Endocrinology Metabolism

Advanced Insulin Usage in the Outpatient Setting

Basal-bolus insulin (Multiple Daily Injections [MDI]) - General Description


This regimen refers to treatment with three or more injections per day using a basal insulin and prandial or bolus insulin. NPH, glargine or detemir insulin are generally used as basal insulin and may be administered as once or twice daily injections. The options for prandial insulin include regular insulin and rapid-acting insulin analogs such as lispro, aspart or glulisine. Regular insulin has a longer duration of action, slower onset and higher likelihood of hypoglycemia. Regular insulin should be given 30 minutes prior to eating. It peaks at 2 to 4 hours and can last 5 to 8 hours. The rapid-acting insulin analogs, such as lispro, aspart and glulisine, should be given 5 to 15 minutes prior to eating and adjusted based on pre-meal blood glucose levels, the carbohydrate content of the meal and anticipated activity. These shorter-acting insulins peak at 45 to 75 minutes and last 2 to 4 hours.


All patients with type 1 diabetes should be started on basal-bolus insulin therapy as early as possible. Intensive therapy may slow the progression of beta cell dysfunction in type 1 diabetes. Patients with Type 2 diabetes, who are unable to achieve hemoglobin A1c, fasting/preprandial and 2-hour postprandial glycemic goals using oral agents plus or minus basal insulin are also good candidates.


This is the ideal regimen in terms of physiological action, flexibility and glycemic control. A basal-bolus regimen can be used to achieve glycemic control in patients with elevated fasting and/or postprandial glucose excursions, matched to any type of diet and any type of lifestyle.


Patients need to be motivated, able and willing to use 4-5 injections daily and perform frequent blood glucose monitoring at least four times per day prior to meals and at bedtime. Comprehensive training in matching insulin to food intake (carbohydrate counting) and insulin adjustment for elevated or low sugars is required. The incidence of hypoglycemia and weight gain is higher with MDI.

Initiation of the basal-bolus regimen in type 2 diabetes

Basal insulin

Several options exist for basal insulin:

  1. NPH insulin is an intermediate-acting insulin with onset at about 2 hours, peak between 4-12 hours, and has a duration of action up to 24 hours, but closer to 12 to 16 hours.

  2. Glargine or detemir insulin are longer-acting basal insulins, with onset of action at around 2 hours and duration of action of 6-24 hours for detemir and 24 hours or longer for glargine. Glargine is reported to be peakless. Detemir may have a slight peak at 3-9 hours.

  3. Degludec insulin is ultra long acting basal insulin with a half-life of over 24 hours and a duration of effect of greater than 42 hours. There is a decrease in glycemic variability compared to glargine.

A common starting dose of basal insulin is 0.2 units/kg body weight, but most patients with Type 2 diabetes are insulin resistant and may require closer to 0.4 to 0.8 units/kg body weight. Bedtime intermediate-acting insulin (NPH insulin) or bedtime or morning long-acting insulin (glargine or detemir) can be initiated at a dose of 0.2 units/kg body weight or 10 units. Basal insulin should be titrated based on fasting blood glucose (FBG) readings.

The Treat-to-Target study in 2003 looked at adding bedtime NPH or glargine insulin to one or two oral agents. This study used an algorithm with an initial basal insulin dose of 10 units at bedtime and adjusted the dose weekly based on the mean FBG values from the preceding 2 days. The target FBG was less than or equal to 100 mg/dL. The dose increase for basal insulin was 8 units if FBG was above 180 mg/dL, 6 units if FBG was 140-180 mg/dL, 4 units if FBG was 120-140 mg/dL, and 2 units if FBG was 100-120 mg/dL. Most patients achieved A1c below 7% with greater hypoglycemia in the NPH group.

A 2005 study by the AT.LANTUS group evaluated a physician-led versus a patient-directed algorithm for titration of glargine insulin until fasting sugar was at a target of between 72-100 mg/dL. The physician-led group had titration of glargine every week versus every 3 days in the patient-directed group. The adjustment in daily basal insulin glargine dose was based on the mean FBG for the previous 3 days. In the physician-led group, the increase in glargine was 0-2 units for FBG between 100-119 mg/dL, 2 units for FBG 120-139 mg/dL, 4 units for FBG 140-179 mg/dL, and 6-8 units for FBG 180 mg/dL or above. In the patient-directed group, the increase in glargine was 0-2 units for FBG between 100-120 mg/dL and 2 units for every level after that. No significant differences in metabolic control or hypoglycemia were found, illustrating that patient-directed titration of basal insulin is safe and efficacious.

The PREDICTIVE 303 study used a simple self-titration algorithm for insulin detemir. The dose was to be reduced by 3 units if FBG was below 80 mg/dL, no change was made if FBG was 80-110 mg/dL, and the dose was increased by 3 units if FBG was above 110 mg/dL. Self-titration every 3 days was compared with standard of care and found to be safe and efficacious as well, with minimal hypoglycemia and no weight gain.

A nice primary care review by Hirsch et al. in 2005 recommends that basal insulin be titrated to keep FBG between 80-109 mg/dL. The dosage of basal insulin should be lowered by 2 units if FBG is below 80 mg/dL, increased by 2 units if FBG is 110-139 mg/dL, increased by 4 units if FBG is 140-179 mg/dL, and increased by 6 units if FBG is greater than 180 mg/dL.

Mooradian et al. describe a protocol for titration of basal insulin in a 2006 paper, recommending a goal FBG of 80-99 mg/dL. Their recommended adjustment of the basal insulin dose is: addition of 8 units for FBG above 180 mg/dL, addition of 6 units for FBG 160-180 mg/dL, addition of 4 units for FBG 140-159 mg/dL, addition of 2 units for FBG 120-139 mg/dL, addition of 1 unit for FBG 100-119 mg/dL, no change for FBG 80-99 mg/dL, subtraction of 2 units for FBG 60-79 mg/dL, and subtraction of 4 units for FBG below 60 mg/dL. The BEGIN trial used a similar, but slightly different titration algorithim

According to the American Diabetes Association / European Association for the Study of Diabetes (ADA/EASD) 2009 algorithm for initiation and adjustment of therapy, basal insulin should be increased by 2 units every 3 days until FBG is consistently in the target range of 70-130 mg/dL (3.9 to 7.2 mmol/L). If FBG is greater than 180 mg/dL (10 mmol/L), basal insulin may be titrated up by 4 units every 3 days.

Prandial insulin

Prandial insulin should be added in patients on basal insulin plus or minus oral agents with a hemoglobin A1c that is above 7% and fasting glucose levels that are at goal at 70-130 mg/dL. A "Basal Plus" regimen and a "Basal-Bolus" regimen have been described. "Basal Plus" refers to the addition of a single pre-prandial dose of insulin while continuing the basal insulin. "Basal-Bolus" refers to the addition of pre-prandial insulin to every meal.

Several methods exist for the initiation and titration of prandial insulin and have been summarized by Ampudia et al. (reference given at end of chapter under "What's the Evidence?").

One option based on the ADA/EASD 2009 algorithm is to use a fixed dose of a rapid-acting analog starting at 4 units before one or more meals depending on postprandial blood glucose levels (PPBG).

A second option is to use a weight-based dose of 0.05 units/kg body weight as the initial dose before a meal.

A third option is to use 10% of the basal insulin dose per meal. A fourth option is described by Owens et al., who recommend first determining the 3-day average of the 2-hour PPBG after each meal and then initiating prandial insulin only before the meal with the highest PPBG excursion. The initial dose is calculated using the PPBG of this main meal in mmol/L divided by 2 (1 mmol/L = 18 mg/dL). Additional prandial injections can be initiated if 2-hour PPBGs are not at goal.

A final option is to initiate prandial insulin based on carbohydrate content of the meal, the pre-meal blood sugar, and anticipated activity. This is a detailed method that is used in patients with type 1 diabetes, who are using an insulin pump or multiple daily injections. See below section on prandial insulin in type 1 diabetes, carbohydrate counting and insulin sensitivity factor (ISF).

Several algorithms have been studied for adjustment of prandial insulin dosage. The ADA/EASD recommend adjusting the prandial insulin by 2 units every three days until the pre-meal blood sugar is in the target range. The regimen by Owens et al. recommends that prandial insulin be increased by 2 units, if the 2-hour PPBG is above 10 mmol/L (180 mg/dL) after breakfast and dinner or above 7.8 mmol/L (140 mg/dL) after lunch.

More complicated titration regimens have also been described. Mooradian et al.'s algorithm is based on preprandial or bedtime glucose levels. Their regimen recommends addition of 3 units for glucose above 180 mg/dL, addition of 2 units for glucose 160-180 mg/dL, addition of 2 units for glucose 140-159 mg/dL, addition of 1 unit for glucose 120 to 139 mg/dL, no change for glucose 100-119 mg/dL, subtraction of 1 unit for glucose 80-99 mg/dL, subtraction of 2 units for glucose 60-79 mg/dL, and subtraction of 4 units for FBG below 60 mg/dL.

Other regimens involve increasing prandial insulin by 1 unit if PPBG level is above a target of 140 mg/dL, adjusting dose based on PPBG using a scale (1 unit is added if PPBG is 136 to 153 mg/dL, 2 units are added if PPBG is 154 to 180 mg/dL, and 3 units are added if PPBG is above 180 mg/dL), or adjustment based on previous prandial insulin dose if PPBG is above target (i.e., adding 1 unit if dose was below 10 units, 2 units if dose was 10 to 20 units, and 3 units if dose was above 20 units).

Initiation of the basal-bolus regimen in type 1 diabetes

The total daily insulin dose (TDD) is usually started at 0.1 to 0.2 units/kg body weight, but most patients will usually need 0.6 to 0.7 units/kg body weight per day. The accurate insulin management system (AIM) uses a calculation of 0.24 multiplied by body weight in pounds to obtain the TDD.

Basal insulin:

See above section on basal-bolus regimen in type 2 diabetes for information regarding NPH, glargine, and detemir insulins.

Half of the TDD should be given as basal insulin. If NPH insulin is used, because it is an intermediate-acting insulin that lasts on average 12 to 16 hours, it can be divided up as 2/3 of the TDD in the morning before breakfast and 1/3 of the TDD at bedtime. If glargine or detemir insulin are chosen, they are longer-acting insulins and can be administered once daily. However, if blood sugar elevations 24 hours after the dose are suspected to be due to inadequate duration of action, the glargine or detemir dose may be divided into 2 doses and administered in the morning and at bedtime.

Titration of basal insulin is based on the fasting morning glucose. According to the ADA/EASD 2009 algorithm for initiation and adjustment of therapy, basal insulin should be increased by 2 units every 3 days until fasting glucose is consistently in the target range of 70 to 130mg/dL (3.9 to 7.2 mmol/L). If fasting glucose is greater than 180 mg/dL (10 mmol/L), basal insulin may be titrated up by 4 units every 3 days. Other titration algorithms exist, as discussed in the above section on basal-bolus regimens in type 2 diabetes.

Prandial insulin:

Pre-meal dosing should be calculated based on the carbohydrate content of the meal, pre-meal blood sugar, and anticipated activity. Various algorithms exist. Regular insulin should be given 30 minutes prior to eating. It peaks at 2 to 4 hours and can last 5 to 8 hours. Rapid-acting analogs such as lispro, aspart and glulisine should be given 5 to 15 minutes prior to eating. These shorter-acting insulins peak at 45 to 75 minutes and last 2 to 4 hours.

Several methods have been described regarding the initiation and titration of prandial insulin. The methods described below in the initiation of the basal-bolus regimen in type 2 diabetes, Prandial Insulin section, can also be used in type 1 diabetes, but the preferred method is using bolus calculation techniques that are generally used in insulin pump patients. These techniques involve carbohydrate counting, insulin-to-carbohydrate ratios, and insulin sensitivity factors.

1. Using carbohydrate counting and insulin-to-carbohydrate ratios:

With this method, patients will count the amount of carbohydrates they eat at each meal in grams and administer a calculated amount of insulin based on the grams of carbohydrates and their insulin-to-carbohydrate ratio (I:C). The two methods used for carbohydrate counting are reading food labels to obtain the grams of total carbohydrates per serving or using an exchange system. In the exchange system, foods are categorized into 3 groups: carbohydrates, meats, and fat. Foods in the carbohydrate group contain 12-15 gm of carbohydrates per serving. Patients who will be using this method should work with a registered dietician to learn this.

Several methods can be used to calculate the I:C ratio:

a) If blood sugars are at goal, the carbohydrate ratio can be determined by dividing the grams of carbohydrates eaten at the meal by the number of units of rapid-acting insulin administered. For example, if 50 gm of carbohydrates are eaten at a meal and 5 units is given for this meal, 50/5 = 10, resulting in an I:C of 1:10 or 1 unit of insulin given per 10 gm of carbohydrates.

b) The 450/500 rule can be used. The total daily dose of insulin (TDD) is divided by 500 or 450 to obtain the I:C. 500 is used for insulin-sensitive individuals, who comprise most patients with type 1 diabetes. 450 is used for insulin-resistant individuals, namely, patients with type 2 diabetes. For example, if the TDD = 60 units, in someone with type 1 diabetes, 60/500 is 0.12, so 1 unit of insulin should be administered for each 12 gm of carbohydrates.

c) The insulin sensitivity factor (ISF), described below, can be multiplied by 0.33 to obtain the I:C.

d) The ratio can be calculated using the 2.8 rule of the accurate insulin management system (AIM): 2.8 multiplied by body weight in pounds/TDD.

2. Insulin sensitivity factor (ISF):

Patients with Type 1 diabetes should use carbohydrate counting and I:C ratios to determine the amount of insulin to be given for each particular meal. The ISF is used to adjust the insulin dose for pre-meal sugars that are above goal. The calculation is 1500 to 1800 divided by the TDD. 1500 can be used for the calculation in patients with type 2 diabetes, who are more insulin-resistant, and 1800 can be used for the more insulin-sensitive type 1 diabetics.

The AIM system uses 1700 as the numerator for type 1 diabetes. For example, if the TDD is 50, and 1500 is used to calculate the ISF, the ISF is 1 unit of insulin for every 30mg/dL above goal.

U-500 Insulin for Severe Insulin Resistance


U-500 regular insulin (500 units/mL) is a highly concentrated form of U-100 regular insulin (100 units/mL). It has a delayed peak of action and longer duration compared with U-100 regular insulin. Its pharmacokinetic profile is similar to NPH insulin. It can be administered as multiple daily injections or via continuous subcutaneous insulin infusion. U-500 insulin can be used as basal and bolus insulin or can be used as bolus insulin added to an existing basal insulin regimen.

A vial of U-500 insulin contains 20 mL and 10,000 units of insulin compared with a vial of U-100 insulin, which contains 10 mL and 1,000 units of insulin. U-500 insulin is not available in an insulin pen form.

Candidates for U-500 insulin

Patients with diabetes and severe insulin resistance are candidates for U-500 insulin. Severe insulin resistance is defined as requiring greater than 200 units of insulin per day or a dose of 2 units/kg body weight per day. Specific conditions with severe insulin resistance in which U-500 could be considered for use include rare type A and B insulin resistance syndromes, acquired or congenital lipodystrophic diabetes, high-dose glucocorticoid use, post-transplant or post-surgical status, and severe systemic infections according to Lane et al. (cited in reference section at end of chapter).

Documentation of U-500 insulin and writing prescriptions

U-500 insulin should be prescribed by documenting the total number of units to be given and dose to be administered, written as volume to be injected and as insulin dose in U-100 syringe units. Errors occur when the prescription is written only in syringe units to be administered. The volume to be administered in a tuberculin syringe is calculated by dividing the insulin dose to be administered by 500. The amount of U-500 insulin to be administered in a U-100 syringe can be calculated by dividing the insulin dose by 5. For example, if a patient is to receive 100 units of U-500 insulin, the dose is drawn up in a U-100 syringe to the 20 unit mark or 0.20 mL drawn up in a tuberculin syringe. The prescription should designate 0.3 to 0.5 mL U-100 syringes to avoid inadvertent overdosage.

Algorithms for U-500 Insulin

When converting the U-100 dose to U-500 insulin, the new dose should be reduced by 10% to 20% if the hemoglobin A1c is below 8%, and increased by 10%-20% if the hemoglobin A1c is above 10%. If the hemoglobin A1c is between 8%-10%, a direct conversion can be made.

U-500 insulin should be injected 30 minutes prior to meals because its onset of action is similar to U-100 regular insulin.

Algorithms have been described by Lane et al. based on total units of insulin to be injected per day:

A. Total daily dose of 150 to 300 units:

U-500 can be divided into two to three pre-meal doses if used without basal insulin. If U-500 is given twice daily, 60% should be administered before the breakfast meal and 40% before the evening meal. If U-500 is given three times daily, 40%-45% should be given before breakfast, 30%-40% before lunch, and 20%-30% before the dinner meal. U-500 can also be used as the bolus component of a basal-bolus regimen. It would be added to an existing regimen that included glargine, detemir or NPH insulin. The proportion of basal and bolus insulin would be unchanged from the U-100 regimen.

B. Total daily dose of 300 to 600 units:

U-500 insulin should be divided and given three to four times per day. If administered as three times daily, the dosages should be as above in the 150 to 300 unit per day regimen. If fasting sugars are elevated, a fourth injection may be added at bedtime. In this case, 30% of the U-500 dose should be given at each meal with no greater than 10% of the dose added at bedtime. If bedtime U-500 insulin is given, 2 to 3 AM blood sugars should be checked to evaluate for nocturnal hypoglycemia. If basal insulin in the form of glargine, detemir, or NPH is used with U-500 insulin given as bolus therapy, continuous subcutaneous insulin therapy should be considered.

C. Total daily dose greater than 600 units:

Four daily injections are recommended, dividing the dose as 25% per dose given at meals and at bedtime or 30% prior to meals and 10% at bedtime.

Use of Glucagon-Like Peptide-1 Mimetics or Pramlintide with Insulin

Glucagon-like peptide-1 mimetics


Glucagon-like peptide (GLP)-1 mimetics are gastrointestinal hormones that target postprandial glucose and are an option for use with basal insulin instead of prandial insulin. GLP-1 mimetics lower postprandial glucose excursions by stimulating glucose-dependent insulin secretion, slowing gastric emptying, suppressing post-meal glucagon secretion, and increasing satiety.

The GLP-1 mimetics include liraglutide administered once daily independent of meals, exenatide given twice daily 30 minutes before meals, and extended-release exenatide, albiglutide, and dulaglutide given once weekly. GLP-1 mimetics are approved for use as add-on therapy in type 2 diabetics who have not achieved optimal glycemic control on one or two oral hypoglycemic agents. It can be considered as monotherapy in patients with contraindications or who experience adverse effects with the oral agents.

In October 2011, exenatide given twice daily before meals was approved by the Federal Drug Administration (FDA) as add-on therapy to glargine insulin. Liraglutide was approved for use with both glargine and detemir insulin in April of 2012. The extended-release once weekly exenatide has not yet been approved by the FDA for use with insulin. The package insert states that Albiglutide has not been studied for use with prandial insulin. Dulaglutide has been studied with prandial insulin, but not basal insulin.

Benefits of GLP-1 mimetics:

GLP-1 mimetics significantly improve postprandial glucose levels, lower hemoglobin A1c by up to 0.9%, have a low incidence of hypoglycemia, and can result in significant weight loss over time (about 2 kg). Further study needs to be done to determine the advantages of adding a GLP-1 mimetic to basal insulin versus using a standard basal-bolus regimen or twice daily premixed insulin.

Drawbacks of GLP-1 mimetics:

Nausea is a common side effect, but wanes over time. Most patients can tolerate the nausea through slow dose titration. Post-marketing reports of pancreatitis and acute renal failure or renal insufficiency are also a concern. Thyroid C-cell tumors (medullary thyroid cancer) have been described in mice and rat studies with liraglutide, but human studies did not find any difference in calcitonin levels between patients taking liraglutide versus other diabetes medications. All of the longer acting GLP-1 agents share a similar warning for thyroid C-cell tumors. Concerns were also brought up findings of pre-cancerous lesions in the pancreas in patients taking these drugs. However, both the European Medicines Agency and the Food and Drug Administration (FDA) stated in 2015 that the available data do not confirm the concerns related to pancreatic cancer. The FDA will continue to review cases of pancreatitis and pancreatic cancer in ongoing studies. These medications tend to be costly since a generic version does not yet exist.

Candidates for GLP-1 agonists and basal insulin:

Most studies on this area have focused on use in obese patients with poor glycemic control. The ADA / EASD algorithm recommends consideration in patients failing lifestyle changes and metformin, although the preferred second-line therapy is a sulfonylurea or basal insulin alone. This regimen would best fit patients with fasting sugars controlled by basal insulin but poor postprandial glucose control, high risk of hypoglycemia, and obesity with high risk of further weight gain.


Exenatide can be started at 5 mcg twice daily injected 30 minutes before a meal. This dose should be continued for 1 month to improve gastrointestinal tolerability and then increased to 10 mcg twice daily. The dose of glargine may need to be reduced in the first 6 to 12 months of therapy and can be adjusted based on fasting sugars. Liraglutide is initiated at 0.6 mg once daily injection for one week. This dose does not provide effective glycemic control, but reduces the risk of gastrointestinal symptoms during dose titration.

After one week, the dose can be increased to 1.2 mg. A further increase in dose to 1.8 mg can be made if further glucose control is needed. Basal insulin dose may need to be reduced as with exenatide. Extended-release exenatide is given as a 2 mg subcutaneous injection once a week at any time of day with or without meals. Albiglutide is given at the same time of day once weekly with or without meals at a dose of 30 mg. If the glycemic response is felt to be inadequate, the dose can be increased to 50 mg once a week. Dulaglutide can be given once a week at any time of the day with a starting dose of 0.75 mg once a week. If this dose is not sufficient for glycemic control, the dose can be increased to 1.5 mg once a week.



Pramlintide is an injectable synthetic analog of human amylin. Amylin is a naturally occurring hormone cosecreted with insulin by the pancreatic beta cells. In type 1 and type 2 diabetes, beta cell dysfunction results not only in absolute and relative insulin deficiency respectively, but also decreased endogenous amylin secretion. Like the GLP-1 mimetics, amylin is most effective in lowering postprandial glucose levels. PPBGs are lowered through suppression of post-meal glucagon secretion, slowing gastric emptying, increasing satiety, and decreasing appetite.


Pramlintide is approved for use for adjunct treatment in type 1 and type 2 diabetics who are on basal insulin and prandial insulin. It may be used concomitantly with metformin and/or sulfonylureas.

Riddle et al. evaluated use of pramlintide in type 2 diabetic patients who take basal insulin only and found that pramlintide lowered A1c by 0.7% with 1.6-kg weight loss. However, the use of pramlintide in this manner is off-label. Huffman et al. also studied pramlintide off-label as a subcutaneous continuous infusion.

Benefits of pramlintide:

Pramlintide can reduce postprandial glucose between 43 to 90 mg/dL, hemoglobin A1c by 0.2 to 0.4% in type 1 diabetics and 0.4 to 0.6% in type 2 diabetics, total daily insulin dose, and weight by 0.5 to 1 kg.

Drawbacks of pramlintide:

The major drawbacks of pramlintide are its subcutaneous route of administration three times daily, nausea, and hypoglycemia if the meal-time insulin dose is not reduced. The degree of hemoglobin A1c lowering is also modest, as mentioned above.

Patients taking pramlintide along with their basal and prandial insulin will be injecting seven to eight times daily unless they are using the pramlintide with an insulin pump, in which case they will be injecting three times daily. Therefore, candidates must have the motivation, training, and ability to intensively manage their diabetes.

Pramlintide is not a good choice for patients with gastroparesis because it can cause nausea and will further slow gastric emptying. It is also not ideal for patients receiving medications that stimulate gastrointestinal motility, such as metoclopramide. The associated nausea should resolve over a period of a month and can be minimized by starting pramlintide only once daily with the largest meal and titrating up slowly over several weeks.


Pramlintide is available as the brand name SymlinPen 60 and 120. The SymlinPen 60 has fixed dosing to deliver 15, 30, 45, or 60 mcg per dose, while the SymlinPen 120 has fixed dosing to deliver 60 or 120 mcg per dose. Both pens should be kept refrigerated until they are opened. Once open, the pens can be kept at room temperature or in the refrigerator for up to 30 days. Both the 60 and 120 mcg pens contain pramlintide concentration of 1000 mcg/mL. The 60 mcg pen has 1.5 mL, while the 120 mcg pen has 2.7 mL.

When pramlintide is started, the meal-time insulin dose should be reduced by 50% to minimize the risk of hypoglycemia. Pramlintide is given with any meal that is over 250 kcal or 30 gms of carbohydrates. Pramlintide should be injected into the thigh or abdomen and a minimum of 2 inches away from the prandial insulin injection site.

Pramlintide is initiated at 15 mcg in type 1 diabetes and titrated up to 30 mcg or 60 mcg with meals as tolerated. In type 2 diabetes, pramlintide is initiated at 60 mcg and titrated up based on tolerability to 120 mcg before each meal. Pramlintide should be given initially once daily with the first bite of the largest meal of the day. The dose or dose frequency should be increased every 3 or more days as tolerated. The meal-time insulin can be given at the same time as pramlintide or can also be given after the meal if the amount of food intake may be less than anticipated due to increased satiety or nausea.

Inhaled Insulin

Using inhalation as a route of insulin delivery has been studied as far back as 1924. The FDA approved an inhaled insulin product named Exubera in 2006, but this was taken off the market in 2007 by the manufacturer after poor acceptance by patients and health care providers and concerns regarding lung cancer seen in previous smokers. Development of another inhaled insulin with the brand name Afrezza continued with approval in June 2014 and is currently available for use.

Afrezza is an inhaled insulin using Technosphere technology. This technology involves adsorption of peptides or proteins onto microparticles made of the excipient fumaryl diketopiperazine (FDKP). FDKP forms microspheres, drugs are microencapsulated within these microspheres, which are then freeze dried to form a powder suitable for inhalation.

Afrezza is a rapid-acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus. It is not a substitute for long-acting basal insulin and it is not recommended for treatment of diabetic ketoacidosis. Afrezza is to be used with meals and must be used in combination with long-acting insulin in type 1 diabetics.

It is administered via oral inhalation with the Afrezza Inhaler using a single inhalation per cartridge. Single-use cartridges are available in a 4 unit dose, an 8 unit dose, and a 12 unit dose. Inhalations from multiple cartridges are necessary for doses exceeding 12 units.

Dose conversion of injected mealtime insulin to Afrezza is shown in Table I.

Table I.

Dose conversion of injected mealtime insulin to Afrezza
Injected Mealtime Insulin Dose Afrezza Dose
Up to 4 units 4 units
4-8 units 8 units
9-12 units 12 units
13-16 units 16 units
17-20 units 20 units
21-24 units 24 units

It has rapid absorption, achieving a maximum concentration in approximately 15 minutes with relative bioavailability of about 37% of subcutaneously administered regular human insulin. It has a faster elimination profile than subcutaneous regular insulin as well.

There is a 'Boxed Warning' advising that acute bronchospasm has been observed in patients with asthma and COPD. It should not be used in patients with asthma or COPD. It should also not be used in patients who smoke or who recently stopped smoking.

Lung function must be evaluated with a medical history, physical exam, and spirometry (FEV1) prior to initiating Afrezza. Spirometry should be assessed again after the first 6 months of therapy and annually thereafter even in the absence of pulmonary symptoms. In patients with decline in FEV1 of greater than or equal to 20% from baseline, discontinuation of Afrezza should be considered.

FEV1 has been found to decline 40ml within the first 3 months and persist for at least 2 years (the duration of the clinical trials examining this). There is not sufficient data regarding reversibility of this after discontinuation of the drug.

In clinical trials, 2 cases of lung cancer were observed in the participants exposed to Afrezza compared to no cases in the comparators. Both cases had prior heavy tobacco use. Two additional cases of lung cancer were reported after clinical trial completion. There is insufficient data to link Afrezza to lung cancer.

The most common adverse reactions in clinical trials were hypoglycemia, cough, and throat pain or irritation.

Afrezza has not been studied in pregnant women or patients younger than age 18 years of age. The effect of hepatic or renal impairment on the pharmacokinetics of Afrezza has also not been studied.

What’s the Evidence?/References

Initiation of the basal-bolus regimen in type 2 diabetes

Riddle, MC, Rosenstock, J, Gerich, J. " The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients". Diabetes Care. vol. 26. 2003. pp. 080-6.

Davies, M, Storms, F, Shutler, S. "Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine". Diabetes Care. vol. 28. 2005. pp. 1282-8.

Meneghini, L, Koenen, C, Weng, W, Selam, JL. " The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes - results of the randomized, controlled PREDICTIVE 303 study". Diabetes Obes Metab. vol. 9. 2007. pp. 902-13.

Hirsch, IB, Bergenstal, RM, Parkin, CG. "A real-world approach to insulin therapy in primary care practice". Clinical Diabetes. vol. 23. 2005. pp. 78-86.

Mooradian, AD, Bernbaum, M, Albert, SG. "Narrative review: a rational approach to starting insulin therapy". Ann Intern Med. vol. 145. 2006. pp. 125-34.

Nathan, DM, Buse, JB, Davidson, MB. "Medical management of hyperglycemia in type 2 diabetes: consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes". Diabetes Care. vol. 32. 2009. pp. 193-203.

Ampudia-Biasco, FJ, Rossetti, P, Ascasco, JF. " Basal plus basal-bolus approach in type 2 diabetes". Diabetes Technol Ther. vol. 13. 2011. pp. S75-S83.

Owens, DR, Luzio, SD, Sert-Langeron, C, Riddle, MC. " Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month 'proof-of-concept' study". Diabetes Obes Metab. vol. 13. 2011. pp. 1020-7.

Owens, DR, van Schalkwyk, C, Smith, P. "Algorithm for the introduction of rapid-acting insulin analogues in patients with type 2 diabetes on basal insulin therapy". Practical Diabetes Int. vol. 26. 2009. pp. 70-7.

Jonassen, I, Havelund, S, Hoeg-Jensen, T, Steensgaard, DB, Wahlund, PO, Ribel, U. "Design of the novel protraction mechanism of insulin degludec, ultra-long-acting basal insulin". Pharm Res.. vol. 29. 2012. pp. 2104-14.

Kalra, S., Gupta, Y. "Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions". N Am J Med Sci. vol. 7. 2015 Mar. pp. 81-85.

Initiation of the basal-bolus regimen in type 1 diabetes

Walsh, J, Roberts, R. "Pumping Insulin: Everything You Need for Success With An Insulin Pump". Torrey Pines Press. 2000.

Bolderman, K. "Putting Your Patients on the Pump". American Diabetes Association. 2002.

Davidson, PC, Hebblewhite, HR, Steed, RD, Bode, BW. " Analysis of guidelines for basal-bolus insulin dosing: basal insulin, correction factor, and carbohydrate-to-insulin ratio". Endocr Pract. vol. 14. 2008. pp. 1095-101.

U-500 Insulin for Severe Insulin Resistance

Dailey, AM, Tannock, LR. " Extreme insulin resistance: indications and approaches to the use of U-500 insulin in type 2 diabetes mellitus". Curr Diab Rep. vol. 11. 2011. pp. 77-82.

Lane, WS, Cochran, EK, Jackson, JA. "High dose insulin therapy: is it time for U-500 insulin?". Endocr Pract. vol. 15. 2009. pp. 71-9.

Use of Glucagon-Like Peptide-1 Mimetics or Pramlintide with Insulin

Glucagon-like peptide-1 mimetics

Perfetti, R. " Combining basal insulin analogs with glucagon-like peptide-1 mimetics". Diabetes Technol Ther. vol. 13. 2011. pp. 873-81.

Buse, JB, Bergenstal, RM, Glass, LC. "Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial". Ann Intern Med. vol. 154. 2011. pp. 103-12.


Traina, AN, Kane, MP. " Primer on pramlintide, an amylin analog". Diabetes Educ. vol. 37. 2011. pp. 426-31.

Riddle, M, Frias, J, Zhang, B. "Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin". Diabetes Care. vol. 30. 2007. pp. 2794-9.

Huffman, DM, McLean, GW, Seagrove, MA. " Continuous subcutaneous pramlintide infusion therapy in patients with type 1 diabetes: observations from a pilot study". Endocr Pract. vol. 15. 2009. pp. 689-95.

Pullman, J, Darsow, T, Frias, JP. "Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes". Vasc Health Risk Manag. vol. 2. 2006. pp. 203-12.

Inhaled Insulin

Neumiller, JJ, Campbell, RK, Wood, LD. " A review of inhaled technosphere insulin". Ann Pharmacotherapy. vol. 44(7-8). 2010. pp. 1231-9.


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