Summary

The insulins are primarily used in the treatment of patients with Type 1 or Type 2 diabetes mellitus.

Treatment goals include achieving appropriate glycemic control, reducing the development andprogression of microvascular complications, and enhancing quality and quantity of life.

The insulins are a heterogeneous class of drugs, differing primarily in their onset of action, time topeak effect, and duration of action; the insulin analogs more closely mimic endogenous insulinsecretion after meals (rapid-acting analogs) and basal insulin secretion (long-acting analogs) ascompared to regular insulin and NPH insulin.

The use of insulin is associated with hypoglycemia and weight gain.

Compared to regular insulin and NPH insulin, the insulin analogs are associated with improvedglycemic control and reduced hypoglycemia.

PharmacologyThe exogenously administered insulins exert their primary effect of lowering blood glucose levels via thepromotion of glucose uptake into peripheral skeletal muscle and adipose tissue, the inhibition ofglycogenolysis (the hydrolysis of glycogen to glucose), and the inhibition of gluconeogenesis (hepaticglucose production). Insulin also regulates fat metabolism by enhancing the storage of fat (lipogenesis)and inhibiting the mobilization of fat for energy in adipose tissues (lipolysis and free fatty acid oxidation).In addition, insulin regulates protein metabolism (through increasing protein synthesis and inhibitingproteolysis in muscle tissue). Biosynthetic insulins are used as replacement therapy in patients withType 1 and Type 2 diabetes mellitus (DM) to restore their ability to properly metabolize carbohydrates,fats, and proteins. Insulin administration also facilitates the replenishment of liver glycogen stores.

The time course of action of the various insulins and insulin analogs may vary considerably in differentindividuals or even within the same individual. The characteristics of activity (time of onset, time to peak,and duration) are listed in the tables as general guidelines. The rate of insulin absorption, andconsequently the onset of activity are known to be affected by the site of injection, exercise, and severalother variables.

Characteristics of Rapid Acting and Short Acting Insulins[50229][63144]

Insulins

Insulin Mean Onset Peak Duration Special Notes

Insulin aspart* (rapid) 10 to 20 minutes 40 to 50minutes

3 to 5 hours Administered around meals for rapid acting products; 30to 60 minutes before meals for regular insulin; covers

insulin needs for meals

Rapid acting insulins mimic endogenous insulin secretionafter meals in non-diabetic patients

Subcutaneous absorption of rapid acting insulins is lessvariable than regular insulin

Regular insulin is available in 2 concentrations; ONLYregular insulin 100 units/mL may be administered

intravenously.

Insulin glulisine* (rapid) 10 to 20 minutes 60 minutes 2 to 4 hours

Insulin lispro (rapid) 10 to 20 minutes 30 to 90minutes

3 to 5 hours

Regular insulin*U-100(short)

30 to 60 minutes 90 to 120minutes

5 to 8 hours

Insulin, inhaled (HumanRecombinant) (rapid)

12 minutes 35 to 55minutes

2.5 to 3hours

*Data available to support IV administration in selected clinical situations

Characteristics of Intermediate and Long-Acting Insulins

Name Onset Peak Duration Special Notes

Isophane insulin(NPH)

(intermediate)

1 to 3hours

4 to12

hours

18 to 24hours

Unwanted peaks of NPH insulin may lead to hypoglycemia; long acting insulinshave decreased variability in patient response than NPH and decreased

hypoglycemia

Insulin glargine and Insulin degludec provide basal coverage for 24 hours with arelatively constant concentration/time profile; other longer-acting insulins

administered 1 to 2 times/day

Concentrated regular human insulin (500 units/mL) has pharmacokinetic differencesfrom lower concentrations of regular insulin, including a slower peak and longer

duration of action

Insulin detemir(long)

1 to 2hours

Nopeak

24 hours

Insulin glargine U-100 (long)

1 to 1.5hours

Nopeak

24 hours

Insulin glargine U-300 (long)

6 hours Nopeak

36 hours

Insulin degludec(long)

1 hour Nopeak

At least42 hours

Human RegularInsulin U-500(intermediate)

30minutes

4 to 8hours

Up to 24hours

Characteristics of Pre-Mixed Insulins

Name Onset Peak Duration Special Notes

Insulin aspart (30%), insulin aspartprotamine (70%)

10 to 20minutes

1 to 3 hours Up to 24 hours Advantages include a decreasednumber of injections and mixing

elimination

Fixed ratios may not meet all glycemicreduction needs

2/3 of the daily insulin dose is givenbefore breakfast and the remaining 1/3

is given before the evening meal

Insulin lispro (25%), insulin lispro protamine(75%)

Insulin lispro (50%), insulin lispro protamine(50%)

10 to 15minutes

1 to 4 hours 16 to 22 hours

Regular insulin (30%), NPH (70%)

Regular insulin (50%), NPH (50%)

30 to 60minutes

1 to 5 hours 12 to 24 hours

Insulin degludec (70%), insulin aspart(30%)

14 minutes 1.5 hours greater than 42hours

Administer once or twice daily with anymain meal and give rapid or short-acting insulin at other meals if needed

Comparative Efficacy

Insulin aspart, insulin lispro, and insulin glulisine are rapid-acting analogs that are consideredequipotent to regular human insulin. When compared to human insulin in clinical trials, all rapid-acting analogs have demonstrated additional decreases in A1C, typically ranging from 0.1% to0.2%. Greater reductions in post-prandial and fasting glucose levels also occur. When compared toeach other, rapid-acting analogs produce similar clinical results.[50197][30573][50198][50199][50200]

Regular insulin is available in 2 concentrations: 100 units/mL and 500 units/mL. Bothconcentrations share a similar peak and onset of action, but U-500 insulin has a duration of actionsimilar to that of NPH (up to 24 hours). Regular U-500 insulin has less day to day variation inabsorption rates and less absorption variation from different body regions compared to regular U-100.[61947] This longer duration of action allows for administration of regular U-500 insulin 2 to 3times per day; regular 100 units/mL is usually administered 3 or more times per day and may alsobe used in combination with oral antihyperglycemic agents or longer-acting insulin products.[44404]

[44405][60488]

Insulin glargine and insulin detemir are long-acting analogs that are considered equipotent toisophane insulin (NPH). Effects on A1C are typically similar to NPH, although some clinical trialshave demonstrated significant differences in favor of the analogs. Fasting glucose levels have beensignificantly lower with the analogs when compared to NPH insulin in several (but not all) trials. Noclinically relevant differences regarding glucose control have been demonstrated between insulinglargine and insulin detemir; however, to achieve equivalent glucose control insulin detemir isfrequently injected twice daily at a higher dose.[50201][50206][50208][50209][50210]

Insulin degludec is a long-acting, once daily insulin that has a longer half-life (25.4 hours) than anyother basal insulin. This long half-life lends itself to a duration of action that is at least 42 hours.[60594] In clinical trials, insulin degludec has been compared to insulin glargine; both insulins reduceA1C levels to a similar degree.[60591][60592][60595][60596]

Insulin Comparative Efficacy Trials

Citation Design/Regimen Results Conclusion

Home, et al. Diabet Med2000;17:762-770.[50197]

Prospective, randomized, open-labelparallel-group trial comparing insulinaspart (n = 698) and regular humaninsulin (n = 349) before main meals inType 1 DM with NPH as basal insulin

Mean A1C after 6 months: Insulinaspart: 7.88 +/- 0.03 vs. regular insulin: 8+/- 0.04; p less than 0.02

Slight improvements in preprandial andpostprandial glucose concentrations forinsulin aspart vs. regular insulin

Slight differences inglucose control existbetween insulinaspart and regularhuman insulin.Insulin aspart maybe advantageous tohuman insulin forlong-term glucosecontrol.

Dailey, et al. DiabetesCare 2004;27:2363-2368.[30573]

Phase III open-label, parallel group RCTcomparing insulin glulisine (n = 435) toregular human insulin (n = 441) in Type 2DM with NPH as basal insulin

Oral hypoglycemic use at randomization:56.3% for insulin glulisine vs. 59.6% forregular human insulin

Mean A1C at 6.5 months: 7.11% forinsulin glulisine vs. 7.22% for regularinsulin, p = 0.0029

Mean post-prandial glucose levels at6.5 months (glulisine vs. regularhuman insulin):

Breakfast: 156 vs. 162 mg/dL; p lessthan 0.05

Dinner: 154 vs. 163 mg/dL; p less than0.05

Oral hypoglycemic use at endpoint(all treatment groups): 58.4%

Insulin glulisine incombination withNPH is associatedwith smallimprovements inglucose controlrelative to regularhuman insulin withNPH in Type 2 DM.

Roach P, et al. Clin Ther1999;21:523-534.[50211]

Randomized, open-label crossover studycomparing glycemic control betweenpremixed lispro/lispro-protamine andhuman insulin mixtures (regular/NPH) inType 1 and Type 2 DM

One group of each DM type receivedlispro mixtures first, followed by humanmixtures. Other 2 groups received humanmixtures followed by lispro mixtures.

Mean A1C at 6 months (all patients):Regular/NPH insulin: 7.57% vs.Lispro/lispro-protamine insulin: 7.72%; p= 0.107

Post-prandial levels (mmol/L) in allpatients after breakfast: Regular/NPHinsulin: 9.74 vs. Lispro/lispro-protamineinsulin: 7.83; p is less than 0.001

Fasting glucose, post-prandial lunch anddinner glucose concentrations notsignificantly different between groups.

Insulin lispromixtures providedsimilar overallglycemic controlwhen compared tohuman insulin, andimproved post-prandial control atbreakfast.

Riddle, et al. DiabetesCare 2003;26:3080-3086.[50208]

Randomized, open-label parallel grouptrial comparing insulin glargine (n = 367)to NPH human insulin (n = 389) atbedtime in Type 2 DM; all patientsrequired to have stable doses of 1 to 2oral antidiabetes drugs for at least 3months

Started with 10 units/kg for both insulinsat bedtime; titrated weekly to targetfasting plasma glucose 100 mg/dL or less

Over 70% taking both metformin andsulfonylurea at baseline

Mean daily dose at 6 months: Insulinglargine: 47.2 +/- 1.3 units vs. NPH: 41.8+/- 1.3 units; p less than 0.05

Mean A1C at 6 months: Insulinglargine: 6.96% vs. NPH: 6.97%

A1C 7% or greater with nodocumented nocturnal hypoglycemia:Insulin glargine: 33.2% vs. NPH: 26.7%;p is less than 0.05

Fasting plasma glucose 100 mg/dL orless with no documented nocturnalhypoglycemia: Insulin glargine: 22.1%vs. NPH: 15.9%; p <is less than 0.03

Insulin glargine andNPH achievedsimilar A1C andfasting plasmaglucose levels.Insulin glargine wasassociated with lesshypoglycemia.

Home, et al. DiabetesCare 2004;27:1081-1087.[50206]

Randomized, open-label parallel grouptrial comparing insulin detemir to NPHhuman insulin in Type 1 DM with insulinaspart as meal time insulin

Insulin detemir (2 groups) regimens:Before breakfast and at bedtime (n =139) or every 12 hours (n = 137)

NPH (1 group) regimen: Before breakfastand at bedtime (n = 132)

Mean A1C (SE) at 4 months: Insulindetemir before breakfast and bedtime:7.78 +/- 0.07% vs. Insulin detemir at 12h intervals: 7.75 +/- 0.07% vs NPH: 7.94+/- 0.07%; p = 0.027 for both determirgroups vs. NPH

Mean pre-breakfast plasma glucose at4 months (mmol/L): Insulin detemirbefore breakfast and bedtime: 8.26 +/-0.2 vs. insulin detemir at 12 h intervals:8.28 +/- 0.2% vs. NPH: 9.05 +/- 0.21%; p= 0.005 for both detemir groups vs. NPH

Weight change (kg): Insulin detemirbefore breakfast and bedtime: 2.91 (95%CI 2.7 to 3.05) vs. insulin detemir at 12 hintervals: 2.95 (95% CI 2.8 to 3.1) vs.NPH: 3.49 (95% CI 3.31 to 3.68); p lessthan 0.001 for both detemir groups vs.NPH

Insulin detemir wassuperior to NPH foroverall glucosecontrol when used ina basal bolusregimen with insulinaspart. Significantlyless weight gainoccurred with insulindetemir.

Heller, et al. Lancet2012;379:1489. [60595]

Randomized, controlled, open-label, treatto target, non-inferiority 52-week trialcomparing treatment with once-dailyinsulin degludec (n = 472) to once-dailyinsulin glargine (n = 157) in Type 1 DMwith insulin aspart as meal time insulin

Patients were receiving basal-bolusinsulin therapy for at least one year priorto study initiation.

Reduction in A1C after 1 year: 0.40%points for insulin degludec and 0.39%points for insulin glargine,(estimatedtreatment difference –0.01% [95% CI –0.14 to 0.11]; p less than 0.0001 for non-inferiority testing)

A1C less than 7% after 1 year: 40%insulin degludec vs 43% insulin glargine

Rates of overall confirmedhypoglycemia (PG less than 3.1mmol/L or severe): insulin degludec42.54 vs. insulin glargine 40.18 episodesper patient-year of exposure; estimatedrate ratio 1.07 [0.89 to 1.28]; p = 0.48)

Rate of nocturnal confirmedhypoglycemia: 25% lower withdegludec than with glargine (4.41 vs.5.86 episodes per patient-year ofexposure; rate ratio 0.75 [0.59 to 0.96]; p= 0.021)

Overall serious adverse event rates:14 vs 16 events per 100 patient-years ofexposure for the insulin degludec andinsulin glargine groups

Reduction in A1Cfrom baseline withinsulin degludec andinsulin glargine wassimilar, thusestablishing non-inferiority of insulindegludec to insulinglargine in improvinglong-term glycemiccontrol in Type 1diabetes. Insulindegludec alsoexhibited adecreased risk ofnocturnalhypoglycemia.

Zinman, et al. DiabetesCare 2012;35:2464-2471.[60592]

Randomized, open-label, treat-to-target52-week trial comparing insulin degludecwith glargine for efficacy and safety ininsulin-naive patients with Type 2 DMinadequately controlled with oralantidiabetic drugs (OADs)

Patients with A1C of 7 to 10% wererandomized to receive once dailydegludec (n = 773) or glargine (n = 257),both with metformin. Insulin was titratedto achieve pre-breakfast plasma glucose(PG) of 3.9-4.9 mmol/L

Reduction in A1C after 1 year: insulindegludec 1.06% vs. insulin glargine1.19%, (estimated treatment difference0.09%) [95% CI -0.04 to 0.22)

Rates of overall confirmedhypoglycemia (PG less than 3.1mmol/L or severe episodes requiringassistance): insulin degludec 1.52 vsinsulin glargine 1.85 episodes perpatient-year of exposure

Rate of nocturnal confirmedhypoglycemia: insulin degludec 0.25vs. insulin glargine 0.39 episodes perpatient-year of exposure; p = 0.038

A1C less than 7% withouthypoglycemia: insulin degludec 42% vsinsulin glargine 46%; P = 0.34

End-of-trial mean daily insulin doses:0.59 units/kg for insulin degludec and0.60 units/kg for insulin glargine

Adverse event rates were similar

Insulins degludecand glargineadministered oncedaily in combinationwith OADs providedsimilar long-termglycemic control ininsulin-naive patientswith Type 2 diabetes,with lower rates ofnocturnalhypoglycemia withdegludec.

Bode, et al. DiabetesCare 2015.[60598]

Randomized, open-label, non-inferiority24-week trial comparing the change inA1C with prandial inhaled insulin (n =174) to that of subcutaneous aspart (n =171), both with basal insulin, in patientswith Type 1 DM and A1C 7.5 to 10%

Trial included an initial 4-week basalinsulin optimization period for titration ofbasal insulin dose to a goal FPG level100 to 120 mg/dL. Mealtime insulin wasswitched to insulin aspart. Throughoutthe trial, patients remained on their pre-enrollment basal insulin

Mean change in A1C at 24 weeks:inhaled insulin (–0.21%) vs. insulinaspart (–0.40%). The between-groupdifference was 0.19% (2.1 mmol/mol)(95% CI 0.02 to 0.36).

A1C less than 7% after 24 weeks:insulin aspart 30.7% vs. inhaled insulin18.3%

Weight change: inhaled insulin patientshad a small weight loss (–0.4 kg)compared with a gain (+0.9 kg) foraspart patients (p = 0.0102)

Rates of hypoglycemia: inhaled insulinpatients had a lower hypoglycemia eventrate than aspart patients (9.8 vs. 14events/patient-month, p less than0.0001)

Adverse Events: Cough (generallymild) was the most frequent adverseevent (inhaled insulin 31.6% vs. insulinaspart 2.3%)

In patients with Type1 DM receiving basalinsulin, A1Creduction withinhaled insulin wasnon-inferior to that ofaspart, with lesshypoglycemia andless weight gain butincreased incidenceof cough.

Fulcher, et al. DiabetesCare 2014.[60600]

Randomized, open-label, multinational,treat-to-target 26-week trial comparinginsulin degludec; insulin aspart withbiphasic insulin aspart 70/30 in adultswith Type 2 DM inadequately controlledwith once- or twice-daily pre- or self-mixed insulin with or without oralantidiabetic drugs. Patients continued onpre-trial oral background therapies whichmay have included any of the followingused alone or in combination: metformin,pioglitazone, DPP-4inhibitor throughoutthe entire trial

Patients received twice daily injections ofinsulin degludec; insulin aspart (n = 224)or biphasic insulin aspart 70/30 (n = 222),administered with breakfast and the mainevening meal and dose titrated to a self-measured premeal PG target of 4 to 5mmol/L

Mean A1C at 26 weeks: 7.1% for bothgroups, with insulin degludec; insulinaspart achieving the prespecified non-inferiority margin for mean change inA1C (estimated treatment difference[ETD] –0.03% points [95% CI –0.18 to0.13])

Reduction in Fasting PG: treatmentwith insulin degludec; insulin aspart wassuperior in lowering fasting PG (ETD –1.14 mmol/L [95% CI –1.53 to –0.76], pless than 0.001) and had a significantlylower final mean daily insulin dose(estimated rate ratio 0.89 [95% CI 0.83to 0.96], p = 0.002)

Rates of hypoglycemia: fewerconfirmed, nocturnal confirmed, andsevere hypoglycemia episodes werereported for insulin degludec; insulinaspart compared with biphasic insulinaspart 70/30

Twice daily treatmentwith insulindegludec; insulinaspart effectivelyimproves A1C andfasting PG levelswith fewerhypoglycemiaepisodes versusbiphasic insulinaspart 70/30 inpatients withuncontrolled Type 2DM previouslytreated with once- ortwice-daily pre- orself-mixed insulin.

Drug Interactions

Antidiabetic drugsThe risk of hypoglycemia may increase with the use of insulin in combination with other antidiabeticagents such as alpha-glucosidase inhibitors, metformin, thiazolidinediones, or oral sulfonylureas. Inaddition, pioglitazone and troglitazone should be administered with caution as the combined use ofinsulin with these drugs significantly increases the risk of heart failure or edema.

Beta-blockersBeta-blockers can inhibit the compensatory actions of epinephrine's response to hypoglycemia. Assuch, hypoglycemia can be prolonged. Additionally, beta-blockers can mask the signs and symptoms ofhypoglycemia, especially tachycardia. Beta-blockers have also been associated with increasing bloodglucose concentrations. While beta-blockers may have negative effects on glycemic control, they reducethe risk of cardiovascular disease and stroke in patients with diabetes.[51005] Furthermore, their useshould not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI,heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown inthe post-MI and heart failure populations when beta-blockers are used, especially in patients withcoexisting diabetes mellitus.[50223]

DiureticsThiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in bloodglucose levels. It appears that the effects of thiazides on glucose control are dose-dependent and lowdoses can be used without significant effects. Patients on insulin therapy should be monitored forchanges in blood glucose control. Insulin dosage adjustments may be necessary.[50223]

Other anti-hypertensive drugs

Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and guanethidine mayenhance the hypoglycemic effects of insulin. Patients should therefore be monitored closely for changesin glycemic control.[50223][21961][42591]

Copyright © 2021 Elsevier Inc. All rights reserved.

Appendix A Therapeutic Use Therapeutic Use Table

Indications Insulin

(Human Recombinant)

Insulin Aspart

Insulin Aspart , Insulin Aspart

Protamine

Insulin Aspart , Insulin

Degludec

Insulin Degludec

Insulin Detemir

Insulin Glargine

Insulin Glulisine

Insulin Isophane (NPH) , Insulin

Regular

Insulin Lispro

Insulin Lispro, Insulin Lispro

Protamine (NPL)

Insulin Regular

Insulin Regular ,

Insulin Suspension Isophane

(NPH)

Insulin Suspension Isophane

(NPH)

Renal Impairment Dosing Adjustment

Yes

Hepatic Impairment Dosing Adjustment

Yes Yes Yes Yes Yes

diabetic ketoacidosis

Yes † Yes † Yes

hyperkalemia Yes † hyperosmolar hyperglycemic state (HHS)

Yes

nutritional supplementation

Yes †

gestational diabetes

Yes Yes Yes Yes Yes Yes

type 1 diabetes mellitus

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

type 2 diabetes mellitus

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes – Labeled Yes † – Off-label, Recommended NR – Off-label, Not Recommended

Dosage requirements are variable, ranging from 0.4 to 1 units/kg/day. Initial therapy can be less aggressive in type 2 DM than for type 1 DM. For type 1 DM, general insulin requirements range from 0.4 to 1 units/kg/day; most patients will require at least 3 administrations of insulin daily to achieve glycemic control.[60607] For type 2 DM, the average initial dose range is 0.2 to 0.6 units/kg/day. When used in combination with oral hypoglycemic agents, many patients with type 2 DM can be initially controlled on a single administration of a longer-acting insulin at a dosage of 10 units per day or 0.1 to 0.2 units/kg/day. However, most patients with type 2 DM will eventually require multiple administrations and total daily doses of 1 unit/kg/day or higher.[60607]

The ultimate goal of treatment in adults is to attain and maintain glycemic control (A1C less than 6.5 to 7, pre-prandial glucose 80 to 130 mg/dL, post-prandial glucose less than 180 mg/dL), improve clinical outcomes (particularly microvascular and macrovascular complications), and reduce mortality.[50185][50186][50187][50188][50189][34541][50190][50191][50321][60607][60608]

In the treatment on type 1 diabetes, insulin therapy may be initiated with a basal-bolus regimen and then further individualized to achieve treatment goals. In the treatment on type 2 diabetes, insulin is generally reserved for patients who continue to have an A1C above target despite dual/triple therapy with metformin and other antidiabetic agents. GLP-1 receptor agonists (GLP-1 RA) are generally the preferred choice to insulin in type 2 DM. Evidence from trials comparing GLP-1 RAs and insulin (basal, premixed, or basal-bolus) shows similar or even better efficacy in A1C reduction; GLP-1 RAs have a lower risk of hypoglycemia and are associated with reductions in body weight compared to weight gain with insulin. In patients who cannot

tolerate a GLP-1 RA, or who fail to meet glycemic targets with dual/triple therapy, insulin therapy with basal insulin should be initiated and titrated to target. If the A1C remains above target, prandial insulin should be added. Consider initial injectable combination (i.e., GLP-1 RA plus basal insulin or prandial/basal insulin) if A1C is greater than 10% and 2% above target. Consider the early introduction of insulin if there is evidence of ongoing catabolism, if symptoms of hyperglycemia are present, or when A1C levels (greater than 10%) or blood glucose levels (300 mg/dL or more) are very high. In patients who are starting on insulin therapy and are taking a thiazolidinedione or sulfonylurea, discontinue or reduce the dose of the oral medication.[50321][60607][60608]

Numerous studies, including the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), have demonstrated that early intensive glycemic control reduces the risk of microvascular complications and may decrease the risk of macrovascular events.[50186][50188][19204][50196]

For routine use, insulin is administered via the subcutaneous route; however, the extent and rate of absorption of exogenous insulin from the subcutaneous tissue (such as the abdomen, upper arm, anterior and lateral aspects of the thigh, and buttocks) may be affected by a number of different factors, including blood perfusion, amount of adipose tissue at the injection site, depth of injection, temperature of the skin, and properties of the insulin molecule.[50195]

Appendix B Adverse Reactions/Side Effects

Top 20 Adverse Reactions / Side Effects Table

Adverse Reaction / Side

Effect

Insulin (Human

Recombinant)

Insulin Aspart

Insulin Aspart , Insulin Aspart

Protamine

Insulin Aspart , Insulin

Degludec

Insulin Degludec

Insulin Detemir

Insulin Glargine

Insulin Glulisine

Insulin Isophane (NPH) , Insulin Regular

Insulin Lispro

Insulin Lispro, Insulin Lispro

Protamine (NPL)

Insulin Regular

Insulin Regular , Insulin

Suspension Isophane

(NPH)

Insulin Suspension

Isophane (NPH)

hypertension Reported Reported Reported Reported Reported Reported 19.6% 3.9% Reported Reported Reported Reported Reported Reported hypoglycemia 67% 27 - 75% 47 - 69% >10% >10% >10% >10% >10% >10% >10% Reported >10% >10% >10%

headache 3.1 - 4.7% 5 - 12% 9 - 35% 5.6 - 9.7%

8.8 - 11.8%

6.5 - 31%

5.5 - 10.3%

5 - 7% 5 - 10% 11.6 - 29.6%

5 - 10% 5 - 10% 5 - 10%

peripheral edema Reported Reported

1.8 - 2.2%

0.9 - 3% Reported 20% 7.5% Reported Reported Reported Reported Reported Reported

wheezing 29% Reported Reported Reported Reported Reported Reported Reported Reported Reported Reported Reported Reported injection site reaction Reported 2% 3.8% <0.5% 2.7% Reported Reported 1 - 21% Reported Reported Reported Reported

infection <2.3% 5.9 - 23%

5 - 12% <9.1% <11.9% 5 - 35.8%

5 - 29% 6.6 - 10.5%

6 - 13.6%

pharyngitis 20.2 - 23.9%

6 - 7% 11.1 - 24.6%

12.9 - 23.9%

9.5 - 17.2%

7.1 - 12.8%

7.6 - 10.6%

6.6 - 33.3%

diarrhea 2.7% 3.2 - 5.4%

7 - 8% 5.1 - 6.3%

11.8% 10.7% 8.6%

influenza 5.8 - 7.7%

13% 6.9% 6.2 - 13.8%

18.7% 4 - 6.2%

rhinitis 3.8 - 6.2%

5% <6.5% 5 - 5.2% 8.1 - 24.7%

abdominal pain 5% 5% 5.3 - 13.4%

7.4%

back pain 4 - 5.2% 7% 8.1% 12.8% cough 25.6 - 29.4% <8.2% 12.1% 17.3%

fever 6.2 - 8.4%

<10.3% 6.2%

sinusitis 5% 5.1% 18.5% arthralgia 14.2% Reported cataracts 18.1% depression 10.5%

hyporeflexia 11%

Hypoglycemia It is estimated that 90% of all patients receiving insulin will experience a hypoglycemic event. Although difficult to define in quantitative terms, plasma glucose of less than 60 mg/dL after an overnight fast and plasma glucose of less than 50 mg/dL after a carbohydrate meal are generally considered to be below normal.[50212] Hypoglycemia can manifest as hunger, pallor, nausea or vomiting, fatigue, diaphoresis, headache, palpitations, numbness of the mouth, tingling in the fingers, tremor, muscle weakness, blurred vision, hypothermia, uncontrolled yawning, irritability, mental confusion, sinus tachycardia, shallow breathing, and loss of consciousness. It should be noted hypoglycemia unawareness, a condition in which patients are less aware that they are hypoglycemic, is increased in patients with a long history of diabetes due to autonomic nervous system dysfunction or taking beta-blockers. Data from clinical trials suggest that use of rapid-acting (insulin aspart, insulin glulisine, and insulin lispro) and basal insulin analogs (insulin detemir, insulin glargine, and insulin degludec) may result in a decreased risk of hypoglycemia compared with traditional human insulin. Insulin degludec has been shown to have a significantly lower rate of nocturnal hypoglycemia compared to insulin glargine in both Type 1 and Type 2 DM.[60592][60595][60602][60604] However, rates of overall hypoglycemia have only been shown to be significantly lower in patients with Type 2 DM; patients with Type 1 DM had a slightly higher rate

of hypoglycemia with insulin degludec compared to insulin glargine.[60604] All patients receiving insulin should receive education about the signs and symptoms of hypoglycemia and have action plans for glucose correction.[50197][50208][30647][50214][50216][50217]

Weight gain Excess weight gain may occur with insulin therapy; the amount of weight gain varies with the intensity of the insulin treatment regimen utilized. In the Diabetes Control and Complications Trial (DCCT), patients who were treated with an intensive insulin regimen gained 4.75 kg more than patients on conventional therapy. Insulin detemir is associated with less weight gain than insulin glargine or NPH insulin. A meta-analysis directly comparing detemir and glargine demonstrated a significant difference of 0.91 kg weight gain between the drugs. In a trial comparing inhaled insulin to insulin aspart, patients using insulin aspart experienced a 0.9 kg weight gain (p = 0.0102) in contrast to patients using inhaled insulin, who experienced a small weight loss.[60598] The risk of any potential weight gain should be balanced by the benefits from improved glycemic control.[19204][50201][50206][50219][50220][50221]

Injection site reactions Injection site reactions such as lipohypertrophy and lipoatrophy can occur following subcutaneous administration of insulin. Lipodystrophy reactions can be avoided by rotating the sites of injection so that a site is not used more than once every 1 to 2 months.

Insulin resistance Insulin resistance may develop in patients requiring daily insulin injections. Exogenously administered insulin has the ability to cause anti-insulin antibodies, which may cause chronic insulin resistance in patients with Type 1 DM. If hyperglycemia resulting from apparent chronic insulin resistance due to anti-insulin antibodies is present, changing the insulin source to a less antigenic product may be helpful. Corticosteroids have been used if changing to a different insulin species source is not effective. In patients with Type 2 DM, insulin resistance is usually associated with obesity and a decrease in tissue sensitivity to insulin. Treatments for Type 2 DM include weight loss and or institution of insulin-sensitizing drugs such as metformin or a thiazolidinedione.[30440]

Appendix C Safety Issues

Safety Issues Table

Safety Issue Insulin (Human

Recombinant)

Insulin Aspart

Insulin Aspart , Insulin Aspart

Protamine

Insulin Aspart , Insulin

Degludec

Insulin Degludec

Insulin Detemir

Insulin Glargine

Insulin Glulisine

Insulin Isophane (NPH) , Insulin Regular

Insulin Lispro

Insulin Lispro, Insulin Lispro

Protamine (NPL)

Insulin Regular

Insulin Regular , Insulin

Suspension Isophane

(NPH)

Insulin Suspension

Isophane (NPH)

REMS MedGuide Yes acute bronchospasm BBW asthma X-BBW chronic obstructive pulmonary disease (COPD)

X-BBW

hypoglycemia X X X X X X X X X X X X X X pulmonary disease X-BBW

X – Contraindicated X-BBW – Contraindicated and Black Box Warning BBW – Black Box Warning, Not Contraindicated Yes – REMS or MedGuide is available

Hypoglycemia Insulin is contraindicated during episodes of hypoglycemia. Patients at risk for hypoglycemia include those who are geriatric or who have brittle diabetes, have received an overdose of insulin, have a delayed or decreased food intake, or are undergoing an excessive amount of exercise relative to their usual insulin dose. Additionally, patients with renal impairment may be at increased risk of hypoglycemia.

Pediatrics Special attention must be given to caloric intake, insulin dosage adjustments, and avoidance of low blood glucose concentrations during the treatment of children and infants receiving insulin. Because children may not be able to identify symptoms of hypoglycemia, target plasma glucose concentrations and A1C treatment goals are higher compared to adult patients.[50226][54796]

Acute Bronchospasm Inhaled insulin is contraindicated in patients with chronic pulmonary disease, such as asthma or chronic obstructive pulmonary disease (COPD) because of the risk of acute bronchospasm in these patients. Prior to initiating therapy with inhaled insulin, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients. Assess pulmonary function (e.g., spirometry) after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of 20% or greater in FEV1 from baseline, consider discontinuing inhaled insulin. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue inhaled insulin.[57572]