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The exogenously administered insulins exert their primary effect of lowering blood glucose levels via the promotion of glucose uptake into peripheral skeletal muscle and adipose tissue, the inhibition of glycogenolysis (the hydrolysis of glycogen to glucose), and the inhibition of gluconeogenesis (hepatic glucose 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 inhibiting proteolysis in muscle tissue). Biosynthetic insulins are used as replacement therapy in patients with Type 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 different individuals 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, and consequently the onset of activity are known to be affected by the site of injection, exercise, and several other variables.
Characteristics of Rapid Acting and Short Acting Insulins
Insulin aspart* (rapid)
Novolog: 15 minutes (range 10 to 20 minutes)
Fiasp: 10 minutes
Novolog: 40 to 50 minutes
Fiasp: 91 to 133 minutes
Novolog: 3 to 5 hours
Fiasp: less than Novolog
Administered around meals for rapid acting products; 30 to 60 minutes before meals for regular insulin; covers insulin needs for meals
Rapid acting insulins mimic endogenous insulin secretion after meals in non-diabetic patients
Subcutaneous absorption of rapid acting insulins is less variable than regular insulin
Regular insulin is available in 2 concentrations; ONLY regular insulin 100 units/mL may be administered intravenously.
Insulin glulisine* (rapid)
3 to 5 hours
Insulin lispro (rapid)
15 to 30 minutes
30 to 90 minutes
Regular insulin* U-100 (short)
30 minutes (range 10 to 75 minutes)
1.5 and 3.5 hours
8 hours (mean 5 to 7 hours)
Insulin, inhaled (Human Recombinant) (rapid)
35 to 55 minutes
2.5 to 3 hours
*Data available to support IV administration in selected clinical situations
Characteristics of Intermediate and Long-Acting Insulins
Isophane insulin (NPH) (intermediate)
4 to 12 hours
Unwanted peaks of NPH insulin may lead to hypoglycemia; long acting insulins have decreased variability in patient response than NPH and decreased hypoglycemia
Insulin glargine and Insulin degludec provide basal coverage for 24 hours with a relatively constant concentration/time profile; other longer-acting insulins administered 1 to 2 times/day
Concentrated regular human insulin (500 units/mL) has different pharmacokinetic from lower concentrations of regular insulin, including a slower peak and longer duration of action
Insulin detemir (long)
1 to 2 hours
6 to 8 hours
Insulin glargine U-100 (long)
Insulin glargine U-300 (long)
Insulin degludec (long)
At least 42 hours
Human Regular Insulin U-500 (intermediate)
4 to 8 hours
13 to 24 hours (mean 21 hours)
Characteristics of Pre-Mixed Insulins
Insulin aspart (30%), insulin aspart protamine (70%)
10 to 20 minutes
1 to 4 hours
Up to 24 hours
Advantages include a decreased number of injections and mixing elimination
Fixed ratios may not meet all glycemic reduction needs
2/3 of the daily insulin dose is given before 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%)
0.8 to 6.5 hours (mean 2.3 to 2.6 hours)
12 to 24 hours
Regular insulin (30%), NPH (70%)
Regular insulin (50%), NPH (50%)
30 to 60 minutes
1 to 5 hours
more than 42 hours
Insulin Comparative Efficacy Trials
Home, et al. Diabet Med 2000;17:762-770.
Prospective, randomized, open-label parallel-group trial comparing insulin aspart (n = 698) and regular human insulin (n = 349) before main meals in Type 1 DM with NPH as basal insulin
Mean A1C after 6 months: Insulin aspart: 7.88 +/- 0.03 vs. regular insulin: 8 +/- 0.04; p less than 0.02
Slight improvements in preprandial and postprandial glucose concentrations for insulin aspart vs. regular insulin
Slight differences in glucose control exist between insulin aspart and regular human insulin. Insulin aspart may be advantageous to human insulin for long-term glucose control.
Dailey, et al. Diabetes Care 2004;27:2363- 2368.
Phase III open-label, parallel group RCT comparing insulin glulisine (n = 435) to regular human insulin (n = 441) in Type 2 DM with NPH as basal insulin
Oral hypoglycemic use at randomization: 56.3% for insulin glulisine vs. 59.6% for regular human insulin
Mean A1C at 6.5 months: 7.11% for insulin glulisine vs. 7.22% for regular insulin, p = 0.0029
Mean post-prandial glucose levels at 6.5 months (glulisine vs. regular human insulin):
Breakfast: 156 vs. 162 mg/dL; p less than 0.05
Dinner: 154 vs. 163 mg/dL; p less than 0.05
Oral hypoglycemic use at endpoint (all treatment groups): 58.4%
Insulin glulisine in combination with NPH is associated with small improvements in glucose control relative to regular human insulin with NPH in Type 2 DM.
Roach P, et al. Clin Ther 1999;21:523-534.
Randomized, open-label crossover study comparing glycemic control between premixed lispro/lispro-protamine and human insulin mixtures (regular/NPH) in Type 1 and Type 2 DM
One group of each DM type received lispro mixtures first, followed by human mixtures. Other 2 groups received human mixtures 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 all patients after breakfast: Regular/NPH insulin: 9.74 vs. Lispro/lispro-protamine insulin: 7.83; p is less than 0.001
Fasting glucose, post-prandial lunch and dinner glucose concentrations not significantly different between groups.
Insulin lispro mixtures provided similar overall glycemic control when compared to human insulin, and improved post-prandial control at breakfast.
Riddle, et al. Diabetes Care 2003;26:3080-3086.
Randomized, open-label parallel group trial comparing insulin glargine (n = 367) to NPH human insulin (n = 389) at bedtime in Type 2 DM; all patients required to have stable doses of 1 to 2 oral antidiabetes drugs for at least 3 months
Started with 10 units/kg for both insulins at bedtime; titrated weekly to target fasting plasma glucose 100 mg/dL or less
Over 70% taking both metformin and sulfonylurea at baseline
Mean daily dose at 6 months: Insulin glargine: 47.2 +/- 1.3 units vs. NPH: 41.8 +/- 1.3 units; p less than 0.05
Mean A1C at 6 months: Insulin glargine: 6.96% vs. NPH: 6.97%
A1C 7% or greater with no documented nocturnal hypoglycemia: Insulin glargine: 33.2% vs. NPH: 26.7%; p is less than 0.05
Fasting plasma glucose 100 mg/dL or less with no documented nocturnal hypoglycemia: Insulin glargine: 22.1% vs. NPH: 15.9%; p <is less than 0.03
Insulin glargine and NPH achieved similar A1C and fasting plasma glucose levels. Insulin glargine was associated with less hypoglycemia.
Home, et al. Diabetes Care 2004;27:1081-1087.
Randomized, open-label parallel group trial comparing insulin detemir to NPH human insulin in Type 1 DM with insulin aspart 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 breakfast and at bedtime (n = 132)
Mean A1C (SE) at 4 months: Insulin detemir before breakfast and bedtime: 7.78 +/- 0.07% vs. Insulin detemir at 12 h intervals: 7.75 +/- 0.07% vs NPH: 7.94 +/- 0.07%; p = 0.027 for both determir groups vs. NPH
Mean pre-breakfast plasma glucose at 4 months (mmol/L): Insulin detemir before 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 detemir before breakfast and bedtime: 2.91 (95% CI 2.7 to 3.05) vs. insulin detemir at 12 h intervals: 2.95 (95% CI 2.8 to 3.1) vs. NPH: 3.49 (95% CI 3.31 to 3.68); p less than 0.001 for both detemir groups vs. NPH
Insulin detemir was superior to NPH for overall glucose control when used in a basal bolus regimen with insulin aspart. Significantly less weight gain occurred with insulin detemir.
Heller, et al. Lancet 2012;379:1489. 
Randomized, controlled, open-label, treat to target, non-inferiority 52-week trial comparing treatment with once-daily insulin degludec (n = 472) to once-daily insulin glargine (n = 157) in Type 1 DM with insulin aspart as meal time insulin
Patients were receiving basal-bolus insulin therapy for at least one year prior to study initiation.
Reduction in A1C after 1 year: 0.40% points for insulin degludec and 0.39% points for insulin glargine,(estimated treatment 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 confirmed hypoglycemia (PG less than 3.1 mmol/L or severe): insulin degludec 42.54 vs. insulin glargine 40.18 episodes per patient-year of exposure; estimated rate ratio 1.07 [0.89 to 1.28]; p = 0.48)
Rate of nocturnal confirmed hypoglycemia: 25% lower with degludec than with glargine (4.41 vs. 5.86 episodes per patient-year of exposure; 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 of exposure for the insulin degludec and insulin glargine groups
Reduction in A1C from baseline with insulin degludec and insulin glargine was similar, thus establishing non-inferiority of insulin degludec to insulin glargine in improving long-term glycemic control in Type 1 diabetes. Insulin degludec also exhibited a decreased risk of nocturnal hypoglycemia.
Zinman, et al. Diabetes Care 2012;35:2464-2471.
Randomized, open-label, treat-to-target 52-week trial comparing insulin degludec with glargine for efficacy and safety in insulin-naive patients with Type 2 DM inadequately controlled with oral antidiabetic drugs (OADs)
Patients with A1C of 7 to 10% were randomized to receive once daily degludec (n = 773) or glargine (n = 257), both with metformin. Insulin was titrated to achieve pre-breakfast plasma glucose (PG) of 3.9-4.9 mmol/L
Reduction in A1C after 1 year: insulin degludec 1.06% vs. insulin glargine 1.19%, (estimated treatment difference 0.09%) [95% CI -0.04 to 0.22)
Rates of overall confirmed hypoglycemia (PG less than 3.1 mmol/L or severe episodes requiring assistance): insulin degludec 1.52 vs insulin glargine 1.85 episodes per patient-year of exposure
Rate of nocturnal confirmed hypoglycemia: insulin degludec 0.25 vs. insulin glargine 0.39 episodes per patient-year of exposure; p = 0.038
A1C less than 7% without hypoglycemia: insulin degludec 42% vs insulin glargine 46%; P = 0.34
End-of-trial mean daily insulin doses: 0.59 units/kg for insulin degludec and 0.60 units/kg for insulin glargine
Adverse event rates were similar
Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with Type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec.
Bode, et al. Diabetes Care 2015.
Randomized, open-label, non-inferiority 24-week trial comparing the change in A1C with prandial inhaled insulin (n = 174) to that of subcutaneous aspart (n = 171), both with basal insulin, in patients with Type 1 DM and A1C 7.5 to 10%
Trial included an initial 4-week basal insulin optimization period for titration of basal insulin dose to a goal FPG level 100 to 120 mg/dL. Mealtime insulin was switched to insulin aspart. Throughout the trial, patients remained on their pre-enrollment basal insulin
Mean change in A1C at 24 weeks: inhaled insulin (–0.21%) vs. insulin aspart (–0.40%). The between-group difference 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 insulin 18.3%
Weight change: inhaled insulin patients had a small weight loss (–0.4 kg) compared with a gain (+0.9 kg) for aspart patients (p = 0.0102)
Rates of hypoglycemia: inhaled insulin patients had a lower hypoglycemia event rate than aspart patients (9.8 vs. 14 events/patient-month, p less than 0.0001)
Adverse Events: Cough (generally mild) was the most frequent adverse event (inhaled insulin 31.6% vs. insulin aspart 2.3%)
In patients with Type 1 DM receiving basal insulin, A1C reduction with inhaled insulin was non-inferior to that of aspart, with less hypoglycemia and less weight gain but increased incidence of cough.
Fulcher, et al. Diabetes Care 2014.
Randomized, open-label, multinational, treat-to-target 26-week trial comparing insulin degludec; insulin aspart with biphasic insulin aspart 70/30 in adults with Type 2 DM inadequately controlled with once- or twice-daily pre- or self-mixed insulin with or without oral antidiabetic drugs. Patients continued on pre-trial oral background therapies which may have included any of the following used alone or in combination: metformin, pioglitazone, DPP-4inhibitor throughout the entire trial
Patients received twice daily injections of insulin degludec; insulin aspart (n = 224) or biphasic insulin aspart 70/30 (n = 222), administered with breakfast and the main evening meal and dose titrated to a self-measured premeal PG target of 4 to 5 mmol/L
Mean A1C at 26 weeks: 7.1% for both groups, with insulin degludec; insulin aspart achieving the prespecified non-inferiority margin for mean change in A1C (estimated treatment difference [ETD] –0.03% points [95% CI –0.18 to 0.13])
Reduction in Fasting PG: treatment with insulin degludec; insulin aspart was superior in lowering fasting PG (ETD –1.14 mmol/L [95% CI –1.53 to –0.76], p less than 0.001) and had a significantly lower final mean daily insulin dose (estimated rate ratio 0.89 [95% CI 0.83 to 0.96], p = 0.002)
Rates of hypoglycemia: fewer confirmed, nocturnal confirmed, and severe hypoglycemia episodes were reported for insulin degludec; insulin aspart compared with biphasic insulin aspart 70/30
Twice daily treatment with insulin degludec; insulin aspart effectively improves A1C and fasting PG levels with fewer hypoglycemia episodes versus biphasic insulin aspart 70/30 in patients with uncontrolled Type 2 DM previously treated with once- or twice-daily pre- or self-mixed insulin.
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. 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. 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. All patients receiving insulin should receive education about the signs and symptoms of hypoglycemia and have action plans for glucose correction.
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. The risk of any potential weight gain should be balanced by the benefits from improved glycemic control.
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 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.
The risk of hypoglycemia may increase with the use of insulin in combination with other antidiabetic agents such as alpha-glucosidase inhibitors, metformin, thiazolidinediones, or oral sulfonylureas. In addition, pioglitazone and troglitazone should be administered with caution as the combined use of insulin with these drugs significantly increases the risk of heart failure or edema.
Beta-blockers can inhibit the compensatory actions of epinephrine's response to hypoglycemia. As such, hypoglycemia can be prolonged. Additionally, beta-blockers can mask the signs and symptoms of hypoglycemia, especially tachycardia. Beta-blockers have also been associated with increasing blood glucose concentrations. While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes. Furthermore, their use should 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 in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.
Thiazide diuretics can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. It appears that the effects of thiazides on glucose control are dose-dependent and low doses can be used without significant effects. Patients on insulin therapy should be monitored for changes in blood glucose control. Insulin dosage adjustments may be necessary.
Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and guanethidine may enhance the hypoglycemic effects of insulin. Patients should therefore be monitored closely for changes in glycemic control.
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.
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.
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.
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