabetes mellitus after pregnancy. (See Cautions: Pregnancy.) ADA states that insulin therapy is preferred in patients with gestational diabetes who, despite dietary management (medical nutrition therapy [MNT]), have fasting blood glucose concentrations of 95 mg/dL or higher, 1-hour postprandial blood glucose concentrations of 140 mg/dL or higher, or 2-hour postprandial blood glucose concentrations of 120 mg/dL or higher. Long-acting and intermediate-acting insulins used in gestational diabetes mellitus include NPH insulin, insulin glargine, and insulin detemir. When short-acting insulins are used, insulin lispro and insulin aspart are preferred over regular human insulin because of the former drugs' rapid onset of action. Oral antidiabetic agents (e.g., glyburide, metformin) are not recommended as first-line therapy because these drugs are able to cross the placenta and data on the safety of these drugs in offspring are lacking,

Women with gestational diabetes should be evaluated for prediabetes or persistent diabetes mellitus at least 4–12 weeks postpartum using a 75-g, 2-hour oral glucose tolerance test. Follow-up should be performed every 1–3 years thereafter if the results of the postpartum glucose tolerance test at 4–12 weeks are normal. Women with impaired glucose tolerance in the postpartum period should attempt lifestyle changes to prevent or delay the progression to diabetes mellitus; initiating therapy with metformin also may be considered. Subsequent pregnancies should be planned to ensure optimal glycemic control throughout pregnancy.

Critical Illness

Moderate glycemic control has been shown to reduce morbidity and mortality in hospitalized patients with critical illness^{† [off-label]} requiring intensive care. Randomized, clinical studies and meta-analyses of studies in surgical patients have indicated lower rates of mortality and stroke with a perioperative blood glucose target of less than 180 mg/dL compared with a target of less than 200 mg/dL; no substantial additional benefit was found with more stringent glycemic control (i.e., blood glucose concentration less than 140 mg/dL). Some experts recommend a blood glucose target of 140–180 mg/dL in most hospitalized patients; more stringent goals (i.e., 110–140 mg/dL) may be appropriate in selected patients if substantial hypoglycemia can be avoided. While some experts recommend initiating insulin therapy when blood glucose concentrations reach 180 mg/dL or higher, other clinicians recommend initiating therapy at lower blood glucose concentrations (e.g., 150 mg/dL or higher). When insulin is used in critically ill patients, most experts recommend that insulin be administered by continuous IV infusion.

Acute Myocardial Infarction

Data from several clinical trials in patients with ST-segment-elevation myocardial infarction (STEMI) suggest that blood glucose concentrations are positively correlated with mortality. Current data suggest that high-dose regular insulin in combination with IV potassium chloride and dextrose (d-glucose) (referred to as glucose-insulin-potassium or GIK therapy) is not beneficial in reducing mortality following ST-segment-elevation myocardial infarction (STEMI) and may even be harmful. The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) state that blood glucose levels should be maintained below 180 mg/dL if possible while avoiding hypoglycemia and that there is no established role for GIK infusions in patients with STEMI.

Hyperalimentation Adjunct

Regular insulin has been added to IV hyperalimentation solutions to assure proper utilization of glucose and reduce glycosuria in diabetic patients. Addition of insulin also may be beneficial in nondiabetic patients whose glycosuria cannot be controlled by adjustment of the infusion flow rate. Because not all nondiabetic patients receiving hyperalimentation therapy require insulin and because of variable adsorption of insulin to the IV infusion system, there is debate over the value of adding insulin to hyperalimentation solutions. If insulin is required in patients receiving hyperalimentation therapy, some clinicians prefer subcutaneous or direct IV injection. Since insulin requirements may vary abruptly in patients receiving hyperalimentation, insulin dosage must be carefully adjusted based on frequent determinations of blood and urine glucose concentrations.

Growth Hormone Reserve Test

IV injection of regular insulin is used as a provocative test for growth hormone secretion.

Hyperkalemia

Regular insulin has also been added to IV dextrose infusions to facilitate an intracellular shift of potassium in the treatment of severe hyperkalemia.

Insulins General Statement Dosage and Administration

Administration

Insulin usually is administered by subcutaneous injection. The subcutaneous route is preferred to IM administration because it provides more prolonged absorption and is less painful. Regular insulin may be given IV or IM under medical supervision with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia and hypokalemia. Regular insulin also may be administered IV for general perioperative use and during the postoperative period following cardiac surgery or organ transplantation; in patients with diabetic ketoacidosis, nonketotic hyperosmolar state, cardiogenic shock, critical illness, or exacerbated hyperglycemia during high-dose corticosteroid therapy, or in those who are not eating; and to facilitate determination of optimal dosage prior to initiating or reinitiating subcutaneous insulin therapy in patients with type 1 or type 2 diabetes mellitus. Rapid-acting insulins (e.g., insulin lispro, insulin glulisine, insulin aspart) have been used IV, but such use offers no advantage over regular insulin (insulin human).

Subcutaneous administration of insulin has been made into the thighs, upper arms, buttocks, or abdomen using a 25- to 28-gauge needle 1.3–1.6 cm in length. With the availability of smaller 30- and 31-gauge needles, the needle tip may become bent to form a hook, which can lacerate tissue or break off to leave needle fragments within the skin. The medical consequences of these needle fragments are unknown but may increase the risk of lipodystrophy or other adverse effects. It is essential to use only syringes calibrated for the particular concentration of insulin administered. To avoid painful injections, patients should inject insulin that is at room temperature. To prevent air bubbles in an insulin pen, the injection pen should be primed with 2 units of insulin before injection; patients should avoid leaving a needle in the pen between injections. In most individuals, a fold of the skin is grasped lightly with the fingers at least 7.6 cm apart and the needle inserted at a 90° angle; thin individuals or children may need to pinch the skin and inject at a 45° angle to avoid IM injection of the dose, especially in the thigh area. Routine aspiration (to check for inadvertent intravascular injection as indicated by the presence of blood in the syringe) after subcutaneous injection of insulin generally is not necessary. The insulin should be injected over a period of at least 6 seconds; presence of air bubbles could interfere with accurate dosing. The push button of the insulin injection pen or other compatible insulin delivery device should continue to be depressed during drug delivery until the needle is withdrawn from the skin to ensure that the full dose has been delivered. Preparations of insulin suspensions that are injected slowly may clog the tip of the needle, preventing completion of the injection. The injection site should be pressed lightly for a few seconds after the needle is withdrawn but should not be rubbed. A planned rotation of sites within one area should be followed so that any one site is not injected more than once every 1–2 weeks. Rotating injection sites within one anatomic region (e.g., rotating injections systematically in the abdominal area) rather than selecting a different anatomic region is recommended to decrease day-to-day variability in insulin absorption. Variability in insulin absorption by injection site is reduced with insulin lispro compared with that with insulin human.

The American Diabetes Association (ADA) states that if an insulin injection seems particularly painful or if blood or clear fluid is observed after withdrawing the needle, patients should be instructed to apply pressure to the injection site for 5–8 seconds without rubbing and perform blood glucose monitoring more frequently that day. If the patient suspects that an appreciable portion of the insulin dose was not administered, blood glucose should be checked within a few hours after the injection and supplemental insulin administered if necessary. (See Dosage and Administration: Administration.)

Although most insulin syringes have been designed to eliminate dead-space volume, dosage errors attributable to the dead-space volume within some insulin syringes may result when 2 types of insulin are mixed in the syringes. Patients stabilized on a particular order of mixing and using a particular brand and design of syringe should not change these factors without first consulting their physician.

Alternatively, specialized delivery devices (e.g., subcutaneous controlled-infusion devices [pumps], insulin pens) have been used to administer insulins, and the manufacturers’ instructions should be consulted for proper methods of assembly, administration (including dosage calibration), and care.

Dosage

Dosage of insulin injection is always expressed in USP units. The number of units in a given volume varies with the strength of the preparation employed. Commercially available insulin human (regular insulin) preparations contain 100 (U-100) or 500 (U-500) units per mL. All commercially available preparations have standardized label colors to facilitate identification. Concentrated (U-500) insulin human injection is indicated in diabetic patients with daily insulin requirements exceeding 200 units, so that a large dose may be administered subcutaneously in a relatively small volume.

Insulin Regimens

Both conventional and intensive insulin treatment regimens have been used in patients with type 1 or type 2 diabetes mellitus. (See Glycemic Control and Microvascular Complications under Uses: Diabetes Mellitus.) Conventional therapy generally consists of 1 or 2 subcutaneous doses of insulin per day (e.g., at breakfast and/or dinner), usually with a mixture of intermediate-acting and rapid- or short-acting insulin; blood glucose concentrations generally are monitored 1–4 times daily. Commercially available premixed insulin combinations may be used if the insulin ratio is appropriate to the patient’s insulin requirements; these preparations may be especially useful in patients with type 2 diabetes mellitus who eat small lunches, geriatric patients, those unable to use more complex regimens, and those with visual impairment. Premixed insulins offer little flexibility for meal size and time, particularly in patients with severe insulin deficiency (i.e., most patients with type 1 diabetes mellitus), since such mixtures of insulins may not provide enough insulin for lunchtime needs.

The selection of a particular insulin treatment program is dependent on a number of factors including the age of the patient, the nature of the disease (ketoacidosis-prone or ketoacidosis-resistant), the presence or absence of symptoms of hyperglycemia, and the experience and judgment of the clinician. Initial total daily insulin dosages in adults and children with type 1 diabetes mellitus generally range from 0.4–1 units/kg; basal insulin requirements with an intermediate-acting or long-acting insulin usually comprise 40–60% of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin. Alternatively, some manufacturers recommend that basal insulin comprise approximately one-third to one-half of the total daily insulin dosage in insulin-naive patients with type 1 diabetes mellitus, with the remainder of the daily dosage given preprandially as rapid- or short-acting insulin.

To initiate therapy in patients with severe symptomatic diabetes, unstable type 1 diabetes, severe metabolic dysfunction, or diabetes with complications, hospitalization and the use of regular insulin may be advisable. Some clinicians suggest that in general, insulin therapy in adults of normal weight may be initiated with 15–20 units daily of an intermediate-acting (e.g., insulin human isophane [NPH]) or long-acting (e.g., insulin glargine, insulin detemir) insulin given subcutaneously before breakfast, dinner, or bedtime; obese patients, because of associated insulin resistance, may initially be given 25–30 units daily. Use of rapid- or short-acting insulin alone before meals may rarely be sufficient in newly diagnosed patients with diabetes mellitus who have some residual basal endogenous insulin secretion.

In patients with type 2 diabetes mellitus who have secondary failure to oral antidiabetic agent(s), an intermediate-acting or long-acting insulin may be added to the existing oral antidiabetic regimen; premixed insulin combinations containing insulin human isophane (NPH) may be given once daily with the evening meal in such patients. Initial dosage of a basal insulin (e.g., intermediate-acting insulin at bedtime, long-acting insulin at bedtime or morning) in patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic agent(s) generally is 0.1–0.2 units/kg daily or 10 units daily. Patients should be advised that initial insulin dosages are approximations and that frequent dosage adjustments will be required over the next few weeks. ADA recommends the use of an evidence-based insulin dosage titration algorithm (i.e., increase of 2 units every 3 days to achieve target fasting plasma glucose concentration).

Virtually all patients with type 1 diabetes mellitus and many with type 2 diabetes mellitus will require 2 or more insulin injections daily with intermediate-acting and/or rapid- or short-acting insulins to maintain adequate control of blood glucose throughout the night while avoiding daytime hypoglycemia. ADA currently recommends the same blood glucose and HbA_1c concentration goals for all nonpregnant adults with type 1 or type 2 diabetes mellitus but states that less stringent treatment goals may be appropriate for certain patients. (See Treatment Goals under Uses: Diabetes Mellitus.) If a patient's HbA_1c remains above target despite the use of adequately titrated basal insulin or daily basal insulin dosages exceeding 0.7–1 unit/kg, or despite achieving target fasting plasma glucose concentrations, prandial insulin should be initiated. Prandial insulin should be given with the largest meal of the day or the meal associated with the greatest postprandial plasma glucose concentration. More prandial insulin may be added in a stepwise manner (i.e., 2, then 3 additional injections) to a patient's regimen as needed. The recommended starting dose of prandial insulin in patients with type 2 diabetes mellitus is either 4 units or 10% of the basal dose at each meal.

Intensive insulin therapy generally refers to regimens consisting of 3 or more doses of insulin per day administered by subcutaneous injection or continuous subcutaneous infusion of insulin via an insulin pump, with dosage adjustments made according to the results of frequent (e.g., at least 3–4 times daily) self-monitored blood glucose determinations and anticipated dietary intake and exercise. Since patients receiving intensive insulin therapy generally will achieve greater postprandial glycemic control than those receiving conventional therapy because of increased use of rapid- or short-acting insulin, patients receiving conventional insulin regimens generally will require a smaller total daily insulin dosage when switched to an intensive insulin regimen.

In patients with type 1 diabetes mellitus who have been receiving conventional insulin therapy (e.g., twice-daily doses of intermediate-acting and rapid- or short-acting insulin given before breakfast and the evening meal), intensive insulin therapy may be initiated with a stepwise approach in which the number of insulin injections per day is gradually increased until near-normal postprandial and basal glycemic control is attained. Alternatively, a dose of long-acting insulin (e.g., insulin glargine) may be administered in the evening in conjunction with doses of a rapid-acting (e.g., insulin lispro, insulin aspart, insulin glulisine) or short-acting (e.g., regular) insulin before each meal. Because of insulin degludec's very long duration of action (e.g., 42 hours) and low variability in insulin concentrations over the dosing interval, it can be administered at any time of day in adults, which may provide greater dosing flexibility than other basal insulins such as insulin detemir or insulin glargine.

A subcutaneous insulin regimen in hospitalized patients is comprised of regularly scheduled subcutaneous injections (basal and prandial) and correctional (supplemental) injections as an adjunct to regularly scheduled insulin to meet nutritional needs. Premixed insulin regimens are not routinely recommended for in-hospital use. Daily insulin dose requirements can be met by various types of insulin, depending on the particular clinical situation. Since insulin human has a longer duration of action than more rapid-acting analogues, use of correctional insulin for premeal or between-meal hyperglycemia before previously administered regular insulin has reached a peak effect may lead to hypoglycemia.

IV insulin is considered the standard of care for management of hyperglycemia in critically ill patients. IV infusion of regular insulin may be used in hospitalized patients with diabetic ketoacidosis, nonketotic hyperosmolar states, cardiogenic shock, exacerbated hyperglycemia during high-dose corticosteroid therapy, poorly controlled diabetes mellitus and widely fluctuating blood glucose concentrations, severe insulin resistance, or as a dose-finding strategy prior to initiation or reinitiation of subcutaneous insulin therapy. IV administration of regular insulin also is recommended during general perioperative care and the postoperative period following cardiac surgery or organ transplantation or when a prolonged postoperative period with no oral intake is anticipated (e.g., cardiothoracic, major abdominal, CNS surgery). The initial perioperative maintenance insulin infusion rate in patients undergoing major surgery is 0.2 units/kg per hour. When regular insulin is administered by continuous IV infusion, bedside glucose testing should be performed every hour until blood glucose concentrations are stable for 6–8 hours; the frequency of testing can then be reduced to every 2–3 hours. Dosing algorithms should achieve correction of hyperglycemia in a timely manner, provide a method to adjust the insulin infusion rate required to maintain blood glucose concentrations within a defined target range, and allow for the adjustment of insulin infusion maintenance rate as patient’s insulin sensitivity or carbohydrate intake changes.

When normoglycemia has been reached after IV insulin infusion in hospitalized patients, some patients will require subcutaneous insulin maintenance therapy and some patients with type 2 diabetes mellitus will have therapy transferred to oral antidiabetic agents. For those who require subcutaneous insulin, basal insulin should be administered 2–4 hours prior to discontinuance of the IV insulin infusion. Converting to basal insulin at 60–80% of the daily IV insulin infusion dose has been shown to be effective.

Data indicate that continuous subcutaneous insulin injection (i.e., insulin pump) may provide a slight advantage in reducing HbA_1c and the risk of severe hypoglycemia compared with multiple daily insulin injections. ADA recommends that most adults, children, and adolescents with type 1 diabetes mellitus should be treated with intensive insulin therapy with multiple daily insulin injections or an insulin pump. ADA also states that an insulin pump may be considered in all children and adolescents requiring insulin therapy, especially those younger than 7 years of age.

Any change of insulin preparation or dosage regimen should be made with caution and only under medical supervision. Should a brand of insulin become unavailable temporarily, the same insulin formulation from another manufacturer may be substituted. Although it is not possible to clearly identify which patients will require a change in dosage when therapy with a different preparation is started, it is known that a limited number of patients will require such a change. Adjustments may be needed with the first dose or may occur over a period of several weeks. In general, the usual initial dosage reduction in these patients is about 10–20%.

Considerations in Monitoring Insulin Therapy

Patients receiving intensive insulin regimens should self-monitor blood glucose concentrations prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when low blood glucose is suspected, after treating low blood glucose (until normoglycemic), and prior to critical tasks (e.g., driving); this may require patients to test up to 6–10 times daily. Patients not receiving intensive insulin regimens, such as those receiving basal insulin only, should at least assess fasting blood glucose concentrations in order to facilitate dosage adjustments; data regarding the exact number of times a patient should ideally check their blood glucose concentrations are lacking in this patient population. Blood glucose concentrations may be influenced by food consumption, exercise, stress, hormonal changes, illness, travel, insulin absorption rates, and insulin sensitivity.

If preprandial blood glucose concentrations consistently exceed 300 mg/dL, patients should be instructed to monitor for ketones in urine or blood (β-hydroxybutyric acid). The presence of ketones in urine or blood may indicate insulin deficiency or insulin resistance; in such cases, clinicians should consider possible causes of insulin deficiency, such as a missed insulin dose or illness, and supplement the dosage of insulin as appropriate.

If blood glucose concentrations are unexpectedly high, additional doses of short- or rapid-acting insulin (e.g., up to 15% of the regular dose) may be necessary to reestablish glycemic control. Blood glucose concentrations should be reassessed approximately 4 hours after additional doses have been given. If blood glucose concentrations are still high, another dose of insulin (e.g., 5% of the regular dose) may be given to achieve glycemic control. Records of self-monitored blood glucose concentrations should be compared with clinician-obtained values for evidence of faulty injection technique or patient noncompliance. Patients should contact their clinician if extra insulin fails to reduce high blood glucose concentrations and/or ketonuria or ketonemia.

Insulin Use During Pregnancy

Insulin requirements generally increase, sometimes dramatically, in pregnant patients with diabetes. In addition, pregnancy may induce a temporary state of diabetes in patients not previously known to be diabetic (i.e., gestational diabetes mellitus). (See Uses: Gestational Diabetes Mellitus.) The increased need for insulin generally begins in the second trimester, and an insulin regimen should be established during preconception care visits. In high-risk pregnancies, hospitalization may be required to ensure an appropriate insulin regimen. Since the renal threshold for glucose may be decreased during pregnancy, blood glucose determinations are needed to ascertain the effectiveness of therapy.

In patients with gestational diabetes mellitus requiring insulin therapy, the usual initial total daily dosage is 0.7–1 units/kg, given in divided doses. In women with gestational diabetes, if fasting and postprandial hyperglycemia are present, an insulin regimen consisting of long-acting or intermediate-acting insulin in conjunction with short-acting insulin is recommended. In women with gestational diabetes mellitus who have only isolated high blood glucose concentrations at specific times of the day, an insulin regimen which focuses on the times when hyperglycemia occurs is preferred (e.g., administering short-acting insulin prior to certain meals of the day).

Maternal blood glucose monitoring in women with gestational diabetes mellitus should be instituted to assess glycemic control. Self-monitoring of fasting and postprandial blood glucose concentrations are recommended in women with gestational diabetes mellitus and pre-existing diabetes mellitus. Additionally, pregnant women who are using an insulin pump or basal-bolus insulin therapy should also test preprandial blood glucose concentrations in order to facilitate insulin dosage adjustments.

Cautions for Insulins General Statement

Endocrine and Metabolic Effects

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, and monitoring of blood glucose concentrations is recommended for all patients with diabetes. The timing of hypoglycemia depends on the time of peak action of insulin in relation to food intake (absorption) and/or exercise. The risk of hypoglycemia is increased in patients with unstable type 1 diabetes, autonomic neuropathy, or irregular eating patterns and in patients receiving intensive insulin therapy or who exercise without making appropriate insulin dosage adjustments or ingesting extra food. Hypoglycemia also may result from increased insulin absorption rates (e.g., increased skin temperature resulting from sunbathing or exposure to hot water). Hypoglycemic reactions also have been reported in patients who were transferred from beef to pork insulin or mixed beef-pork preparations or from pork insulin (no longer commercially available in the US) to insulin human; however, preparations containing beef insulin alone or in combination with pork insulin are no longer commercially available in the US. Hypoglycemia also may occur in association with increased insulin sensitivity that accompanies secondary adrenocortical insufficiency or Addison’s disease.

Symptoms of hypoglycemia usually are manifested when the administered insulin reaches its peak action and may include hunger, pallor, fatigue, mild or profuse perspiration, headache, nausea, palpitation, numbness of the mouth, tingling in the fingers, tremors, muscle weakness, blurred or double vision, hypothermia, uncontrolled yawning, nervousness, irritability or agitation, difficulty in concentrating, mental confusion, aggressiveness, drowsiness, tachycardia, shallow breathing, seizures, and loss of consciousness. Insulin overdosage may result in psychic disturbances such as aphasia, personality changes, or maniacal behavior. Homeostatic responses to hypoglycemia include cessation of insulin release and mobilization of counterregulatory hormones such as glucagon, epinephrine, and less acutely, growth hormone and cortisol. These responses become defective, and early warning signs of hypoglycemia may be diminished or absent, in patients with long-standing type 1 diabetes mellitus diabetic neuropathy, and/or those receiving drugs such as β-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia (e.g., tremors, palpitations) or intensive insulin therapy. If untreated, severe prolonged hypoglycemia can result in irreversible brain damage.

Hypoglycemic reactions in geriatric diabetic patients may mimic a cerebrovascular accident. In addition, because of an increased incidence of macrovascular disease in geriatric patients with type 2 diabetes mellitus, such patients may be more vulnerable to serious consequences of hypoglycemia, including fainting, seizures, falls, stroke, silent ischemia, myocardial infarction, or sudden death.

The more vigorous the attempt to achieve euglycemia, the greater the risk of hypoglycemia. In the Diabetes Control and Complications Trial (DCCT), the incidence of severe hypoglycemia, including multiple episodes in some patients, was 3 times higher in patients receiving intensive insulin treatment (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) than in those receiving conventional treatment (1 or 2 insulin injections daily, self-monitoring of blood or urine glucose values, education about diet and exercise). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in patients with type 2 diabetes mellitus, the incidence of severe hypoglycemia (episodes requiring medical assistance) was 10.5 or 3.5% in patients receiving intensive (median achieved HbA_1c concentrations: 6.4%) or conventional (median achieved HbA_1c concentrations: 7.5%) treatment, respectively. Hypoglycemia is the major risk that must be considered against the benefits of intensive insulin therapy. An increased rate of mortality was noted among patients in the ACCORD trial receiving intensive treatment; preliminary exploratory analyses evaluating numerous variables, including hypoglycemia, were unable to identify an explanation for increased mortality in the intensive therapy group. However, in DCCT, there was no increase in mortality or permanent neuropsychologic morbidity associated with the increased rate of severe hypoglycemia in that study. Since symptoms of hypoglycemia may develop suddenly, diabetic patients should be instructed to carry a ready source of carbohydrate as well as some form of diabetic identification. Episodes of late postprandial hypoglycemia (i.e., 4–6 hours after a meal) observed with the use of short-acting insulin before meals occur as a consequence of hyperinsulinemia present when the meal has been almost totally absorbed. The potential for late postprandial hypoglycemia observed with short-acting insulin may be reduced by altering the timing, frequency, and content of meals, altering exercise patterns, frequently monitoring blood glucose concentrations, adjusting insulin dosage, and/or switching to a more rapid-acting insulin (e.g., insulin lispro, insulin glulisine).

Rebound Hyperglycemia

Hyperglycemia that occurs as a result of excessive counterregulatory hormone responses to hypoglycemia (Somogyi effect, posthypoglycemic hyperglycemia) appears to occur principally in patients with type 1 diabetes mellitus. While the exact mechanism of this effect is unknown and there is controversy regarding whether it even exists, it has been suggested that excessive doses of an intermediate-acting (e.g., isophane [NPH]) insulin in the evening lead to nocturnal hypoglycemia and a compensatory release of counterregulatory hormones (e.g., epinephrine, growth hormone, cortisol, glucagon), resulting in increased hepatic glucose production and rebound hyperglycemia the following morning. The existence of such “rebound” hyperglycemia and/or the frequency with which it occurs has been questioned since the effect often has not been reproducible in clinical studies (particularly in adults), and neuroendocrine counterregulatory responses to hypoglycemia are known to be reduced in patients with long-standing diabetes mellitus. Some clinicians suggest that morning hyperglycemia occurring after an episode of nocturnal hypoglycemia results principally from overzealous intake of carbohydrate in an attempt to correct the hypoglycemia; other proposed mechanisms for this effect include the waning action of the insulin that caused the hypoglycemia and hypoglycemia-induced insulin resistance.

Manifestations suggesting an excessive insulin dosage in patients with hyperglycemia include excessive appetite and weight gain, nocturnal hypoglycemia, extreme variations in glucose concentrations, and frequent ketosis (especially in the absence of glycosuria), with worsening of these manifestations when insulin dosage is increased. The Somogyi effect must be differentiated from the “dawn phenomenon,” which is characterized by early morning hyperglycemia that appears related to nocturnal growth hormone release and the patient’s inability to compensate for increased blood glucose concentrations with an increase in endogenous insulin secretion; differentiation of the Somogyi effect and the dawn phenomenon may be accomplished by monitoring blood glucose at 3 a.m. Recommended treatment for the Somogyi effect, if it is suspected, is gradual reduction of the evening intermediate-acting insulin dosage or addition of/increase in the size of the nighttime snack (with a slowly absorbable carbohydrate) in conjunction with continuous blood glucose monitoring. (See Dosage and Administration: Dosage.) The dawn phenomenon reflects a relative deficiency of insulin and is treated by increasing the evening intermediate-acting insulin dose and/or later administration of that dose (i.e., at bedtime rather than at dinner).

Potassium Effects

Hypokalemia may occur with insulin therapy since insulin promotes an intracellular shift of potassium as a result of stimulating cell membrane Na+- K+-ATPase. Untreated hypokalemia may result in respiratory paralysis, ventricular arrhythmia, and death.

Dermatologic and Sensitivity Reactions

Localized allergic reactions such as pruritus, erythema, swelling, stinging or warmth at the site of injection may develop in patients receiving insulin. Localized allergic reactions may occur within 1–3 weeks after initiating insulin therapy, are relatively minor, and usually disappear within a few days to weeks. Poor injection technique may contribute to localized injection site reactions.

Manifestations of immediate hypersensitivity commonly occur within 30–120 minutes after the injection, may last for several hours or days, and usually subside spontaneously. True insulin allergy is rare and is characterized by generalized urticaria or bullae, dyspnea, wheezing, hypotension, tachycardia, diaphoresis, angioedema, and anaphylaxis. These reactions may represent a secondary anamnestic response and occur most frequently after intermittent insulin therapy or in patients with increased circulating insulin antibodies. Severe cases of generalized insulin allergy may be life-threatening. (See Cautions: Precautions and Contraindications.) There is some evidence that the incidence of allergic reactions has decreased with the availability of more purified insulin (e.g., insulin human, insulin lispro). In addition, several studies have shown insulin human and insulin lispro to be less immunogenic than animal-source insulin (i.e., purified pork insulin, beef insulin). Preparations containing beef or pork insulin are no longer commercially available in the US.

Atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injections. (See Cautions: Precautions and Contraindications.) Lipoatrophy is thought to be the result of an immune reaction to some contaminant of insulin.

Insulin Resistance

Resistance to insulin in patients with type 1 diabetes mellitus occurs infrequently and may be caused by either immune or nonimmune factors. Patients with insulin resistance usually require more than 200 units of insulin daily; in comparison, data from a small number of patients who had undergone pancreatectomy indicate that 10–44 units of insulin daily were required to control secondary diabetes mellitus.

Insulin resistance in patients with type 2 diabetes mellitus is frequently associated with obesity. This type of resistance results from tissue insensitivity to insulin, which may be caused by a decrease in the number of insulin receptors or a decreased affinity of insulin for the receptors. The principal treatment for obesity-related insulin resistance is weight reduction.

Acute insulin resistance may develop in diabetic patients with infections, surgical or other trauma, emotional disturbances, or additional endocrine disorders (e.g., hyperthyroidism, acromegaly, Cushing’s syndrome); therapy is aimed at relieving the intercurrent medical illness. Insulin requirements usually increase during pregnancy. (See Insulin Use during Pregnancy under Dosage and Administration: Dosage.)

Chronic insulin resistance resulting from immunity may occur when insulin therapy is reinstituted after a period of withdrawal. Most patients with chronic insulin resistance have been found to have markedly elevated concentrations of circulating insulin antibodies. Chronic insulin resistance resulting from immunity has been decreased by changing from beef (no longer commercially available in the US) to pork insulin (since some patients have selective resistance to beef insulin) or by changing to a purified insulin preparation (e.g., insulin human). Animal insulins are no longer commercially available in the US. Insulin lispro also has been effective in establishing glycemic control in patients with insulin resistance. Patients with insulin immune resistance who are switched to another type of insulin should be started at a lower dosage because their dosage requirements may be greatly decreased. Although administration of corticosteroids has been associated with induction of diabetes mellitus and insulin resistance, these drugs have been used with limited success in the treatment of immune-mediated insulin resistance. Sulfated insulin (not commercially available in the US) has been used in patients with immune-mediated insulin resistance in whom other methods had failed.

Ocular Effects

Transient presbyopia or blurred vision may occur in diabetic patients given insulin whose blood glucose concentrations have been uncontrolled for an extended period of time or in newly diagnosed diabetic patients in whom rapid glycemic control has been achieved. Patients with proliferative retinopathy who have hemoglobin A_1c (HbA_1c) concentrations exceeding 10% are at highest risk of worsening retinopathy. When blood glucose concentration is lowered in these patients, the osmotic equilibrium between the lens and ocular fluids occurs slowly but visual acuity will stabilize eventually. Some clinicians recommend that HbA_1c concentrations be reduced slowly (2% per year) in such patients and that frequent ophthalmologic examinations (e.g., every 6 months or when symptoms appear) be performed to ensure aggressive treatment of progressive retinopathy. New eyeglasses should not be prescribed for these patients until vision has stabilized.

Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients receiving insulin and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema). If heart failure develops, it should be managed according to current standards of care, and discontinuance of the PPAR-γ agonist or reduction of the dosage must be considered. Concomitant use of rosiglitazone and insulin therapy is not recommended.

Precautions and Contraindications

Formulation Considerations

Any change in insulin should be made cautiously and only under medical supervision. Patients should be informed of the reasons for any change in the insulin regimen and the potential need for additional glucose monitoring. Changes in insulin strength, manufacturer, type (e.g., regular, NPH), or method of manufacture may necessitate a change in dosage. Patients receiving insulin should be monitored with regular laboratory evaluations, including blood glucose determinations and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations, to determine the minimum effective dosage of insulin when used alone, with other insulins, or in combination with an oral antidiabetic agent.

Hypoglycemia and Hypokalemia

As hypoglycemia and hypokalemia may occur with insulin therapy, care should be taken in patients who are most at risk for the development of these effects, including patients who are fasting, those with defective counterregulatory responses (e.g., patients with autonomic neuropathy, adrenal or pituitary insufficiency, those receiving β-adrenergic blocking agents) or patients who are receiving potassium-lowering drugs. Insulin human is contraindicated during episodes of hypoglycemia. As IV insulin has a rapid onset of action, increased attention to hypoglycemia and hypokalemia is necessary. Blood glucose and potassium concentrations should be monitored closely when insulin is administered IV. Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentration. The potential for late postprandial hypoglycemia observed with short-acting insulin may be reduced by altering the timing, frequency, and content of meals, altering exercise patterns, frequently monitoring blood glucose concentrations, adjusting insulin dosage, and/or switching to a more rapid-acting insulin (e.g., insulin lispro, insulin glulisine). Patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes should be particularly vigilant in monitoring their blood glucose concentrations frequently, especially before activities such as driving; intensive insulin therapy should be used with caution in these patients. Maintenance of higher target blood glucose concentrations for at least several weeks is advisable in patients with a history of hypoglycemic unawareness or one or more episodes of severe hypoglycemia to avoid further hypoglycemia, partially reverse hypoglycemic unawareness, and reduce the risk of future episodes. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals. All adolescents with diabetes mellitus should monitor their blood glucose concentrations before driving and take corrective action to avoid hypoglycemia and cognitive-motor impairments. Such adolescents should carry a source of glucose in the car and should cease driving immediately should symptoms of hypoglycemia occur.

Management of Hypoglycemia

Oral administration of 15–20 g of dextrose is the preferred treatment for mild hypoglycemia, although any form of carbohydrate that contains glucose may be used, such as orange or other fruit juice, sugar, hard candy, regular nondiet soda, or dextrose gel or chewable tablets. The dose may be repeated in 15 minutes if blood glucose concentrations remain below 70 mg/dL (as determined by self-monitoring of blood glucose concentrations) or if symptoms of hypoglycemia are still present. Once blood glucose concentrations return to normal, ADA suggests that patients eat a meal or snack to prevent the recurrence of hypoglycemia.

In children and adolescents, administration of 15 g of an easily-absorbed carbohydrate followed by a protein-containing snack is sufficient for mild hypoglycemia; younger children may require about 10 g of carbohydrate to alleviate symptoms. Adjustments in the carbohydrate amounts should be based on blood glucose concentrations. Treatment of moderate hypoglycemia requires that someone other than the child or adolescent administer treatment, usually 20–30 g of glucose to restore blood glucose concentrations to greater than 80 mg/dL. Severe hypoglycemia (associated with altered states of consciousness, including coma and seizures) requires treatment with glucagon or IV dextrose solutions. (See Acute Toxicity: Treatment.)

Following a hypoglycemic reaction, patients should review the probable cause (e.g., excessive exercise, insufficient food intake, inappropriate insulin dosage) with their clinician and take action to prevent further such reactions. Alterations in snack patterns and adjustment in timing and/or dosage of insulin relative to activity levels should be discussed. (See Acute Toxicity.)

Sensitivity Reactions

Patients who have had severe allergic reactions to insulin (i.e., generalized rash, swelling, or breathing difficulty) should be skin-tested with any new insulin preparation before it is initiated. Desensitization may be required in patients with a potential for allergic reaction. Because patients may have selective allergic reactions to pork or beef insulin, or to protamine or proteins, further allergic reactions may be prevented by substitution of an insulin that contains less protein (i.e., purified insulins, including insulin human) or that does not contain protamine. Pure beef and mixed beef-pork insulins are no longer commercially available in the US.

Patient Instructions

It is important that the patient receive careful instruction in the importance of proper mixing and storage of insulin, timing of insulin dosing, adherence to meal planning, regular physical exercise, periodic HbA_1c concentration testing, recognition and management of hypoglycemia and hyperglycemic reactions, and periodic assessment of diabetic complications.

Patients and their families should be informed of the potential risks and advantages of conventional and intensive insulin therapy. While an intensive insulin regimen consisting of multiple insulin injections daily may not be advisable clinically in certain patient populations, such a regimen also may be problematic in noncompliant patients (e.g., substance abusers, psychiatric patients) or patients who not capable of adjusting their insulin requirements based on frequent self-monitoring of blood glucose concentrations.

Patients should be aware of the need for possible changes in the dosage of insulin and the need for additional monitoring of blood glucose concentrations during an illness, emotional disturbances or stress, or travel. Adjustment of insulin dosage may be needed if patients change their physical activity or usual meal plan.

Patients should be aware of symptoms of diabetic ketoacidosis and should monitor blood ketones if preprandial blood glucose concentrations repeatedly exceed 250–300 mg/dL or if they have an acute illness. Patients should be advised about sick-day procedures to assist in managing their diabetes during acute illness. Patients should contact their physician if results of self-monitored blood glucose concentrations are consistently abnormal.

Administration Considerations

Careful instruction about insulin administration technique and periodic reevaluation can minimize the likelihood of local adverse effects associated with faulty technique (e.g., lipoatrophy, lipohypertrophy). (See Dosage and Administration: Administration.) Subcutaneous injection sites should be rotated to prevent tissue damage that can occur with repeated subcutaneous injections of insulin into the same site. Direct injection of insulin into the outside edge of the atrophied area may result in improvement or complete disappearance of the atrophy in some patients. Rotating injection sites within one anatomical region (e.g., rotating injections systematically in the abdominal area) rather than selecting a different anatomical region is recommended to decrease day-to-day variability in insulin absorption. Variability in insulin absorption by injection site is reduced with insulin lispro compared with that with insulin human. Patients should be instructed to contact their clinician if lipoatrophy, lipohypertrophy, or local adverse effects (e.g., burning, itching, swelling) occur at the site of injection. Direct injection of insulin into the outside edge of the atrophied area may result in improvement or complete disappearance of the atrophy in some patients.

Pediatric Precautions

In young patients (i.e., those younger than 6 years of age) who may be unable to recognize, articulate, and/or manage hypoglycemia, the risk of hypoglycemia should be considered when setting glycemic targets. However, some data indicate that lower HbA_1c targets can be achieved in young children without increased risk of severe hypoglycemia. The risks of hypoglycemia and the developmental burdens of intensive insulin regimens in children and adolescents should be weighed against the long-term health benefits associated with achieving a lower HbA_1c.

ADA generally recommends that all children and adolescents with type 1 diabetes mellitus be treated with intensive insulin regimens; all children and adolescents should self-monitor blood glucose concentrations multiple times daily (up to 6–10 times per day), including premeal and prebedtime determinations, as needed for safety (e.g., prior to exercise or driving), or during the presence of hypoglycemic symptoms. Continuous glucose monitoring should be considered in all children and adolescents with type 1 diabetes mellitus.

Geriatric Precautions

Long-term studies conducted in geriatric patients with diabetes mellitus demonstrating the benefits of tight glycemic, blood pressure, and lipid control are lacking. Older adults are at an increased risk of developing hypoglycemia due to multiple factors such as renal insufficiency and cognitive deficits. It is important to prevent hypoglycemia in older adults to reduce the risk of cognitive decline and other adverse effects. Treatment goals for older patients should be individualized and should take into consideration multiple patient specific factors (e.g., comorbidities, cognitive function, functional status, life expectancy). Although control of hyperglycemia is important in geriatric patients with diabetes mellitus, greater reductions in morbidity and mortality may result from control of all cardiovascular risk factors. However, intensive management of diabetes mellitus and coexisting conditions may not be feasible in a proportion of geriatric patients, and clinicians may have to prioritize reduction of some of these risks. In frail geriatric patients with appreciable comorbid conditions, short life expectancy, cognitive or functional impairment, or noncompliance with treatment recommendations, clinicians may choose to enact treatment goals that enhance the quality of life and to treat symptoms or related conditions associated with diabetes mellitus.

Pregnancy

Pregnancy

Diabetic pregnancy is a high-risk state for both mother and fetus/infant. Women with diabetes mellitus who are pregnant or planning pregnancy require tight glycemic control. In women with preexisting diabetes mellitus or gestational diabetes mellitus, the ADA currently recommends a target fasting blood glucose concentrations of less than 95 mg/dL, a 1-hour postprandial blood glucose concentrations of less than 140 mg/dL, a 2-hour postprandial blood glucose concentration of less than 120 mg/dL, and a target HbA_1c concentration of less than 6% in such women. If women cannot achieve these glycemic targets without substantial hypoglycemia, less stringent targets may be appropriate and should be individualized.

Patients with diabetes mellitus should inform their physician if they are pregnant or intend to become pregnant; preconception glycemic control is crucial in preventing congenital malformations and reducing the risk of other complications, Many experts recommend institution of strict glycemic control, including use of intensive insulin regimens as needed, before conception and throughout pregnancy in patients with diabetes. (See Insulin Use During Pregnancy under Dosage and Administration: Dosage.) Experts recommend the use of insulin for the management of both type 1 and type 2 diabetes mellitus in pregnant women. Newer rapid-acting insulin analogs have been used increasingly in pregnant women, and based on current evidence, insulin lispro and insulin aspart are not teratogenic. These rapid-acting insulin analogs have been shown to be safe and effective during pregnancy and may provide better postprandial glycemic control with less hypoglycemia than regular insulin. In an open-label clinical study of pregnant women with type 1 diabetes mellitus, insulin detemir therapy did not increase the risk of fetal abnormalities. Additionally, there was no difference in pregnancy outcomes or the health of the fetus and newborn with insulin detemir use. Experience with insulin degludec and insulin glargine in pregnant women is limited.

Maintenance of normal glycemia during pregnancy appears to reduce the risk of congenital malformations, fetal macrosomia and other neonatal morbidities (e.g., hypoglycemia, hypocalcemia, polycythemia, hyperbilirubinemia) as well as perinatal mortality (e.g., miscarriage, intrauterine death, stillbirth). Diabetic women of childbearing age should be informed about the risks of unplanned pregnancy and the appropriate use of contraception until glycemic control is achieved.

Drug Interactions

Drugs That May Have a Variable Effect on Glycemic Control

Anabolic steroids, lithium salts, pentamidine, clonidine, and β-adrenergic blocking agents have variable effects on glucose metabolism as such agents may impair glucose tolerance or increase the frequency or severity of hypoglycemia. In addition, β-adrenergic blocking agents may suppress hypoglycemia-induced tachycardia but not hypoglycemic sweating, which may actually be increased; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation.

Nonselective β-adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsic sympathomimetic activity are more likely to affect glucose metabolism than more selective β-adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsic sympathomimetic activity (e.g., acebutolol, pindolol). Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of anxiety) mediated by catecholamines may be masked by either nonselective or selective β-adrenergic blockade or by other sympatholytic agents such as centrally acting α-adrenergic blocking agents (e.g., clonidine) or reserpine. These drugs should be used with caution in patients with diabetes mellitus, especially in those with labile disease or in those prone to hypoglycemia. Use of low-dose, selective β₁-adrenergic blockers (e.g., metoprolol, atenolol) or β-adrenergic blocking agents with intrinsic sympathomimetic activity in patients receiving insulin may theoretically decrease the risk of affecting glycemic control. When insulin and a β-adrenergic blocking agent are used concomitantly, the patient should be advised about and monitored closely for altered glycemic control.

Other Drugs Affecting Glycemic Control

The hypoglycemic activity of insulin may be potentiated by concomitant administration of alcohol, α-adrenergic blocking agents, certain antidepressants (e.g., monoamine oxidase inhibitors), glucagon-like peptide-1 (GLP-1) receptor agonists, guanethidine (no longer commercially available in the US), oral hypoglycemic agents, pramlintide, salicylates, sulfa antibiotics, certain angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and inhibitors of pancreatic function (e.g., octreotide). When such drugs are added to or withdrawn from therapy in patients receiving insulin, patients should be observed closely for evidence of altered glycemic control and possibly decreased insulin requirements.

Drugs with hyperglycemic activity that may antagonize the activity of insulin and exacerbate glycemic control in patients with diabetes mellitus include asparaginase, calcium-channel blocking agents, diazoxide, certain antilipemic agents (e.g., niacin), corticosteroids, danazol, estrogens, oral contraceptives, isoniazid, phenothiazines, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), thiazide diuretics, furosemide, ethacrynic acid, and thyroid hormones. When such drugs are added to or withdrawn from therapy in patients receiving insulin, patients should be observed closely for evidence of altered glycemic control and possibly increased insulin requirements.

Acute Toxicity

Pathogenesis

Acute hypoglycemia may result from excessive insulin dosage relative to food intake and/or energy expenditure, and numerous conditions may predispose to the development of insulin-induced hypoglycemia (e.g., defective counterregulatory response, hypoglycemic unawareness, insulin dosage errors, excessive alcohol intake, diabetic nephropathy, adrenal insufficiency, gastroparesis). (See Cautions: Precautions and Contraindications.) Hypoglycemia may result from overinsulinization, irregular eating patterns, increased physical activity, and/or decreased carbohydrate content of meals.

Manifestations

Hypoglycemia, which may be severe, is the principal manifestation of acute insulin overdosage. Symptoms of moderate hypoglycemia include aggressiveness, drowsiness, confusion, and autonomic symptoms. Severe hypoglycemia is associated with altered states of consciousness, including coma and seizures. Severe hypoglycemia may result in loss of consciousness and seizures, with resultant neurologic sequelae (e.g., cerebral damage, seizures); fatalities have been reported following severe, insulin-induced hypoglycemia Other complications reported with insulin overdosage include hypokalemia, respiratory insufficiency/failure, pulmonary edema, congestive heart failure, hypertension, and cerebral edema.

Treatment

Mild hypoglycemia (symptoms of sweating, pallor, palpitations, tremors, headache, behavioral changes) may be relieved by oral administration of carbohydrate-containing food or drink (e.g., orange or other fruit juice, lump sugar, candy). (See Management of Hypoglycemia under Precautions and Contraindications: Hypoglycemia and Hypokalemia, in Cautions.)

Severe hypoglycemia (associated with altered states of consciousness, including coma and seizures) requires treatment with glucagon or IV dextrose solutions. Severe insulin-induced hypoglycemia occurs infrequently but constitutes a medical emergency requiring immediate treatment. Adults with severe hypoglycemia (e.g., symptoms of lethargy, headache, confusion, sweating, agitation, seizures) or who are comatose from insulin overdosage and have adequate liver glycogen stores should receive 1 unit (1 mg) of subcutaneous, IM, or IV glucagon; patients should have a vial of glucagon available for family members to administer in emergency situations. Family members should be instructed in the proper administration of glucagon and the indications for its use. Patients unresponsive to or unable to receive glucagon should be given approximately 10–25 g of glucose as 20–50 mL of 50% dextrose injection IV. Higher or repeated doses of IV dextrose may be required in severe cases (e.g., intentional overdosage), and subsequent continuous IV infusion of glucose at 5–10 g/hour may be necessary to maintain adequate blood glucose concentrations until the patient is conscious and able to eat. The patient should be monitored closely until complete recovery is assured as hypoglycemia may recur. To prevent late or recurrent hypoglycemic reactions, oral carbohydrate should be given as soon as the comatose patient awakens.

In children and adolescents with severe hypoglycemia, glucagon at a dose of 30 mcg/kg subcutaneously up to a maximum of 1 mg (1 unit) will increase blood glucose concentrations within 5–15 minutes but may be associated with nausea and vomiting. A lower glucagon dose of 10 mcg/kg results in a lower glycemic response but is associated with less nausea. Repeated episodes of hypoglycemia or longstanding diabetes mellitus may result in defective glucose counterregulation and hypoglycemia unawareness. In such patients, blood glucose should be monitored frequently to avoid recurrent episodes.

Pharmacology

Exogenous insulin elicits all the pharmacologic responses usually produced by endogenous insulin.

Insulin stimulates carbohydrate metabolism in skeletal and cardiac muscle and adipose tissue by facilitating transport of glucose into these cells. Nerve tissues, erythrocytes, and cells of the intestines, liver, and kidney tubules do not require insulin for transfer of glucose. In the liver, insulin facilitates phosphorylation of glucose to glucose-6-phosphate which is converted to glycogen or further metabolized.

Insulin also has a direct effect on fat and protein metabolism. The hormone stimulates lipogenesis and inhibits lipolysis and release of free fatty acids from adipose cells. Insulin also stimulates protein synthesis.

Administration of suitable doses of insulin to patients with type 1 (insulin-dependent) diabetes mellitus temporarily restores their ability to metabolize carbohydrates, fats, and proteins; to store glucose in the liver; and to convert glycogen to fat. When insulin is given in suitable doses at regular intervals to a patient with diabetes mellitus, blood glucose is maintained at a reasonable concentration, the urine remains relatively free of glucose and ketone bodies, and diabetic acidosis and coma are prevented. The action of insulin is antagonized by somatotropin (growth hormone), epinephrine, glucagon, adrenocortical hormones, thyroid hormones, and estrogens.

Insulin promotes an intracellular shift of potassium and magnesium and thereby appears to temporarily decrease elevated blood concentrations of these ions.

Insulins General Statement Pharmacokinetics

Absorption

Because of its protein nature, insulin is destroyed in the GI tract and usually is administered parenterally; however, regular insulin also has been administered via oral inhalation. Regular insulin also has been administered intranasally^{† [off-label]} or transdermally^{† [off-label]} in a limited number of patients. Following subcutaneous or IM administration, insulin is absorbed directly into the blood. Rate of absorption depends on many factors including route of administration, site of injection, volume and concentration of the injection, and type of insulin. One study in lean, healthy, fasting adults indicates that regular insulin is absorbed more rapidly following IM administration than when it is given subcutaneously. Absorption may be delayed and/or decreased by the presence of insulin-binding antibodies, which develop in all patients after 2–3 months of insulin treatment. Absorption of regular insulin following intranasal or transdermal administration generally has been variable and incomplete, and absorption enhancers (e.g., bile salts) have been used to facilitate delivery of insulin given by these routes. Some data suggest that intrapulmonary absorption of insulin and other peptides may be enhanced in cigarette smokers.

Commercially available insulin preparations differ mainly in their onset, peak, and duration of action following subcutaneous administration. Currently available insulin preparations are classified as rapid-acting, short-acting, intermediate-acting, or long-acting. The values for onset, peak, and duration of action of insulin injections shown in Table 1 are only approximate; substantial interindividual and intraindividual variation in these values may occur based on site of injection, injection technique, tissue blood supply, temperature, presence of insulin antibodies, exercise, excipients in insulin formulations, and/or interindividual and intraindividual differences in response. In addition, human insulins may have a more rapid onset and shorter duration of action than porcine insulins (no longer commercially available in the US) in patients with diabetes. Similarly, insulin aspart has a more rapid onset and shorter duration of effect than insulin human; differences in pharmacodynamics between the 2 types of insulins are not associated with differences in overall glycemic control.

The hypoglycemic effect of commercially available mixtures containing insulin human isophane (NPH) 70 units/mL and insulin human 30 units/mL (Novolin 70/30, Humulin 70/30) usually occurs within 30 minutes, peaks within 1.5–12 hours, and persists for up to 24 hours. The hypoglycemic effect of the commercially available mixture containing insulin human isophane (NPH) 50 units/mL and insulin human 50 units/mL usually occurs within 0.5–1 hour, peaks within 1.5–4.5 hours, and persists for 7.5–24 hours. The addition of insulin lispro protamine 75 units/mL to insulin lispro 25 units/mL in the commercially available mixture (Humalog 75/25) or 50 units/mL of insulin lispro protamine to insulin lispro 50 units/mL in the commercially available mixture (Humalog 50/50) does not affect the onset of hypoglycemic effect compared with that with insulin lispro alone, which usually occurs within 0.25–0.5 hours, peaks within 2 hours, and persists for more than 22 hours. The hypoglycemic effect of the commercially available mixture containing insulin aspart protamine 70 units/mL and insulin aspart 30 units/mL usually occurs within 10–20 minutes, peaks within 1–4 hours, and persists for up to 24 hours. When administered in fixed combination with insulin aspart protamine, rapid absorption of the insulin aspart component is preserved, and absorption of insulin aspart protamine component is prolonged.

Distribution

Insulin is rapidly distributed throughout extracellular fluids. It is not known whether insulin aspart is distributed into milk. Insulin aspart is minimally bound to plasma proteins (0–9%).

Elimination

Insulin has a plasma half-life of a few minutes in healthy individuals; however, the biologic half-life may be prolonged in diabetic patients, probably as a result of binding of the hormone to antibodies, and in patients with renal impairment as a result of altered degradation/decreased clearance. Following subcutaneous administration, the half-life of insulin aspart averages 81 minutes. The half-life of insulin aspart in fixed combination with insulin aspart protamine is about 8–9 hours. Data from a pharmacokinetic study in patients with a wide range of body mass index, indicate that clearance of insulin aspart is reduced by 28% in obese patients with type 1 diabetes mellitus compared with that in leaner patients.

Insulin is rapidly metabolized mainly in the liver by the enzyme glutathione insulin transhydrogenase and to a lesser extent in the kidneys and muscle tissue. In the kidneys, insulin is filtered at the glomerulus and almost completely (98%) reabsorbed in the proximal tubule. About 40% of this reabsorbed insulin is returned to venous blood and 60% is metabolized in the cells lining the proximal convoluted tubule. In normal patients, only a small amount (less than 2%) of a filtered insulin dose is excreted unchanged in the urine.

In a pharmacokinetic study in a limited number of patients receiving an IV infusion (1.5 milliunits/kg per minute for 120 minutes) of either insulin aspart or insulin human, the mean insulin clearance was similar for the 2 types of insulins (1.22–1.24 L/hour per kg).

Chemistry and Stability

Chemistry

Insulin is a hormone secreted by the beta cells of the pancreatic islets of Langerhans. Insulin is a protein with a molecular weight of about 6000 and is composed of 2 chains (A and B chains) of amino acids connected by disulfide linkages.

The potency of insulin is standardized according to its ability to lower blood glucose concentrations of normal fasting rabbits as compared to the USP Insulin Reference Standard. Potency is expressed in USP units per mL.

Insulin Aspart

Insulin aspart is a rapid-acting, biosynthetic (recombinant DNA origin) insulin human analog that is structurally identical to insulin human except for the replacement of aspartic acid with proline at position 28 on the B chain of the molecule.

Insulin Degludec

Insulin degludec is a long-acting, biosynthetic (recombinant DNA origin) insulin human analog that is prepared using a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin degludec differs structurally from insulin human by the deletion of threonine at position 30 on the B chain and by the acylation of lysine at position 29 on the B chain with hexadecandioic acid, a 16-carbon fatty acid, via a glutamic acid spacer.

Insulin Detemir

Insulin detemir is a long-acting, biosynthetic (recombinant DNA origin) insulin human analog that is prepared using a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin detemir differs structurally from insulin human by the deletion of threonine at position 30 on the B chain and by the acylation of lysine at position 29 on the B chain with myristic acid, a 14-carbon fatty acid.

Insulin Glargine

Insulin glargine is a long-acting, biosynthetic (recombinant DNA origin) insulin human analog that is prepared using special laboratory strains of nonpathogenic E. coli, insulin glargine that differs structurally from insulin human by the replacement of asparagine with glycine at position 21 of the A chain and the addition of 2 arginine groups to the C-terminus of the B chain.

Insulin Glulisine

Insulin glulisine is a rapid-acting, biosynthetic (recombinant DNA origin) insulin human analog that is structurally identical to insulin human except for the replacement of asparagine at position 3 on the B chain with lysine and by replacement of lysine at position 29 on the B chain with glutamic acid.

Insulin Human

Commercially available insulin human (regular insulin) is structurally identical to human insulin. Insulin human is not extracted from the human pancreas but rather is prepared biosynthetically using recombinant DNA technology and special laboratory strains of Escherichia coli or Saccharomyces cerevisiae. Biosynthetic insulin human isophane (NPH insulin) is an intermediate-acting, sterile suspension of zinc insulin crystals and protamine sulfate in buffered water for injection.

Insulin Lispro

Insulin lispro is a rapid-acting, biosynthetic (recombinant DNA origin) insulin human analog that is structurally identical to insulin human except for transposition of the natural sequence of lysine and proline on the B chain of the molecule.

Stability

Insulin Human

Regular insulin (insulin human) injection may be mixed with other insulin preparations that have an approximately neutral pH (e.g., insulin human isophane [NPH]). Whenever regular insulin is mixed with other insulin preparations, regular insulin should be drawn into the syringe first in order to avoid transfer of the modified insulin preparation into the regular insulin vial.

When regular insulin is mixed with NPH insulin, binding of added regular insulin occurs in vitro because of excess protamine in the formulation of NPH. In vitro binding of regular insulin by NPH insulin is rapid and marked, occurring within about 5–15 minutes after mixing; however, these chemical changes appear to have no clinical importance since the onset and duration of action of mixtures containing regular and NPH insulins are similar to those observed when these insulins are administered separately.

Mixtures containing regular insulin and NPH insulin appear to be stable for at least 1 month when stored at room temperature or 3 months when stored at 2–8°C; however, the possibility of microbial contamination should be considered. Fixed combinations that contain 30 units/mL of insulin human injection and 70 units/mL of insulin human isophane (NPH) suspension (Humulin 70/30, Novolin 70/30), 25 units/mL of insulin lispro and 75 units/mL of insulin lispro protamine suspension (Humalog mix 75/25), 30 units/mL of insulin aspart and 70 units/mL of insulin aspart protamine (Novolog mix 70/30), 50 units/mL of insulin lispro and 50 units/mL of insulin lispro protamine (Humalog mix 50/50), and those that contain 50 units/mL of insulin human injection and 50 units/mL of insulin human isophane (NPH) suspension (Humulin 50/50) are commercially available.

Regular insulin may be mixed in any proportion with water for injection or 0.9% sodium chloride injection for use in an insulin subcutaneous infusion pump. However, the mixtures should be used within 24 hours after preparation, since changes in pH and dilution of buffer may affect stability. Insulins are physically and chemically compatible with Lilly’s insulin diluting fluids, and may be mixed in any proportion for use in an infusion pump. The mixtures using Lilly’s insulin diluting fluids are stable for up to 4 weeks when stored at room temperature. Lilly’s insulin diluting fluids are not commercially available; the preparations and specific information about their use should be obtained from the manufacturer. Regular insulin may form crystal deposits on the tubing of insulin infusion pumps.

Studies indicate that the addition of regular insulin to an IV infusion solution may result in adsorption of insulin to the container and tubing. The amount of an insulin dose lost by adsorption to an IV infusion system is highly variable and depends on the concentration of insulin, the type and surface area of the infusion system, the duration of contact time, and the flow rate of the infusion. The lesser the concentration of insulin in solution or the slower the rate of flow of solution, the greater the percentage of adsorption. Adding more insulin to the solution may saturate binding sites of the infusion system. Alternatively, insulin injection may be administered from a syringe directly into a vein or IV tubing with no significant loss due to adsorption. Insulin adsorption is decreased by the presence of negatively charged proteins, such as normal serum albumin. In one study, addition of 7 mL of 25% normal human serum albumin to 500 mL of 0.9% sodium chloride injection with 5, 10, 20, or 40 units of insulin prevented significant insulin adsorption.

Insulin Aspart, Insulin Glulisine, and Insulin Lispro

When a rapid-acting insulin is mixed with a longer-acting insulin (i.e., insulin human isophane [NPH]), the rapid onset of action of the rapid-acting insulin (i.e., insulin lispro, insulin aspart) is not affected; therefore, such insulins can be mixed. A slight decrease in absorption rate but not total bioavailability is seen when rapid-acting insulin and insulin human isophane (NPH) are mixed. In clinical trials, postprandial glycemic control was similar when a rapid-acting insulin was mixed with either insulin human isophane (NPH) or extended insulin human zinc (Ultralente, no longer commercially available in the US). Insulin lispro has been administered with a longer-acting insulin (insulin human isophane [Humulin N]) in the same syringe. Mixing of insulin lispro with other insulins may be associated with physicochemical changes (either immediately or over time) that could alter the physiologic response to the insulins. Insulin aspart or insulin glulisine may be mixed with insulin human isophane (NPH). Although some attenuation of peak serum insulin aspart or insulin glulisine concentrations was observed when administered concomitantly with insulin human isophane (NPH) in the same syringe, the time to peak concentration and total bioavailability of insulin aspart were not substantially affected. If insulin aspart or insulin glulisine is mixed with insulin human isophane (NPH), insulin aspart should be drawn into the syringe first and the mixture administered immediately after mixing. The manufacturer states that the effect of mixing insulin aspart with insulins of animal origin (no longer commercially available in the US), insulins produced by other manufacturers, or crystalline insulin zinc formulations has not been studied. The manufacturer of insulin glulisine states that the effects of mixing insulin glulisine in the same syringe with insulins other than insulin human isophane (NPH), or mixing insulin glulisine with diluents or other insulins when used in external subcutaneous infusion pumps have not been studied.

Unopened insulin aspart alone or in fixed combination with insulin aspart protamine should be stored at 2–8°C until the expiration date and protected from light. Insulin aspart alone or in fixed combination with insulin aspart protamine should not be subjected to freezing; do not use insulin aspart if freezing has occurred or if exposed to temperatures exceeding 37°C. In-use vials, cartridges, or injection pens containing insulin aspart alone should be stored at temperatures below 30°C for up to 28 days. In-use vials containing insulin aspart in fixed combination with insulin aspart protamine vials may be stored at temperatures below 30°C for up to 28 days, provided such vials are kept as cool as possible and away from direct heat and light. Opened insulin aspart should not be exposed to excessive heat or sunlight; do not use the drug if exposure to temperatures exceeding 37°C has occurred. Opened vials of insulin aspart may be refrigerated. Cartridges of insulin aspart assembled into an injection pen or other compatible insulin delivery device should not be refrigerated. Punctured cartridges containing insulin aspart in fixed combination with insulin aspart protamine or Novolog Mix 70/30 FlexPen are stable for up to 14 days if stored at temperatures below 30°C; do not refrigerate and keep away from direct heat and sunlight. Infusion bags containing insulin aspart or insulin human regular are stable at room temperature for 24 hours. A certain amount of insulin will be adsorbed initially to material of the infusion bag. The infusion set (tubing, reservoirs, catheters, needle) and the drug in the reservoir should be discarded at least every 48 hours or after exposure to temperatures exceeding 37°C.

When insulin aspart, insulin lispro, or insulin glulisine is used in an external subcutaneous insulin infusion pump, the drug should not be diluted or mixed with any other insulin. Malfunctioning of the external infusion pump or infusion set (e.g., infusion set occlusion, leakage, disconnection or kinking) or insulin degradation can lead to hyperglycemia or ketosis within a short time period because of the small subcutaneous depot of insulin with continuous infusion administration and the rapid onset and short duration of action of insulin aspart, insulin lispro, or insulin glulisine. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. If these problems cannot be corrected promptly, patients should resume therapy with subcutaneous injections of insulin and contact their clinician. Patients who are switching from multiple-injection therapy or infusion with buffered regular insulin to subcutaneous infusion with insulin aspart may be particularly susceptible to hyperglycemia or ketosis, and interim therapy with subcutaneous injections with insulin aspart may be required.

In vitro studies have shown that pump malfunction, loss of cresol, and insulin degradation may occur with the use of insulin aspart or insulin glulisine for more than 2 days at 37°C. Insulin aspart, insulin glulisine, and insulin lispro should not be exposed to temperatures exceeding 37°C during administration. The temperature of insulin aspart or insulin glulisine may exceed ambient temperature when the pump housing, cover, tubing, or sport case is exposed to sunlight or radiant heat. Insulin aspart or insulin glulisine exposed to higher than recommended temperatures should be discarded. To avoid insulin degradation, infusion set occlusion, and loss of preservative (cresol), infusions sets (reservoir syringe, tubing, and catheter) and insulin aspart, insulin lispro, or insulin glulisine in the reservoir should be replaced and a new infusion site selected at least every 48 hours. The 3-mL insulin lispro cartridge used in the DisetronicD-TRON or DisetronicD-TRON plus insulin infusion device should be discarded after 7 days, even if some drug still remains in the reservoir.

Insulin Degludec

The manufacturer states that insulin degludec must not be mixed with any other insulin or solution.

Insulin Detemir

The manufacturer states that insulin detemir must not be diluted or mixed with any other insulin or solution. Such dilution or mixing of insulin detemir may result in unpredictable alterations in the pharmacokinetic and/or pharmacodynamic characteristics (e.g., onset of action, time to peak effect) of insulin detemir and/or the mixed insulin.

Insulin Glargine

The manufacturer states that insulin glargine must not be diluted or mixed with any other insulin or solution. Such dilution or mixing of insulin glargine may result in clouding of the solution and unpredictable alterations in the pharmacokinetic and/or pharmacodynamic characteristics (e.g., onset of action, time to peak effect) of insulin glargine and/or the mixed insulin.

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