Note: Insulin NPH is an intermediate-acting basal insulin formulation. Insulin requirements vary between patients; monitor glucose levels frequently and individualize dose.
Diabetes mellitus, type 1, treatment:
Note: Insulin NPH must be used concomitantly with rapid- or short-acting insulins (ie, multiple daily injection regimen). The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.
General insulin dosing:
Initial TDD: SUBQ: ~0.4 to 0.5 units/kg/day; conservative initial doses of 0.2 to 0.4 units/kg/day may be considered to avoid the potential for hypoglycemia; higher initial doses may be required in patients with obesity, or who are sedentary or presenting with ketoacidosis (AACE [Handelsman 2015]; ADA 2022).
Usual TDD maintenance range: SUBQ: 0.4 to 1 units/kg/day in divided doses (ADA 2022).
Division of TDD (multiple daily injections):
Basal insulin: SUBQ: Generally, 40% to 50% of the TDD is given as basal insulin (intermediate- or long-acting) (AACE [Handelsman 2015]; ADA 2022). Insulin NPH may be administered in 2 divided doses daily (either as equally divided doses, or as ~2/3 of the dose before the morning meal and ~1/3 of the dose before the evening meal or at bedtime). Alternatively, dividing insulin NPH into 3 or 4 doses per day may reduce hypoglycemic risk and establish more consistent basal insulin profile (Peters 2013).
Prandial insulin: SUBQ: The remaining portion (ie, 50% to 60%) of the TDD is then divided and administered before, at, or just after mealtimes depending on the formulation (eg, short-, rapid-, or ultra-rapid acting) (AACE [Handelsman 2015]; ADA 2022).
Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. To minimize hypoglycemia risk, basal insulins are generally titrated once or twice weekly (eg, every 3 or 7 days) (ADA 2022; McCall 2012).
Diabetes mellitus, type 2, treatment:
Note : Preferred in patients with symptomatic hyperglycemia (eg, weight loss, polydipsia, polyuria) or with ketonuria; may also be used in patients with severe hyperglycemia (eg, fasting glucose >250 mg/dL, random glucose consistently >300 mg/dL, HbA1c >9%), or if glycemic goals are not met despite adequately titrated metformin with or without other noninsulin agents (ADA 2022; Wexler 2022). Consider discontinuation or a dose reduction of sulfonylureas and thiazolidinediones when initiating basal insulin therapy (ADA/EASD [Davies 2018]).
Initial: SUBQ: 10 units/day or 0.1 to 0.2 units/kg/day administered as a single dose (usually at bedtime) (ADA 2022; Lipska 2017). In patients with HbA1c >8%, fasting glucose >250 mg/dL, or insulin resistance, 0.2 to 0.3 units/kg/day is recommended (AACE/ACE [Garber 2020]; Wexler 2022). Some experts use a minimum of 10 units/day and do not exceed 20 units/day for the initial dose (Wexler 2022).
Dosage adjustment :
For persistently elevated fasting plasma glucose: SUBQ: Increase daily dose by 2 to 4 units or by 10% to 20% every 2 to 3 days to achieve fasting plasma glucose target while avoiding hypoglycemia (AACE/ACE [Garber 2020]; ADA 2022; Wexler 2022).
For elevated HbA1c despite achieving fasting plasma glucose target: SUBQ: Encourage lifestyle modifications. Consider adding other medications (eg, a glucagon-like peptide-1 receptor agonist, prandial insulin before the largest meal); in patients using NPH insulin once daily, an alternative is to switch to a twice-daily regimen by administering ~80% of the current daily dose in 2 divided doses (eg, two-thirds of the daily dose in the morning and one-third of the daily dose at bedtime). In some patients, higher insulin NPH doses (eg, >0.5 units/kg/day) may provide diminishing additional improvements in HbA1c (AACE/ACE [Garber 2020]; ADA 2022).
For hypoglycemia: SUBQ: For unexplained mild to moderate hypoglycemia, consider decreasing daily dose by 10% to 20% (ADA 2022); for severe hypoglycemia requiring assistance from another person, or if blood glucose <40 mg/dL, consider decreasing daily dose by 20% to 50% (AACE/ACE [Garber 2020]; Wexler 2022). Note: Use of long-acting basal analogs may be preferred over insulin NPH if hypoglycemia is a primary concern (AACE/ACE [Garber 2020]; ADA 2022).
Dosage adjustment when adding prandial insulin: SUBQ: In patients whose glucose levels are close to target (eg, HbA1c <8%), consider decreasing the basal insulin daily dose by 4 units or by 10% (ADA 2022).
Preoperative dosage adjustment: Dose reductions are applied to the morning and/or evening insulin NPH doses as follows:
Evening scheduled dosage adjustment: SUBQ: Reduce insulin NPH dose by 10% to 25% the evening before the procedure; may administer the full dose if preoperative hypoglycemia risk is low (eg, glucose levels generally >200 mg/dL) (ES [Umpierrez 2012]; Khan 2022).
Morning scheduled dosage adjustment: SUBQ: For patients not using prandial insulin, reduce insulin NPH dose by 10% to 25% the morning of the procedure; may administer the full dose if preoperative hypoglycemia risk is low (eg, glucose levels generally >200 mg/dL). For patients using prandial insulin, omit prandial insulin after fasting begins and administer one-half to two-thirds of the total morning insulin dose (basal + prandial) as insulin NPH the morning of the procedure (ES [Umpierrez 2012]; Khan 2022).
Patients with diabetes receiving enteral feedings (ADA 2022): Note: TDD of insulin is divided into a basal component (intermediate- or long-acting insulin) and nutritional and correctional components (regular insulin or rapid-acting insulins).
Basal component: SUBQ: Continue previous basal insulin dose or administer 30% to 50% of TDD as insulin NPH; if basal insulin naive, administer insulin NPH 5 units every 12 hours.
Patients with diabetes undergoing surgery: SUBQ: On the evening before surgery or procedure, reduce the usual dose by 25%; on the morning of surgery or procedure, reduce the usual dose by 25% to 50% (ADA 2022; Pichardo-Lowden 2012).
Conversion from long-acting insulin analogs to insulin NPH: Consider initiating insulin NPH at 80% (eg, 20% reduction) of previous basal insulin total daily dose; administer as a single dose (usually at bedtime) or in 2 divided doses (ADA 2022; Lipska 2017).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
There are no dosage adjustments provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
(For additional information see "Insulin NPH: Pediatric drug information")
Insulin NPH is an intermediate-acting insulin formulation which is usually administered subcutaneously once or twice daily. When compared to insulin regular, insulin NPH has a slower onset and longer duration of activity. Insulin doses should be individualized based on patient needs; adjustments may be necessary with changes in physical activity, meal patterns, acute illness, or with changes in renal or hepatic function. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision. Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.
Type 1 diabetes mellitus: Children and Adolescents: Note: For basal insulin coverage, long-acting insulin analogs are preferred over insulin NPH due to decreased risk of hypoglycemia (AACE/ACE [Handelsman 2015]; ADA 2018; ADA [Chiang 2014]). The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined.
Initial total daily insulin: SubQ:Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2018); usual range: 0.4 to 1 units/kg/day in divided doses (AACE/ACE [Handelsman 2015; ADA 2018; Silverstein 2005); lower doses (0.25 units/kg/day) may be used especially in young children to avoid potential hypoglycemia (Beck 2015); higher doses may be necessary for some patients (eg, obese, concomitant steroids, puberty, sedentary lifestyle, following diabetic ketoacidosis presentation) (AACE/ACE [Handelsman 2015]; ADA 2018)
Usual total daily maintenance range: SubQ: Doses must be individualized; however, an estimate can be determined based on phase of diabetes and level of maturity (ISPAD [Danne 2018]; ISPAD [Sundberg 2017]):
Partial remission phase (Honeymoon phase): <0.5 units/kg/day
Prepubertal children (not in partial remission):
Infants ≥6 months and Children ≤6 years: 0.4 to 0.8 units/kg/day
Children ≥7 years: 0.7 to 1 units/kg/day
Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day
Division of daily insulin requirement (multiple daily injections):
Basal insulin: Generally, ~30% to 50% of the total daily insulin is given as basal insulin (intermediate- or long-acting) (AACE/ACE [Handelsman 2015]; ADA 2018; ISPAD [Danne 2018]; Peters 2013). When utilizing a twice daily NPH regimen, ~50% to 60% of the total daily insulin administered as NPH has been recommended with more (~2/3) of the total daily insulin administered in the morning and less (~1/3) of the total daily dose administered in the evening or at bedtime (ISPAD [Danne 2014]). Dividing the total daily dose of insulin NPH into 3 or 4 doses per day may reduce hypoglycemic risk and establish a more consistent basal insulin profile (Peters 2013).
Prandial insulin: The remaining portion of the total daily dose is then divided and administered before or at mealtimes (depending on the formulation) as rapid-acting (eg, aspart, glulisine, lispro) or short-acting (regular). In most type 1 patients, the use of a rapid-acting insulin analog is preferred over regular insulin to reduce hypoglycemia risk (AACE/ACE [Handelsman 2015]; ADA 2018; ADA [Chiang 2014]; ISPAD [Danne 2018]).
Dose titration: Treatment and monitoring regimens must be individualized to maintain premeal and bedtime glucose in target range, titrate dose to achieve glucose control, and avoid hypoglycemia. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.
Patients receiving enteral/parenteral feedings: Data is limited in pediatric patients; in adults, the following is recommended: Bolus or continuous enteral feedings: SubQ: Continue previous basal insulin dose or if basal insulin naive, administer 30% to 50% of total daily dose of insulin received while being fed as insulin NPH (ADA 2018); administer in conjunction with nutritional and correctional insulin dosing with a rapid-acting or regular insulin.
Surgical patients (ISPAD [Jefferies 2018]): Note: Diabetic patients should be scheduled as the first case of the day.
Minor surgeries:
Morning procedure: Administer 50% to 70% of the usual morning dose of insulin NPH OR administer IV insulin (regular) infusion; begin IV fluids containing dextrose; in general, rapid acting insulin should be omitted until after surgery and patient is able to eat unless it is needed to correct significant hyperglycemia and/or significant ketone (>0.1 mmol/mol) production is present.
Afternoon procedure: Administer 70% to 100% of the usual morning dose of insulin NPH depending on the amount of breakfast allowed.
Postprocedure: Once normal oral intake is achieved, resume usual insulin regimen; monitor closely due to risk of changes related to surgery (postoperative stress, medication changes, inactivity)
Major surgeries: Omit morning insulin (short and long acting) and start IV insulin (regular) infusion and IV dextrose; patients on continuous subcutaneous insulin infusion (CSII) should discontinue CSII when IV insulin infusion is started; once normal oral intake is resumed, then resume usual insulin regimen; monitor closely due to risk of changes related to surgery (postoperative stress, medication changes, inactivity)
Type 2 diabetes mellitus: Limited data available: Note: The goal of therapy is to achieve an HbA1c <7% as quickly as possible using the safe titration of medications. Initial therapy in metabolically unstable patients (eg, plasma glucose ≥250 mg/dL, HbA1c >9% and symptoms excluding acidosis) may include once daily intermediate-acting insulin or basal insulin in combination with lifestyle changes and metformin. In patients who fail to achieve glycemic goals with metformin and basal insulin, may consider initiating prandial insulin (regular insulin or rapid acting insulin) and titrate to achieve goals. Once initial goal reached, insulin should be slowly tapered over 2 to 6 weeks by decreasing the insulin dose by 10% to 30% every few days and the patient transitioned to lowest effective doses or metformin monotherapy if able (AAP [Copeland 2013]; ADA 2018; ISPAD [Zeitler 2018]).
Children ≥10 years and Adolescents with ketosis/ketoacidosis/ketonuria: SubQ: Initial: 0.25 to 0.5 units/kg/dose once daily; use in in combination with lifestyle changes and metformin to achieve goals (ISPAD [Zeitler 2018])
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
There are no dosage adjustments provided in manufacturer's labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension, Subcutaneous:
HumuLIN N: 100 units/mL (3 mL [DSC], 10 mL) [contains metacresol, phenol]
NovoLIN N: 100 units/mL (10 mL) [contains metacresol, phenol]
NovoLIN N ReliOn: 100 units/mL (10 mL) [contains metacresol, phenol]
Suspension Pen-injector, Subcutaneous:
HumuLIN N KwikPen: 100 units/mL (3 mL) [contains metacresol, phenol]
NovoLIN N FlexPen: 100 units/mL (3 mL) [contains metacresol, phenol]
NovoLIN N FlexPen ReliOn: 100 units/mL (3 mL) [contains metacresol, phenol]
No
SUBQ: For subcutaneous administration into the thigh, upper arm, buttocks, or abdomen; do not administer IM or IV, or in an insulin pump. Absorption rates vary amongst injection sites; be consistent with area used while rotating injection sites within the same region to reduce the risk of lipodystrophy or localized cutaneous amyloidosis. Rotating from an injection site where lipodystrophy/cutaneous amyloidosis is present to an unaffected site may increase risk of hypoglycemia.
In order to properly resuspend the insulin, vials should be carefully inverted or rolled at least 10 times, Humulin N KwikPen should be rolled between the palms ten times and inverted 180° ten times, and Novolin N FlexPen should be inverted 180° twenty times prior to the first injection and ten times thereafter. Cartridges [Canadian product] should be inverted 180° at least ten times. Properly resuspended insulin NPH should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided.
Per the manufacturer labeling, Humulin N from a vial may be mixed with insulin lispro or insulin regular and Novolin N from a vial may be mixed only with insulin regular. When mixing insulin NPH with other insulins in a syringe, insulin NPH should be drawn into the syringe after the other insulin preparations. Do not dilute or mix other insulin formulations with insulin NPH contained in a cartridge [Canadian product] or prefilled pen. When there are less than 12 units remaining in Novolin N FlexPen, replace it with a new one to ensure even mixing.
For prefilled pens, prime the needle before each injection with 2 units of insulin. Once injected, hold the needle in the skin for at least 5 seconds (Humulin N KwikPen) or at least 6 seconds (Novolin N FlexPen) after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered.
SUBQ: Administer subcutaneously into the thigh, upper arm, buttocks, or abdomen; do not administer IM, IV, or in an insulin pump. Rotate injection sites within the same region to reduce the risk of lipodystrophy.
In order to properly resuspend the insulin, vials should be carefully shaken or rolled several times. Humulin N KwikPen should be rolled between the palms 10 times and inverted 180° 10 times, and Novo N FlexPen should be inverted 180° 20 times prior to the first injection and 10 times thereafter. Properly resuspended insulin NPH should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided. When mixing insulin NPH with other preparations of insulin (eg, insulin aspart, insulin glulisine, insulin lispro, insulin regular), insulin NPH should be drawn into the syringe after the other insulin preparations. Do not dilute or mix other insulin formulations with insulin NPH contained in a cartridge or prefilled pen.
For prefilled pens, prime the needle before each injection with 2 units of insulin; see manufacturer's labeling for specific procedure. Once primed, set dial to the appropriate dose, insert needle into clean skin, and activate device; once insulin is injected, hold the needle in the skin for 5 seconds (Humulin N KwikPen) or ≥6 seconds (Novolin N FlexPen) after the dose dial has returned to 0 units to ensure the full dose has been administered before removing the needle. If dose is >60 units, more than 1 injection will be required; split dose and administer in multiple injections.
Diabetes mellitus, types 1 and 2, treatment: Treatment of types 1 and 2 diabetes mellitus to improve glycemic control in adults and pediatric patients.
Gestational diabetes mellitus
HumuLIN N may be confused with HumuLIN R, HumaLOG, Humira
NovoLIN N may be confused with NovoLIN R, NovoLOG
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error. Due to the number of insulin preparations, it is essential to identify/clarify the type of insulin to be used.
Cross-contamination may occur if insulin pens are shared among multiple patients. Steps should be taken to prohibit sharing of insulin pens.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Peripheral edema
Dermatologic: Injection site pruritus
Endocrine & metabolic: Amyloidosis (cutaneous at injection site), hypoglycemia, hypokalemia, lipodystrophy, lipohypertrophy, weight gain
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Immunologic: Immunogenicity
Local: Atrophy at injection site, erythema at injection site, hypertrophy at injection site, injection site reaction, swelling at injection site
Neuromuscular & skeletal: Swelling of extremities
Ophthalmic: Visual disturbance
Hypersensitivity to insulin NPH or any component of the formulation; during periods of hypoglycemia
Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type, and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may change over time in the same patient; awareness may be less pronounced in those with long-standing diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia. In clinical trials insulin NPH has been associated with a modestly increased risk of hypoglycemia (including nocturnal hypoglycemia) compared with long-acting analogs (Lipska 2017; Rosenstock 2005; Rys 2015; Singh 2009). However, an observational study in patients with type 2 diabetes from a large health care delivery system found no difference in the incidence of ER visits or hospitalization for hypoglycemia with NPH compared with glargine/detemir when treating to conventional targets in a real world setting (Lipska 2018).
• Hypersensitivity: Hypersensitivity reactions (serious, life-threatening and anaphylaxis) have occurred. If hypersensitivity reactions occur, discontinue administration and initiate supportive care measures.
• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium and supplement potassium when necessary.
Disease-related concerns:
• Bariatric surgery:
– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (Korner 2009; Peterli 2012). Rates and timing of type 2 diabetes improvement and resolution vary widely by patient. Insulin dose reduction of ≥75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014). Avoid the use of bolus insulin injections or dose conservatively with close clinical monitoring in the early phases after surgery.
– Weight gain: Insulin therapy is preferred if antidiabetic therapy is required during the perioperative period (Mechanick 2019). Evaluate risk versus benefit of long-term postoperative use and consider alternative therapy due to potential for insulin-induced weight gain (Apovian 2015).
• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.
• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.
Special populations:
• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia). A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2022).
Dosage form specific issues:
• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC, 2012).
Other warnings/precautions:
• Administration: Insulin NPH is NOT intended for IV or IM administration.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Insulins. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Insulins. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Risk D: Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: Consider reducing the liraglutide dose if coadministered with insulin. Prescribing information for the Saxenda brand of liraglutide recommends a dose decrease of 50%. Monitor blood glucose for hypoglycemia. Risk D: Consider therapy modification
Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely for signs and symptoms of hypoglycemia. Risk D: Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, consider insulin dose reductions to avoid hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure, and consider pioglitazone dose reduction or discontinuation if heart failure occurs Risk D: Consider therapy modification
Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Risk D: Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Risk X: Avoid combination
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2022; Blumer 2013).
Due to pregnancy-induced physiologic changes, insulin requirements tend to increase as pregnancy progresses, requiring frequent monitoring and dosage adjustments. Following delivery, insulin requirements decrease rapidly (ACOG 201 2018; ADA 2022).
Insulin is the preferred treatment of type 1 and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus, when pharmacologic therapy is needed (ACOG 190 2018; ACOG 201 2018; ADA 2022). NPH insulin may be used to treat diabetes mellitus in pregnancy (ACOG 190 2018; ACOG 201 2018; Blumer 2013)
Both exogenous and endogenous insulin are present in breast milk (study not conducted with this preparation) (Whitmore 2012). Insulin is not systemically absorbed via breast milk but may provide local benefits to the infant GI tract (Anderson 2018).
Appropriate glycemic control is required for the establishment of lactation in patients with diabetes mellitus (Anderson 2018). Breastfeeding provides metabolic benefits to mothers with type 1, type 2, and gestational diabetes mellitus as well as their infants; therefore, breastfeeding is encouraged (ACOG 201 2018; ADA 2022; Blumer 2013). Breastfeeding also influences maternal glucose tolerance; close monitoring of patients treated with insulin is recommended as dose adjustments may be required (ADA 2022; Anderson 2018). A small snack before breastfeeding may help decrease the risk of hypoglycemia in patients with pregestational diabetes (ACOG 201 2018; Reader 2004). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Diabetes mellitus: Blood glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors) (ADA 2022); electrolytes; renal function; hepatic function; weight.
Gestational diabetes mellitus: Blood glucose 4 times daily (1 fasting and 3 postprandial) until well controlled, then as appropriate (ACOG 190 2018).
Hospitalized patients: In patients who are eating, monitor blood glucose before meals and at bedtime; in patients who are not eating or are receiving continuous enteral feeds, monitor blood glucose every 4 to 6 hours (ADA 2022; ES [Umpierrez 2012]). More frequent monitoring may be required in some cases (eg, recurrent hypoglycemia, changes in nutrition, medication changes affecting glycemic control) (ES [Umpierrez 2012]).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2022; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (ADA 2022):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2022):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Pregnant patients:
HbA1c: Pregestational diabetes (type 1 or type 2) (ADA 2022):
Preconception (patients planning for pregnancy): <6.5%.
During pregnancy <6% (if can be achieved without significant hypoglycemia) or <7% if needed to prevent hypoglycemia.
Capillary blood glucose: Note: Less stringent targets may be appropriate if goals cannot be achieved without causing significant hypoglycemia (ADA 2022).
Gestational diabetes mellitus (ACOG 190 2018; ADA 2022):
Fasting: <95 mg/dL.
Postprandial: <140 mg/dL (at 1 hour) or <120 mg/dL (at 2 hours).
Pregestational diabetes mellitus (type 1 or type 2) (ADA 2022 ):
Fasting: 70 to 95 mg/dL.
Postprandial: 110 to 140 mg/dL (at 1 hour) or 100 to 120 mg/dL (at 2 hours).
Hospitalized adult patients (ADA 2022): Target glucose range: 140 to 180 mg/dL (majority of critically ill and noncritically ill patients; <140 mg/dL may be appropriate for selected patients, if it can be achieved without excessive hypoglycemia). Initiate insulin therapy for persistent hyperglycemia at ≥180 mg/dL.
Perioperative care in adult patients (ADA 2022): Target glucose range during perioperative period: Consider targeting 80 to 180 mg/dL.
Children and adolescents:
Preprandial glucose: 70 to 130 mg/dL (ISPAD [Dimeglio 2018]).
Postprandial glucose: 90 to 180 mg/dL (ISPAD [Dimeglio 2018]).
Bedtime/overnight glucose: 80 to 140 mg/dL (ISPAD [Dimeglio 2018]).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia; less aggressive goals (<7.5% or <8%) may be appropriate in patients who cannot articulate symptoms of hypoglycemia, cannot check glucose frequently, have a history of severe hypoglycemia, or have extensive comorbid conditions (ADA 2022; ISPAD [Dimeglio 2018]).
Surgical patients (ISPAD [Jefferies 2018]):
Intraoperative: 90 to 180 mg/dL.
ICU, postsurgery: 140 to 180 mg/dL.
Classification of hypoglycemia (ADA 2022):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.
Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Insulin stimulates lipoprotein lipase synthesis and activity; this results in hydrolysis of triglycerides into free fatty acids and storage of free fatty acids in adipocytes, thereby reducing circulating triglyceride levels (Rawla 2018; Sadur 1982; Song 2019). In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.
Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin NPH, an isophane suspension of human insulin, is an intermediate-acting insulin.
Note: Onset and duration of hypoglycemic effects depend upon the route of administration (absorption and onset of action are more rapid after deeper IM injections than after SUBQ), site of injection (onset and duration are progressively slower with SUBQ injection into the abdomen, arm, buttock, or thigh respectively), volume and concentration of injection, and the preparation administered. Rate of absorption, onset, and duration of activity may be affected by exercise, presence of lipodystrophy, local blood supply, and/or temperature.
Onset of action: 1 to 2 hours.
Peak effect: 4 to 12 hours.
Duration: 14 to 24 hours.
Time to peak, plasma: 6 to 10 hours.
Suspension (HumuLIN N Subcutaneous)
100 units/mL (per mL): $17.84
Suspension (NovoLIN N ReliOn Subcutaneous)
100 units/mL (per mL): $16.52
Suspension (NovoLIN N Subcutaneous)
100 units/mL (per mL): $16.52
Suspension Pen-injector (HumuLIN N KwikPen Subcutaneous)
100 units/mL (per mL): $37.70
Suspension Pen-injector (NovoLIN N FlexPen ReliOn Subcutaneous)
100 units/mL (per mL): $20.82
Suspension Pen-injector (NovoLIN N FlexPen Subcutaneous)
100 units/mL (per mL): $20.82
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