Insulin Therapy

Introduction

Insulin therapy is most commonly reserved for patients in whom an adequate trial of diet, exercise, oral antidiabetic drugs (OADs) and/or glucogonlike peptide 1 (GLP-1) receptor agonists (RAs) have not allowed the patient to achieve adequate control once adherence and persistence has been evaluated. However, institution of insulin therapy is commonly delayed inappropriately for months to years in such patients. Both physicians and patients are hesitant to start “the needle” because of fear, ignorance, old wives’ tales and unfounded fears about time constraints. There is no question that the benefits of improved glycemic control outweigh the initial hassles and risks of insulin therapy. We encourage early use of insulin soon after it is evident that OADs and/or GLP-1 RAs are failing. Although the word failing is commonly used, in reality the medications are working but may not be able to keep the patient in an ideal glycemic range because of the progressive nature of type 2 diabetes (T2D). The current (2024) ADA guidelines also state that if the patient’s A1C is above his or her goal on a GLP-1 RA, then insulin should be started, even if only temporary.

Many insulin regimens are recommended, although it is not clear from the literature which regimen is best. This chapter will focus on the different insulin regimens commonly used to normalize or near normalize glucose levels, time in range and A1C in patients with T2D.

Based on the natural history of T2D, many patients will eventually require therapy with insulin. The period of time before insulin is required tends to be highly variable and is based on numerous factors. The most important explanation is the extent of β-cell exhaustion resulting in relative endogenous insulinopenia. This leads to progressive loss of compensatory hyperinsulinemia, which is required to achieve and maintain a sufficient degree of glycemic control, especially in patients taking oral hypoglycemic agents. In other cases, obesity, pregnancy, or any number of medications including steroids, as well as a variety of illnesses, may exacerbate the insulin-resistant state and convert a patient previously well controlled on an oral-agent regimen to one requiring insulin.

In addition to the natural history of T2D, there is heterogeneity in its pathophysiology because of hereditary factors, which may influence when patients require insulin. Some patients diagnosed with T2D may actually be closer to insulin-dependent or type 1 diabetes (T1D) with insulinopenia. Many of these patients have been shown to have islet cell antibody (ICA) positivity or antibodies to glutamic acid decarboxylase (GAD), with a decreased C-peptide response to glucagon stimulation and a propensity for primary oral medication failure. Latent autoimmune diabetes in adults, or latent autoimmune diabetes in adults (LADA), is the term coined by the ADA to label this type of patient. There are also wide geographic and racial differences that may influence the need for insulin therapy. For example, Asian patients with T2D tend to be thinner, to be diagnosed with diabetes at an earlier age, to experience failure of oral hypoglycemic agents much sooner and to be more sensitive to insulin therapy than the classic Caucasian patient with central obesity.

Insulin therapy can improve or correct many of the metabolic abnormalities present in patients with T2D. Exogenous insulin administration significantly reduces glucose levels by suppressing hepatic glucose production, increasing PPG levels and improving the abnormal lipoprotein levels commonly seen in patients with insulin resistance. Insulin therapy may also decrease or eliminate the effects of glucose toxicity by reducing hyperglycemia to improve insulin sensitivity and β-cell secretory function.

Selecting an Insulin Preparation

There are four types of insulin: animal, human, insulin analogues and inhaled. Although purified insulins from animal sources (e.g., beef and pork) were the original type, they are no longer manufactured in the United States. Currently, human insulin is the predominant form used. More recently, a number of insulin analogues have been developed. These include the rapid-acting analogues (Figure 18-1), as well the long-acting analogues. In addition, there are several premixed formulations containing a rapid- or short-acting insulin or analogue and a long- or intermediate-acting insulin. Therefore, the insulin preparations available to control blood glucose in patients with T2D include:

• Rapid-acting insulin analogues (lispro U-100 and U-200, aspart, glulisine, inhaled human insulin)
• Short-acting preparations (regular human insulin U-100 and U-500)
• Intermediate-acting insulins (NPH)
• Long-acting insulins (glargine U-100, detemir)
• Ultralong-acting insulin (degludec U-100 and U-200, glargine U-300)
• Premixed preparations (degludec + aspart injection [Ryzodeg], human insulin isophane suspension + human insulin injection [Humulin or Novolin], aspart protamine suspension + aspart injection [Novolog], lispro protamine suspension + lispro injection [Humalog])

Short/rapid-acting insulins, as well as long-acting insulin preparations, are needed to mimic the pattern of insulin delivery that normally controls blood glucose in nondiabetic individuals. Basal insulin therapy with long-acting insulin is required to suppress hepatic glucose production overnight and between meals, while short/rapid insulin preparations are needed as bolus insulin to prevent hyperglycemia after meals and for correction dosing to treat incidental hyperglycemia at any time of the day and night. Short-acting insulin may be needed in concert with basal insulin replacement regimens but not in all clinical situations.

The fast-acting insulin analogues are preferential to regular insulin due to their favorable clinical features. Administration is convenient as they should be given before eating (see discussion below). Their faster onset of action limits postprandial hyperglycemic peaks by matching serum insulin availability to appearance of meal-derived glucose into the circulation. Their shorter duration of action also reduces development of late postprandial hypoglycemia.

Many of the complications of insulin therapy are less common because of the advent of more purified human preparations and insulin analogues.

Selecting an appropriate insulin preparation also depends on the desired time course of action or pharmacokinetics. The values shown in Table 18-1 are general guidelines that can vary considerably among individuals, especially those with T2D. Other factors that influence the action of insulin in an individual include:

• Dose
• Site and depth of injection
• Local tissue blood flow
• Skin temperature
• Exercise.

The time courses of action of several insulins are shown graphically in Figure 18-2. The recommended interval between an injection of regular or rapid-acting insulin and mealtime is 30 to 45 and 15 to 20 minutes, respectively in order to reduce the post prandial rise in glucose values. The patient should wait longer if the blood glucose is higher. Proper timing of the premeal injection can markedly improve the postprandial blood glucose level and possibly reduce the incidence of delayed hypoglycemia. Eating within a few minutes of the injection, or before the injection of regular insulin, markedly reduces the ability of the insulin to prevent a rapid rise in blood glucose and may increase the risk of delayed hypoglycemia. The rapid-acting insulins have alleviated much of this problem because of their rapid onset and short duration of activity, however the timing of the injection before meals is extremely important as stated above. Common insulin regimens used in adult diabetes are listed in Table 18-2.

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Application of Intensive Insulin Therapy

The goals of therapy should be individually tailored. Ideal candidates for intensive management should be:

• Motivated
• Adherent
• Educable
• Without other medical conditions and physical limitations that preclude accurate and reliable glucose monitoring and insulin administration.

In addition, caution is advised in patients who are elderly or who are unaware of the signs and symptoms of hypoglycemia. Other limitations to achieving normoglycemia may include high titers of insulin antibodies, especially in those patients with a prior history of intermittent insulin use of animal origin. The site of insulin injection may also change the pharmacokinetics, and absorption can be highly variable, especially if lipohypertrophy is present. The periumbilical area has been shown to be one of the more desirable areas in which to inject insulin because of the consistent absorption kinetics observed at this location, however rotation of injection sites is important to avoid lipohypertrophy.

Prior to initiating insulin therapy, the patient should be well educated in the:

• Technique of SMBG and ideally CGM
• Proper techniques of mixing insulins and administration depending on the use of vial and syringe or an insulin pen
• Self adjustment of insulin dose if appropriate
• Dietary and exercise strategies.

The patient, family members and co-workers also need to be informed about hypoglycemia prevention, recognition and treatment. Initial and ongoing education by a diabetes management team is crucial for long-term success and safety. One of the newer rescue glucagon preparations should be prescribed and taught how to use (Gvoke HypoPen, Zegalogue pen, or Baqsimi nasal insulin). All three of these preparations are much easier to use than the older glucagon kits and have a longer shelf live as well.

There is no one perfect insulin or insulin regimen that fits all patients with insulin-requiring T2D. However, there is a natural progression of regimens that can be used as a general algorithm when considering insulin therapy. The ADA recommends that insulin therapy be considered once blood glucose is inadequately controlled with OADs and other non-insulin injectable agents alone (i.e., when blood glucose is ≥300 mg/dL to 350 mg/dL and/or A1C is ≥10% to 12%), and further recommends that glucogonlike peptide 1 receptor agonist (GLP-1 RA) be considered before insulin.

Basal insulin is effective and easy to initiate, and the ADA recommends beginning with 10 U/day or 0.1-0.2 U/kg/day, depending on the severity of hyperglycemia. Insulin therapy can then be intensified if the patient is unable to meet their A1C target. When progressing from basal insulin, the ADA recommends either adding one rapid insulin injection or inhaled insulin before the largest meal. If not already part of the regimen, adding a GLP-1 RA is also an option that could address elevated post prandial elevations in a patient on basal insulin. If the patient is still unable to meet their A1C target over time, insulin therapy can be further intensified with stepwise additional injections of prandial or inhaled insulin, and even further with a full basal-bolus/inhaled regimen. A twice-daily premixed analog insulin or a self-mixed/split-mixed insulin regimen may also be considered.

Combination Therapy

Combination therapy usually refers to the use of OADs (daytime) together with a single injection of intermediate-acting insulin at bedtime or a long-acting insulin given anytime of the day. The rationale for using a basal insulin strategy is based on the pathophysiology of fasting hyperglycemia in T2D. The underlying tenet for combination therapy assumes that if basal insulin lowers the fasting glucose level to normal levels, the daytime OAD and/or GLP-1 RA will be more effective at controlling postprandial hyperglycemia and maintaining euglycemia throughout the day. Metabolic profiles in T2D have clearly demonstrated that the fasting plasma glucose (FPG) is a major determinant or predictor of glycemic control throughout the day. The FPG level is highly correlated with the degree of hepatic glucose production during the early morning hours, which is suppressed by basal insulin. In addition, bedtime intermediate-acting insulin’s peak action coincides with the onset of the dawn phenomenon (early morning resistance to insulin caused by diurnal variations in growth hormone and possibly norepinephrine levels), which usually occurs between 3 and 7 am and in a minority of clinical situations may be more effective than a long-acting basal insulin with flat pharmacokinetics.

Patient selection is very important when considering combination therapy. The question of whether a patient is still responding in a satisfactory manner to OAD(s) is of primary importance. Patients also have a higher likelihood of success using daytime OADs and/or basal insulin if the duration of diabetes is less than 10 to 15 years, do not have extremely high FPG and bedtime values over 300 mg/dL and have evidence of endogenous insulin secretory ability.

Measurement of C-peptide is not routinely used and is not recommended. In addition, standard measurement conditions and levels for C-peptide have not been established for this clinical situation. A fasting (0.2 nmol/L or 0.6 ng/mL) or glucagon-stimulated (>0.40 nmol/L or 1.2 ng/mL) C-peptide value indicates some degree of endogenous insulin secretory ability. Patients with T2D diagnosed under the age of 35 more often have atypical forms of diabetes. Subjects with diabetes longer than 10 to 15 years in duration tend to have a greater chance of β-cell exhaustion and thus be less responsive to the OADs, however these are generalizations and every patient may respond differently.

There are also a number of practical reasons why combination therapy may be beneficial:

• The patient does not need to learn how to mix different types of insulin.
• Patient adherence and acceptance are better with single rather than multiple injections of insulin.
• The patient does not need to take injections during work or other activities (first thing in the morning or at bedtime).
• It enables the patient to be initiated to insulin in a simple straightforward manner.
• Self-titration of the basal insulin allows for patient involvement and engagement.

Combination therapy also requires a lower total dose of exogenous insulin than a full regimen of two or three injections per day. This usually contributes to less weight gain.

Calculation of the initial basal insulin dose is typically 0.1 to 0.2 U/kg/day or 10 U/day. It can also be based on clinical judgment or on various formulas using FPG level or body weight. For example, one can divide the average FPG (mg/dL) by 18 or divide the body weight in kilograms by 10 to calculate the initial basal dose. To reach FPG targets insulin must be adjusted based on self-monitoring of blood glucose (SMBG). The ADA recommends that insulin dose be adjusted by 10% to 15% or 1 to 2 units once or twice weekly. If hypoglycemia is experienced, the insulin dose should be decreased by 4 units or 10% to 20%. Recommended dose adjustments based on the complexity of insulin therapy are shown in Table 18-3.

Patient self-titration is an ideal way to make sure the dose is adjusted upward in a timely manner and to engage the patient in his or her own care. Although there are several patient self-titration schedules, the authors prefer a daily self-titration schedule, such as that proposed by the Canadian Diabetes Association (CDA)(Table 18-4). Patients can take their SMBG/ continuous glucose monitoring (CGM) level first thing in the morning, look at the titration instructions and give the appropriate dose of basal insulin at one time, adjusting dose by 1-2 U every day until the FPG target of 80-130 mg/dL, or any target deemed safe for the patient, is met.

Once the FPG levels are consistently in a desirable range, the prelunch, predinner and bedtime blood glucose must be monitored to determine if the oral hypoglycemic agents and/or GLP-1 RAs are maintaining daytime euglycemia. If glucose toxicity is present, the patient should wait for a few weeks of normal or near-normal prebreakfast blood glucose values before monitoring for daytime control. It is also important to ask the patient to occasionally do paired testing with the bedtime and fasting glucose values to avoid over-basalinization. If the patient goes to bed at ~200mg/dl most nights and wakes up in the same high range then working on the post-dinner/bedtime values would be important. If you do not look at the bedtime numbers and continue to titrate the basal insulin upwards, it could lead to a situation where too much basal insulin could cause hypoglycemia, especially if the patient has an unusual normal glucose value at bedtime.

It is recommended that after the addition of basal insulin, patients remain on their maximum dose of OAD and/or GLP-1 RA. If the daytime blood glucose levels start to become excessively low, the dose of oral medication must be adjusted downward, especially SFUs. This is not an uncommon scenario because glucose toxicity may be reduced as a result of improved glucose control, leading to enhanced sensitivity to OADs, GLP-1 RAs and insulin.

The BEYOND trial compared the efficacy of switching from a prior basal-bolus insulin (BBI) regimen to either intensification of the BBI regimen, a regimen of fixed ratio of basal insulin plus a GLP-1 RA, or a regimen basal insulin plus an SGLT2 inhibitors. The combination basal insulin GLP-1 RA/SGLT2 inhibitor regimens demonstrated non-inferior A1C control and significantly lower proportion of patients with hypoglycemia (7.8% for basal insulin with a GLP-1 RA and 5.9% for basal insulin with an SGLT2 inhibitor, compared to 17.8% with intensified BBI; P = 0.015). As the combination regimens require fewer insulin doses and fewer injections at no efficacy cost and improved hypoglycemia-related safety, they represent an attractive option for the simplification of intensive insulin treatment.

In summary, combination therapy can be a simple and effective tool to normalize glycemia and A1C levels in selected patients with T2D in whom OADs and/or GLP1-RAs fail. The most common clinical situation in which combination therapy can be successful is when bedtime intermediate-acting or anytime long-acting basal insulin is given and progressively increased so as to normalize the FPG level. When the FPG level is brought under control, the success of combination therapy is dependent upon the ability of the daytime OADs and/or GLP1-RAs to maintain euglycemia. If this cannot be achieved, then other OADs and/or GLP-1 RAs can be used or other insulin regimens employed.

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Premixed Insulin

Based on the results of SMBG/CGM, combination therapy can be altered to reduce hyperglycemia at identified times during the day. For example, a common situation seen is an improvement in the fasting, prelunch and predinner blood glucose, although the postdinner blood glucose level remains excessively high (>200 mg/dL). In this clinical situation, an injection of premixed fast-acting analogue and intermediate or long-acting insulin (ie, Humalog Mix 75/25, Humalog Mix 50/50, Novolog Mix 70/30 or Ryzodeg 70/30) twice daily instead of the daily dose of basal insulin alone may be more efficacious (Table 18-3 and Table 18-4 for ADA and CDA recommendations, respectively). This regimen will often improve the postdinner blood glucose values, because the premixed insulin contains rapidly acting insulin yet will still allow overnight glucose control secondary to the basal component. With this regimen, however, one must be more cautious of early morning hypoglycemia if using neutral protamine Hagedorn [insulin] (NPH) because the intermediate insulin given before dinner will exert its peak effect earlier.

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Multiple Daily Injection Regimens

In patients who have inadequately controlled A1C levels on a basal insulin-only regimen, one possible strategy is to add a single injection of a rapid-acting insulin or inhaled insulin before the largest meal. This regimen of two injections per day is efficacious in patients with T2D, but is inadequate for patients with T1D, likely because of pathophysiologic differences between T1D and T2D, particularly in:

• Endogenous insulin secretory ability
• Insulin resistance
• Counterregulatory mechanisms.

More intensive insulin regimens with multiple daily injections (MDIs) will be needed for those patients who do not achieve glycemic goals with pre-mixed or two-injections-per-day regimens. The basal bolus insulin strategy, which can be utilized in patients with either T1D or T2D, incorporates the concept of providing continuous basal insulin secretion throughout the day and night, with brief increases in insulin levels at the time of meal ingestion via bolus or inhaled doses. A strategy that provides for some flexibility is the mealtime administration of the rapid-acting insulin analogues or inhaled insulin immediately prior to meals and an intermediate- or long-acting insulin (e.g., NPH [given at bedtime], glargine, detemir, or degludec) as the basal insulin.

Improved mealtime glucose control with the rapid-acting analogues has exposed the gaps in basal insulin coverage given alone. A once-daily basal insulin analogue with a relatively smooth pharmacokinetic profile would result in a more physiologic pattern of basal insulin replacement. Insulin glargine (U-100 and U-300), detemir and degludec (U-100 and U-200) in combination with rapid-acting insulin have demonstrated effective glycemic control and a lower incidence of nocturnal hypoglycemia than with other insulin preparations currently used for basal insulin supplementation.

As demonstrated in the AUTONOMY study, there are several simple self-titration regimens available to patients initiating prandial insulin that can safely and effectively achieve glycemic goals while maintaining low rates of nocturnal and severe hypoglycemia. AUTONOMY enrolled patients inadequately controlled on basal insulin plus OADs, and after switching them to an insulin glargine-containing regimen with appropriate titration to maximize the fasting glucose level, patients were randomized 1:1 to initiate insulin lispro therapy following either an every-day or every-3-days self-titration algorithm. The primary efficacy measure of the trial was A1C change from baseline to trial completion at 24 weeks. The two self-titration algorithms (Q1D and Q3D prandial titration regimens) demonstrated comparable reductions in A1C and improvements in 7-point SMBG profiles. By implementing either self-titration strategy, approximately 50% of patients previously unable to reach the A1C target of ≤7.0% were able to at week 24. Overall, AUTONOMY demonstrated that even simple patient-driven mealtime insulin self-titration algorithms can safely and effectively improve glycemic control.

As outlined in the AUTONOMY study, patients following either titration algorithm (Q1D or Q3D) should initiate prandial insulin with a single injection at breakfast (Table 18-5). Following Q1D titration, patients use the previous day’s pre-lunch blood glucose measurement to determine their pre-breakfast dose adjustment. Following Q3D titration, the median of the previous 3 days’ pre-lunch blood glucose measurements is used to guide dose adjustment. In an example where a patient has pre-lunch blood glucose values of 112 mg/dL on Monday, 122 mg/dL on Tuesday, and 118 mg/dL on Wednesday, patients following either titration algorithm would use the 118 mg/dL value to adjust their pre-breakfast insulin dose. This would result in a +1 U and +2 U dose adjustment in patients following the Q1D and Q3D titration algorithm, respectively (Table 18-5).

After a stable dose is achieved at breakfast, additional prandial insulin doses can be added to subsequent meals, in sequence, if required. Like the pre-breakfast insulin dose, pre-lunch and pre-dinner doses should be titrated based on the blood glucose value(s) obtained prior to the subsequent meal on the preceding day(s). There are a lot of variations on this type of regimen. Patients can start with their biggest meal of the day and of course use of continuous glucose monitoring (CGM) would make titration more effective and safer as these devices have alerts and alarms to alert the patient to impending hypoglycemia.

In summary, there is no perfect insulin regimen for all insulin-requiring patients with T2D. There is a natural progression of insulin regimens as there is a natural history of T2D. An easy first option when initiating insulin therapy is a combination therapy using any non-insulin agents plus a basal insulin. If glycemic goals are still not met, then a single rapid mealtime injection can be added or the patient can switch to a twice-daily injection of premixed insulin. Premixed insulin can be an easy transition and can be especially effective in patients with obesity. A natural transition from the simpler regimens is the basal bolus MDI regimen, with a fast-acting analogue or inhaled insulin before meals and a long-acting basal insulin given once a day. GLP-1 RAs are also an option, if not already prescribed, to address post prandial hyperglycemia when the A1C is still elevated with fasting glucose values are adequate.

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Insulin Therapy in Obese or Thin Patients

There are a number of important aspects of intensive glucose control with insulin in patients with obesity and T2D:

• First, the average daily dose of insulin needed to aggressively control such patients may approximate 1 U/kg.
• Second, the total daily insulin requirement can successfully be split equally between the prebreakfast and predinner injections.
• Third, patients with obesity using a split-mixed regimen will require approximately 70% of their total insulin requirement as intermediate- or long-acting basal insulin with the remainder as a mealtime insulin, such as Humalog, Lyumjev, Novolog, Fiasp, Apidra and regular insulin Afrezza.
• Fourth, the split-mixed regimen in patients with obesity and T2D is usually devoid of the common problems seen with this regimen in T1D, particularly early morning hypoglycemia and fasting (preprandial) hyperglycemia.
• Fifth, mild and severe hypoglycemic events are much less frequent in patients with T2D compared with patients with T1D undergoing intensive insulin therapy.
• Sixth, the use of fast-acting insulin analogues including inhaled insulin instead of the older regular insulins may be helpful in terms of reducing postprandial hyperglycemia, A1C and the incidence of delayed hypoglycemia.
• Seventh, the use of CGM is vitally important in MDI patients and most likely be covered my insurance or medicare if on 3 or more injections a day.
• Finally, weight gain with peripheral hyper­insulinemia frequently occurs in T2D when glucose control is intensified with insulin therapy.

There are several acceptable methods to initiate a more intensive insulin regimen in T2D. A simple alternative method is initiating a split-mixed regimen in patients with obesity using Novolog Mix 70/30, Humalog Mix 75/25, Humalog Mix 50/50, or Ryzodeg 70/30 with an initial total daily insulin dose (0.4 to 0.8 U/kg) equally split between the prebreakfast and predinner injections. Adjustments are made based on SMBG results, which may dictate the need to change the ratio of intermediate or basal- to fast-acting insulin either upward or downward or transitioning to an MDI regimen or insulin pump. For patients with severe obesity, the insulin requirements rise dramatically as ideal body weight increases above 150%. In contrast, caution should be used when starting thin patients with T2D on insulin, especially premixed insulins with fixed doses of fast-acting insulin (initial total daily dose 0.2 to 0.5 U/kg). This group tends to be more sensitive to the glucose-lowering effects and thus more prone to severe hypoglycemia.

Insulin Pump Therapy

An insulin pump is a device used as an alternative to insulin shots to deliver insulin into the body. The device is small and is carried on the body at all times. Insulin is transferred into the body through a thin tube that runs under the skin and every 2 or 3 days the placement of the tube is changed. In addition, there are several patch pumps on the market specifically designed for people with type 2 diabetes on multiple daily injection (MDI). These pumps are programmed to deliver a continuous basal rate of insulin, as well as a higher doses before meals. The bolus amount will depend upon the meal and SMBG/CGM, meaning that patients using a pump still need to check their SMBG/CGM several times a day. There has been an explosion of hybrid-closed loop (HCL) systems (Tandem CIQ, Omnipod 5, Medtronic 780G, DIY Looping) developed primarily for T1D patients but can be also effective in T2D. These HCL systems provide continuous communication of the CGM glucose values to the insulin pump that can give more or less insulin automatically 24/7. If interested, please see the Taking Control Of Your Diabetes website for more information (tcoyd.org).

Insulin-pump therapy has been traditionally used for people with T1D. People with T1D usually do not have insulin resistance; therefore, they require lower basal rates and smaller insulin boluses for corrections and meals. Because patients with T2D have the underlying defect of insulin resistance in addition to β-cell failure, they have increased insulin requirements. Insulin-pump therapy is extremely valuable in patients with insulin-requiring T2D who:

• Are experiencing wide and erratic fluctuations in blood glucose levels
• Have not achieved glycemic control with subcutaneous (SC) injections
• Frequently experience severe hypoglycemia, or have hypoglycemia unawareness
• Are pregnant
• Experience a spike in blood glucose early in the morning (the “dawn phenomenon”)
• Have an erratic schedule and are seeking a more flexible lifestyle.

There are several benefits to using a pump. First, patients do not require multiple insulin shots every day. Second, patients have more control over what they can eat, since they do not need to plan their meals ahead of time. Instead, they can adjust the bolus dose to meet their needs. Third, it offers better glycemic control, with fewer highs and lows. Fourth, better glycemic control results in fewer hypoglycemic events. Therefore, there is less overeating to compensate for hypoglycemia and weight gain may be less of an issue.

Disadvantages to insulin pumps include a potentially high cost compared with insulin shots, the risk of diabetic ketoacidosis (DKA) if the tube is displaced or damaged, the risk of infection at the site of entry and the potentially bothersome necessity of carrying the pump at all times.

Many older patients with the diagnosis of insulin-requiring T2D have true late-onset T1D. It has been documented in the literature that when large groups of patients with insulin-requiring T2D were tested for anti-GAD antibodies, approximately 5% to 8% were positive. Such individuals are thinner at the time of diagnosis, generally do not respond well to oral agents and require insulin, although they do not present with DKA. This condition is now formally called latent autoimmune diabetes in adults (LADA). This is another group that could potentially benefit from insulin-pump therapy. In general, if a patient with insulin-requiring T2D cannot achieve glycemic control with an intensive insulin-injection regimen, insulin-pump therapy should be considered.

Tandem t:flex Insulin Pump

Insulin pump therapy reduces average blood glucose levels and overall insulin needs in patients with T2D compared with standard therapy using multiple injections. However, the limited reservoir size of pumps has been a barrier for patients with T2D wanting to adopt this insulin delivery method. The t:flex is an insulin pump manufactured by Tandem Diabetes Care, that was approved in the United States in 2015. It holds 300 units of fast-acting insulin. A larger volume version of the t:slim insulin pump, the t:flex is no longer being produced. The newer Tandem Control IQ mentioned above is a HCL system working with the Dexcom CGM and can be very successfully used in patients with Type 2 diabetes.

Insulin Patch Pumps

Patch pumps are a newly developed type of insulin pump. They are smaller than traditional pumps, attach directly to the skin, and usually have a cannula that goes directly from the device to the skin with no tubing. Some of the devices are simplified for patients with type 2 diabetes, and can deliver bolus insulin, basal insulin or both. Patch pumps can be completely disposable, or with a few disposable components. None of these devices is prefilled; all must be filled by the user.

V-Go Device

The V-Go wearable insulin delivery device developed by Valeritas is specifically designed for patients with T2D who require mealtime insulin. It is a disposable device that delivers insulin at a continuous preset basal rate with on-demand bolus dosing at mealtimes. The device is changed every 24 hours by the patient. V-Go comes with present basal rates of 20, 30, or 40 units per 24 hours and up to 36 units (in 2 unit increments) of insulin for mealtime dosing. There is no external controller and the device is easy to use and always with the patient, a simple way to deliver basal-bolus insulin therapy.

CeQur Simplicity

CeQur Simplicity is a 3-day insulin delivery patch (not technically a pump) designed to meet mealtime insulin requirements and simplify insulin delivery. The patch holds up to 200 units of mealtime insulin and delivers a 2-unit dose via a subcutaneous cannula with each simultaneous click of the 2 buttons on either side of the device. The patch can be worn under clothing and the 2 buttons can be accessed either directly or through clothing. In the United States, the patch is approved for use with rapid-acting insulins lispro and aspart. CeQur Simplicity offers a safe, preferred alternative to other delivery methods.

Omnipod

The Omnipod is an insulin pump with flexible settings for basal rates and manual boluses. It can hold 200 units of U100 insulin and can be used for 80 hours. The device can be programmed with up to 24 basal rates in a single program and can have up to 6 programs. Boluses may be adjusted in intervals of 0.05U and may be programmed as a standard wave, an extended wave (timing controlled by user) or a dual wave (both standard and extended). The Omnipod is programmed by a handheld controller with a built-in blood glucose meter and a bolus calculator. Omnipod it has been on the market for over 10 years, and the newest version is Omnipod 5, a fully on-body system in which the HCL device is not connected via tubes to the infusion site. The HCL algorithms are contained within the patch pump or Pod, and so the HCL system will continue to function if the personal diabetes manager (PDM) is misplaced or left behind.

Smart Insulin Pens

Smart insulin pens are digital, connected insulin pens that automatically transmit information about time and amount of insulin administered to the user’s mobile device. They can provide dose reminders and help to calculate the bolus. Data from the smart insulin pen are transferred wirelessly via bluetooth to a smartphone, eliminating the need for manual self-report logbooks. Recent trials suggest that smart insulin pens have the potential to improve glycemic control and decrease glucose variability.

The first smart pen to receive FDA approval (2017) was InPen. In 2020, InPen received a new, updated version. This device is designed for use with rapid-acting insulin U-100 Humalog and NovoLog. It can also prepare reports for healthcare professionals. There are also several other smart insulin pens on the market: ESYSTA (Emperra), Pendiq 2.0 (Pendiq) and NovoPen 6 (Novo Nordisk).

Newer Insulins

Rapid-Acting Insulins (Lispro, Aspart, Glulisine, Inhaled Human Insulin)

Insulin Lispro

Insulin lispro (Humalog and the newer formulation Lyumjev) is indicated to improve glycemic control in adults and children with diabetes mellitus. It was the first fast-acting insulin analogue introduced in 1995. It is an effective agent for improving glycemic control while minimizing delayed hypoglycemia. The rapid onset of action appears to be mainly due to its faster absorption (peaking at approximately 30 to 150 minutes compared with 90 to 300 minutes for regular insulin) when injection is SC. Its unique absorption and action properties are the result of a reversal in the two adjacent amino acids: lysine at position 28 and proline at position 29 on the β-chain.

Some of the drawbacks of the older regular insulin preparations have been their slow onset of action as well as delayed clearance, resulting in inefficient control of postprandial excursions in blood glucose levels. With the faster rise and fall of the serum insulin level following a lispro injection, it is easier to coordinate the timing of insulin injections with the subsequent meal. Another advantage to this fast-acting insulin is that it does not have as prolonged an action as regular insulin, thereby reducing the incidence of delayed hypoglycemic reactions.

Insulin lispro is available in several forms and strengths: as U-100 in vials (3 mL or 10 mL) and U-100 and U-200 in prefilled 3 mL KwikPen or Tempo Pen devices. Insulin lispro U-100 and U-200 can both be administered by subcutaneous injection. This method is generally used in regimens with an intermediate- or long-acting insulin. Subcutaneous injections should be given in tissue of the abdominal wall, thigh, upper arm, or buttocks within 15 minutes prior to a meal or immediately afterwards (Humalog) or at the start of a meal or within 20 minutes after starting a meal (Lyumjev).

Insulin lispro U-100 can also be administered by an insulin pump into the subcutaneous tissue of the abdominal wall. However, the safety and efficacy of this method has only been assessed in clinical trials enrolling patients with T1D. Insulin lispro U-200 should not be mixed with any other insulin, nor should it be administered intravenously or used with insulin pumps.

Lyumjev is a recently (2020) approved formulation of insulin lispro. Lymjev is currently approved for adults only, and with a choice of U-100 or U-200 strengths. In phase 3 trials in patients with T1D and T2D, Lyumjev showed non-inferiority to Humalog, as well as a very similar safety profile. Pharmacokinetics and glucodynamics trials have demonstrated that Lyumjev produces more rapid glucose lowering: within 20 minutes in patients with T1D (compared to 31 minutes with Humalog) and 32 minutes in patients with T2D (compared to 45 minutes with Humalog), which is why it can be administered up to 20 minutes after starting a meal.

Insulin Aspart

Insulin aspart (Novolog and the newer formulation Fiasp) is another fast-acting insulin analogue developed by substituting proline with aspartate on the β-chain of the insulin molecule. The substitution of proline with aspartic acid in insulin aspart reduces its tendency to form hexamers like regular insulin. Insulin aspart has more rapid absorption and faster onset of action—within 10 to 20 minutes (Novolog) and 2 to 15 minutes (Fiasp)— than regular insulin, although both are absorbed to a similar extent. Insulin aspart peaks between 40 and 50 minutes (Novolog) or 30 and 60 minutes (Fiasp) and has a duration of action of 3 to 5 hours. Insulin aspart U-100 is available in several package sizes, including 10 mL vials, 3 mL PenFill cartridges and 3 mL FlexPen and FlexTouch devices.

Because of its rapid onset and short duration, insulin aspart should be used in regimens along with intermediate- or long-acting insulin or with external pumps for subcutaneous insulin infusion. If administered by subcutaneous injection or insulin pump, insulin aspart should be taken immediately (within 5 to 10 minutes) before a meal (Novolog) or at the start of the meal or to 20 minutes after starting a meal (Fiasp). Intravenous administration at concentrations of 0.05 U/mL to 1.0 U/mL can also be performed under medical supervision for glycemic control, with close monitoring of blood glucose and potassium levels.

The continuous subcutaneous infusion of insulin aspart has been investigated in patients with T2D. A 16-week open-label trial enrolling 127 adult patients compared pre-prandial insulin aspart injection in conjunction with NPH to insulin aspart administered by an external insulin pump. At trial completion, the two groups had similar reductions in A1C and rates of hypoglycemia.

The FDA approved an even faster acting mealtime insulin aspart (Fiasp) in 2017. The main difference compared to Novolog is a faster absorption time – Fiasp enters the bloodstream in 2.5 minutes and can be taken as late as 20 minutes into a meal. This property derives from vitamin B3, a Fiasp excipient not present in Novolog. Phase 3 trials in adult and pediatric patients with T1D and T2D have demonstrated the non-inferiority of Fiasp to Novolog.

Insulin Glulisine

Insulin glulisine (Apidra) is a fast-acting insulin analogue that was developed by replacing the asparagine in position B3 by lysine, and lysine at position B29 by glutamic acid. Like other rapid-acting insulins, insulin glulisine has a more rapid onset of action compared with regular human insulin when administered subcutaneously, due to it being more rapidly absorbed. It has an onset of action of approximately 25 minutes, reaching peak activity 40-50 minutes after injection and has a duration of action of between 4 and 5 hours. Median peak concentrations of insulin glulisine are increased compared with regular human insulin (84 microUnits/mL and 41 microUnits/mL, respectively). It should generally be used in regimens with an intermediate or long-acting insulin.

Insulin glulisine U-100 is available in 10 mL vials or a 3 mL prefilled SoloStar device. When administered by subcutaneous injection, insulin glulisine should be given 15 minutes prior to a meal or within 20 minutes after starting a meal. Administration through an insulin pump is possible; however, continuous subcutaneous infusion has only been supported by clinical trials enrolling patients with T1D. Under medical supervision for glycemic control, insulin glulisine may also be administered intravenously at concentrations of 0.05 Units/mL to 1 Unit/mL.

Inhaled Human Insulin

More recently, a rapid-acting, inhalable insulin formulation (Afrezza) has been approved to improve glycemic control in adult patients with diabetes mellitus. Afrezza consists of single-use plastic cartridges filled with a white powder containing insulin, which is administered via oral inhalation. It is pre-metered into single-use dose (4-, 8-, or 12-unit) cartridges to be used with a thumb-sized inhaler. The units of inhaled insulin are not equivalent to subcutaneously injected insulin; e.g. 8 units of inhaled insulin are equivalent to ~4 units of injected insulin, but the pharmacokinetics are quite different. For the T2D population requiring insulin therapy, patient resistance, as well as clinical inertia on the part of the health care professional, act as barriers to starting insulin. The small discrete size of the Afrezza inhaler device, as well as its rapid onset of action, makes it an attractive option for patients with T2D. It provides patients with another insulin-therapy option to manage their diabetes but does not require multiple daily injections, which has proven to be promising for patients needing to start mealtime insulin who are needle adverse and want an easy and effective way to improve their postprandial glucose values. This method of administration could ease the process of initiating insulin and could improve patient adherence.

Afrezza is administered at the beginning of meals; the appropriate dose is calculated based on the individual’s metabolic needs, blood glucose monitoring results and glycemic control goals (Figure 18-3). Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (ie, macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness. Once inhaled, Afrezza dissolves upon contact with the lung surface and is rapidly dissolved into the systemic circulation. Approximately 59% of the inhaled dose reaches the lung. The remaining material is distributed in the oropharynx (30%) and stomach (10%).

Pharmacokinetics/Pharmacodynamics

Afrezza is rapidly absorbed compared with subcutaneously injected insulin (12-15 minutes to maximum serum insulin compared with 30 to 150 minutes for insulin lispro) and more rapidly eliminated. Although it does not have a faster onset of activity, the result is a much faster peak effect of about 15 minutes, compared with several hours for insulin lispro. (Figure 18-4).

Efficacy

The efficacy of Afrezza was compared with placebo inhalation in 353 patients with T2D inadequately controlled on optimal/maximally tolerated doses of metformin only or two or more OADs in a 24-week, double-blind study. Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. OADs doses were kept stable. At week 24, treatment with Afrezza plus OADs provided a mean reduction in A1C that was significantly greater than the A1C reduction observed in the placebo group (Table 18-6).

Safety

The safety of Afrezza has been studied extensively, both preclinically and in a clinical program involving more than 3017 subjects, with 1026 and 1991 having T1D and T2D, respectively. Hypoglycemia was the most common adverse events experienced by patients, as it is for other types of insulin. Other common adverse events associated with the use of Afrezza in patients with T2D were cough and throat pain or irritation, which diminish over time. Caregiver and patient monitoring are keys to monitoring and managing hypoglycemia. Although Afrezza is associated with minimal or no weight gain and hypoglycemia risk, these risks are substantially lower than those associated with sulfonylureas and injectable insulin. In a study comparing Afrezza with injected insulin, 31% of patients receiving Afrezza had hypoglycemia compared with 49% on insulin aspart.

Pulmonary Function

In patients without chronic lung disease, Afrezza caused a small decline in lung function over time as assessed by forced expiratory volume (FEV₁) (40 mL [95% CI: -80, -1]) compared with comparator-treated patients. The FEV₁ decline occurred during the first 3 months of treatment and persisted throughout therapy, for up to 2 years. A decline of ≥15% in FEV₁ was observed in 6% of Afrezza-treated patients compared with 3% of comparator-treated patients. During the treatment period, the annual rate of FEV₁ decline did not worsen with increased duration of use. There is now data to indicate the effect is reversed upon treatment discontinuation. Full PFTs are not needed and the FEV1 can be measured quickly in the clinic.

Before initiating Afrezza treatment, a detailed medical history, physical examination and spirometry should be performed to identify potential lung disease in all patients. The long-term safety and efficacy of Afrezza in patients with chronic lung disease have not been established.

Acute bronchospasm has been observed following Afrezza treatment in patients with asthma and patients with COPD. Because of the risk of acute bronchospasm, Afrezza is contraindicated for the use in patients in with chronic lung disease or asthma, as airway mechanics in these patients may change the pharmacokinetics of inhaled insulin.

In an analysis of data from 13 phase 2 and 3 trials comprising a total of 5,505 patients, 3,017 of whom received Afrezza, respiratory adverse events were similar across treatment groups. The only exception was mild cough, which was more common with Afrezza (28.0%) than with active comparators (5.2%). Lung malignancies were observed in only 2 patients on Afrezza, both active smokers; the rate of malignancy was no higher than in the general population.

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Short-Acting Insulin (Regular Human Insulins)

Regular human insulins are polypeptide hormones structurally identical to human insulin. One of the most commonly used regular insulins is Humulin R, which is produced by recombinant DNA technology using non-pathogenic laboratory bacteria. Two concentrations of Humulin R are available: U-100 and the more concentrated U-500.

Humulin R U-100

Humulin R U-100 is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with T1D and T2D. It may be administered either by subcutaneous injection or intravenous infusion. With subcutaneous use, the onset of action is within 10 to 75 minutes after administration of doses within the 0.05 units/kg to 0.4 units/kg range. Peak effects are observed after approximately 3 hours, and the duration of action is approximately 8 hours, with a range of 3 to 14 hours.

The dosing regimen of injected Humulin R U-100 should be individualized according to the needs of the patient. However, it is typically administered three or more times a day. It should be injected in the abdominal wall, thigh, gluteal region, or upper arm approximately 30 minutes prior to a meal.

Efficacy of Humulin R U-100 Administered by Subcutaneous Injection

The safety and efficacy of Humulin R U-100 administered by subcutaneous injection were assessed in a 48-month, open-label, single-arm study enrolling 129 patients with T1D or T2D. Patients were administered Humulin R U-100 and Humulin N, alone or in combination. A1C was not measured in this study, but total mean glycohemoglobin improved from 14.3 ± 3.1% at baseline to 10.1 ± 2.8% at trial completion. Weight increased from 72 ± 23 kg at baseline to 80 ± 22 kg at trial completion. Twenty-one percent of patients reported hypoglycemia during the trial.

Humulin R U-500

A greater insulin dose is required to maintain glycemic control as insulin resistance increases and insulin secretion decreases. Obesity compounds this effect since it adds to inherent insulin resistance in patients with T2D. A larger dose requires a greater volume of subcutaneously injected insulin, which can result in discomfort, pain and uncertain dosing due to leakage. Thus, there are certain patients with T2D that would benefit from a more concentrated formulation than the usual U-100.

Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. U-500 has been available for decades, and until more recently, had been the only concentrated insulin therapy available to patients with T2D. It is most commonly used in the treatment of patients with high insulin needs, such as those who have obesity or are pregnant. More infrequently, U-500 is used in patients with severe insulin resistance due to genetic defects in the insulin receptor or from insulin receptor antibodies. Although degludec U-200 and glargine U-300 are more recently approved concentrated insulin options, neither formulation is designed to provide dual basal and mealtime coverage like that provided by U-500.

Compared with Humulin R U-100, U-500 takes a longer time to reach its peak effect and has a lower maximum serum insulin concentration, resulting in a prolonged glucose-lowering effect. The peak effect is observed ~30 minutes post-injection, so U-500 should be administered approximately 30 minutes prior to meals. U-500 is typically used two or three times daily, although the dosing regimen should be individualized to the needs of the patient.

U-500 is a suitable replacement for U-100 multiple dose injection therapy and can significantly improve A1C in highly insulin-resistance patients. Adherence has also been shown to be improved in patients administered U-500 vs U-100. However, U-500 is associated with weight gain and an increased total daily insulin dose. Hyperglycemia, hypoglycemia and death resulting from medication errors have also been reported, due to dispensing, prescribing, or administration mistakes. Patients should be advised to pay attention to details at every level of care to prevent such errors. Instruct patients to check their insulin label before each injection to verify its concentration. Patients who are prescribed the vial must also be prescribed the U-500 insulin syringe to avoid medication errors.

For many years, U-500 was available only in vials. The introduction of the prefilled 3 mL KwikPen has since simplified dosing and administration.

U-500 should only be administered by subcutaneous injection. It should not be administered intravenously or intramuscularly, nor should it be diluted or mixed with any other insulin products or solutions.

Long-Acting Insulins (Detemir, Glargine U-100)

Insulin Detemir

Insulin detemir (Levemir) is a long-acting insulin analog approved for once- or twice-daily treatment of adult and pediatric patients with diabetes. Produced by recombinant DNA technology, it differs from human insulin in that one amino acid (threonine) has been omitted on one chain and a fatty acid has been attached to the other chain. Its slow absorption and long duration of action (~6 to 23 hours, depending on dose) are mediated by its strong self-association and extensive binding with albumin (approximately 98% bound), respectively. Compared with neutral protamine Hagedorn [insulin] (NPH) insulin, detemir has slower, more prolonged absorption. Its time action profile is relatively flat with a duration of action that ranges from 6 hours at the lowest dose to 23 hours at the highest dose and a C_max between 3 and 9 hours.

In a 24-week clinical trial enrolling insulin-naïve patients with T2D, insulin detemir was compared with NPH insulin. Insulin was administered twice-daily in both regimens, and in combination with 1 or 2 oral antidiabetic agents (metformin, an insulin secretagogue, or an alpha-glucosidase inhibitor). Insulin detemir and NPH insulin had comparable effects on lowering A1C. Another 22-week study found similar results for A1C and FPG lowering when insulin detemir and to NPH insulin were part of a regimen with insulin aspart.

Insulin detemir (U-100) is available in a 10-mL vial and 3-mL prefilled disposable FlexTouch pen capable of delivering 1 to 60 units of insulin in a single injection.

Insulin Glargine U-100

Insulin glargine (Lantus) U-100 was the first peakless long-acting basal insulin analogue. Lantus is a long-acting insulin used to treat adults with T2D and adults and pediatric patients (6 years and older) with T1D for the control of high blood glucose. It should be administered once a day at the same time each day to lower blood glucose. Splitting the dose of Lantus is rarely needed and should be based on home or continuous glucose monitoring results and not on an arbitrary dosage amount.

Produced by recombinant DNA technology, insulin glargine differs from human insulin by an asparagine-to-glycine substitution at A21 of the A-chain and an addition of two arginines to the C-terminus of the B-chain. It exists in an acidic form and cannot be mixed in the same syringe with other insulins, and cannot be administered via an insulin pump. After SC injection, insulin glargine forms microcrystalline precipitates that gradually release insulin. Glargine has its onset of action at 4 to 6 hours and a peakless duration of action of >24 hours, depending on dose. The rate of absorption does not differ for different injection sites and the pharmacokinetics within subjects is fairly consistent.

Efficacy

The efficacy of insulin glargine U-100 was evaluated in several clinical trials. In a 52-week trial, patients were administered OADs (a sulfonylurea, metformin, acarbose, or a combination of these drugs) and either insulin glargine or NPH insulin. Insulin glargine was as effective as NPH insulin in reducing A1C and fasting glucose, with similar rates of severe symptomatic hypoglycemia. Both insulins were administered once daily at bedtime. A similar trial was conducted for 28 weeks in patients with T2D, but who were not receiving OADs, and regular human insulin was used as mealtime insulin, as needed. Once-daily bedtime insulin glargine was found to have similar effectiveness as either once- or twice-daily NPH insulin in reducing A1C and fasting glucose, with a similar incidence of hypoglycemia.

A 5-year study enrolling patients with T2D assessed the efficacy of once-daily insulin glargine compared with twice-daily NPH insulin in the progression of retinopathy and A1C change from baseline. Both groups of patients had a similar glycemic goal of a FPG ≤100 mg/dL. After 5 years, the insulin glargine group has a lower daily basal insulin dose, a smaller mean reduction in baseline A1C, and a similar incidence of severe symptomatic hypoglycemia compared with NPH insulin. Progression of retinopathy was assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS) and was found to be similar between patient groups.

The ORIGIN trial compared the efficacy of insulin glargine to standard of care on major adverse cardiovascular (CV) outcomes in 12,537 participants ≥50 years of age with abnormal glucose levels or early T2D and established cardiovascular disease (CVD) or CV risk factors at baseline. The trial found that the incidence of major adverse CV outcomes was similar between treatment groups.

Considerations for Patients Starting or Switching to Insulin Glargine

In insulin-naïve patients, insulin glargine should be initiated at a starting dose of 0.2 U/kg or up to 10 U once daily. If patients are switching to insulin glargine from other insulin therapies, the following guidelines should be followed:

• When switching from a treatment regimen that uses an intermediate- or long-acting insulin, a change in basal insulin dose may be required. In addition, the timing and amount of shorter-acting insulins and doses of any OADs may also need to be adjusted.
• When switching from a once-daily NPH insulin regimen, patients should initiate therapy with the same dose as that being discontinued.
• When switching from a twice-daily NPH insulin regimen, patients should initiate therapy with a dose that is 80% of the total dose being discontinued. This reduction in dose lowers the risk of hypoglycemia.

Safety

The safety of insulin glargine was assessed in 1,563 patients with T2D who received either insulin glargine or NPH insulin. The most common adverse events occurring in ≥5% of patients were hypoglycemia, upper respiratory tract infection, infection, and retinal vascular disorder. Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin glargine. In adults, the proportion of patients experiencing severe symptomatic hypoglycemia was similar between insulin-glargine and NPH-treated patients (7.8% vs 11.9%, respectively).

Basaglar U-100 (Insulin Glargine Follow-On Biologic)

Lantus (insulin glargine) was developed by Sanofi-Aventis and approved by the FDA in 2000. However, patent protection expired in 2015, permitting other companies to manufacture their own versions of this drug. Basaglar, the insulin glargine biosimilar manufactured by Eli Lilly and Company, was approved later that year. A biosimilar product is a biological product approved based on the demonstration that it is highly similar to an FDA-approved biological product, with no clinically meaningful differences in safety and efficacy. Basaglar has been approved for the same indication as Lantus: to improve glycemic control in adults and pediatric patients with T1D and in adults with T2D.

Basaglar U-100 is available as a solution for injection in a KwikPen, a 3 mL prefilled delivery device. Between 1 and 80 units can be delivered subcutaneously with each injection. Basaglar should be injected once daily at the same time each day. This product should not be infused intravenously or administered using an insulin pump due to the risk of severe hypoglycemia.

Efficacy Compared with Insulin Glargine U-100

In clinical trials enrolling adult patients with T2D, the glucose-lowering effect of once-daily Basaglar U-100 plus OADs was compared with that of once-daily insulin glargine U-100 products plus OADs. Patients were either insulin-naïve and had failed to achieve glycemic control while on at least two OADs or were already using an insulin glargine U-100 product plus at least two OADs, with or without adequate glycemic control. Treatment with Basaglar was found to be noninferior to insulin glargine U-100 products in reducing A1C from baseline (adjusted mean change from baseline = -1.3 for both treatment arms; 95% CI, 0.05 [-0.07, 0.17]).

Basaglar has also been shown to be noninferior to insulin glargine U-100 products at reducing baseline A1C in patients with T1D.

Considerations for Patients Starting or Switching to Basaglar

In patients with T2D initiating Basaglar, the recommended dose is 0.2 units/kg or up to 10 units once daily. The dose and timing of other anti-diabetic products may need to be adjusted.

If patients are switching to Basaglar from other insulin therapies, the following guidelines should be followed:

• When switching from other insulin glargine products (U-100) to Basaglar, maintain the dose of the other insulin glargine product. The timing of administration should be determined by the physician.
• When switching from a once-daily insulin glargine product (U-300) to once-daily Basaglar, the recommended dose is 80% of the discontinued product to reduce the risk of hypoglycemia.

Semglee U-100 (Insulin Glargine-yfgn)

Semglee is another insulin glargine biosimilar developed by Mylan and approved by the FDA in 2021. It is indicated to improve glycemic control in adults and pediatric patients with T1D and T2D. The recommended starting dose of Semglee in patients with T2D who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. Patients may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs. Semglee is available as 10mL multiple-dose vial or 3mL single-patient-use prefilled pen.

Efficacy Compared with NPH

The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in seven open-label, randomized, active-controlled, parallel trials, including three trials of adult patients with T1D, one trial of pediatric patients with T1D and three trials of adult patients with T2D. Insulin glargine was noninferior to NPH insulin with regard to the reduction in A1C.

Switching to Semglee from Other Insulin Therapies

The prescribing information for Semglee contains the following guidelines on changing to Semglee from other insulin therapies:

• If changing patients from once-daily insulin glargine, 300 units/mL, to once-daily Semglee, the recommended initial Semglee dose is 80% of the insulin glargine, 300 units/mL dose that is being discontinued.
• If changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Semglee, change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.
• If changing patients from once-daily NPH insulin to once-daily Semglee, the recommended initial Semglee dose is the same as the dose of NPH that is being discontinued.
• If changing patients from twice-daily NPH insulin to once-daily Semglee, the recommended initial Semglee dosage is 80% of the total NPH dose that is being discontinued.

Refer to the above section on Lantus for information on switching to insulin glargine from other insulin regimens.

Ultralong-Acting Insulin (Glargine U-300, Degludec U-100 and U-200)

Insulin Glargine U-300

Despite pharmacodynamic and pharmacokinetic studies demonstrating a 24-hour duration of action for insulin glargine and detemir, lower doses can have a variable duration. This has led 13% of and 48% of patients with T2D adopting a twice daily regimen with glargine and detemir, respectively, to improve overnight hyperglycemia. However, doing so increases the risk of nocturnal hypoglycemia. There is therefore a need for basal insulins with true 24-hour coverage, a low risk of hypoglycemia, minimal intrapatient variability and a flexible dosing schedule. More concentrated formulations are also needed for patients with severe insulin resistance and high injection volume requirements. For years, Humulin R U-500 was the only concentrated insulin therapy available, but more recently, insulin glargine U-300 (Toujeo) and degludec U-200 have been introduced to the marketplace.

Insulin glargine U-300 is an ultralong-acting insulin for subcutaneous injection. It has a more prolonged pharmacokinetic/dynamic profile than glargine U-100 and offers the benefit of a smaller volume of subcutaneous injection. U-300 delivers insulin glargine at a reduced rate from the subcutaneous depot, resulting in even flatter and prolonged pharmacokinetic and pharmacodynamic profiles. On a unit-to-unit basis, U-300 has a lower maximum glucose lowering effect but a much longer duration of action compared with U-100 that extends up to 36 hours. U-300 is currently available in a 1.5 mL SoloStar prefilled pen that carries 450 units, 50% more than the U-100 pen. The FDA recently approved a Max SoloStar, a Toujeo (U-300) pen that contains 900 units of insulin and can dose up to 160 units at a time in doses of 2-unit increments. It is stable at a room temperature for 42 days, which is enough for the pen’s contents to be used up if prescribed at ≥20 units daily. This large dose pen reduces waste and insulin shorting (skipping the dose if the pen runs empty without the reserve to give the full prescribed dose) by the patient.

The safety and effectiveness of once-daily U-300 was compared with that of once-daily U-100 in open-label, randomized, active-control, parallel phase 3 studies of up to 26 weeks in patients with T1D and T2D (Table 18-7). In these EDITION trials, the reduction in A1C and FPG with U-300 titrated to goal was similar to that with U-100 titrated to goal. At trial completion, depending on the patient population and concomitant therapy, the daily insulin dose was higher for patients administered U-300 than U-100. However, there were no clinically important differences in body weight between treatment groups. In a subsequent meta-analysis of clinical trials, U-300 was shown to be associated with significantly less severe and any-time hypoglycemia than U-100.

Overall, glargine U-300 can be safety administered once daily in combination with OADs or mealtime insulin. It is an option for patients with high insulin needs or for those who are particularly concerned about hypoglycemia.

Insulin Degludec U-100 and U-200

Insulin degludec (Tresiba) is a long-acting insulin analog that is injected subcutaneously, once-daily at any time of day. Compared with human insulin, the amino acid threonine at position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been added. Tresiba has a half-life of 25 hours and a long duration of action of at least 48 hours. These properties allow Tresiba to be administered once daily (subcutaneously) at any time of day.

Insulin degludec forms a depot of multi-hexamers after injection into the subcutaneous tissue, which delays absorption into the systemic circulation. Slow absorption rate and binding to circulating albumin are responsible for the protracted time action profile.

Tresiba was approved by the FDA in 2015 for use alone or in combination with OADs or bolus insulin for glycemic control in adults with T1D or T2D. Insulin degludec is available in 100 units/mL (U-100) and 200 units/mL (U-200) 3 mL FlexTouch disposable prefilled pens, permitting maximum doses of 80 U and 160 U per injection, respectively and the pen holds 600 units of insulin.

Efficacy

The efficacy of insulin degludec administered once daily either at the same time each day or at any time each day, in combination with a mealtime insulin or OADs, was assessed in six randomized, open-label, treat-to-target active-controlled trials enrolling patients with T2D. Overall, insulin delgudec was noninferior to insulin glargine U-100 or insulin detemir in achieving glycemic control and showed significant improvement over sitagliptin.

In two trials comparing the efficacy of insulin degludec (either U-100 or U-200) with insulin glargine in insulin-naïve patients concurrently receiving metformin with or without a DPP4-inhibitor, insulin degludec was found to be noninferior to insulin glargine in reducing A1C from baseline. The efficacy of insulin degludec (U-100) was also compared with inulin glargine in insulin-naïve patients as an add-on to one or more oral agents, including metformin, sulfonylurea, glinides, or alpha-glucosidase inhibitors. This trial also demonstrated the noninferiority of insulin degludec in reducing A1C from baseline (adjusted mean change from baseline = -1.42 and -1.52 for insulin degludec and insulin glargine, respectively; estimated treatment difference [95% CI] = 0.11 [-0.03; 0.24]).

Insulin degludec is also noninferior to insulin glargine in reducing A1C in insulin-experienced patients. In a trial enrolling patients who were inadequately controlled on basal insulin alone, OADs alone, or both basal insulin and OADs, insulin degludec was administered either once daily at the same time each day or once daily at any time each. The trial demonstrated that that insulin degludec administered at alternating times was noninferior to insulin glargine administered once-daily in reducing A1C from baseline (adjusted mean change from baseline = -1.17 and -1.21 for insulin degludec and insulin glargine, respectively; estimated treatment difference [95% CI] = 0.04 [-0.12;0.20]). In a trial which enrolled patients inadequately controlled on premix insulin, bolus insulin alone, basal insulin alone, OADs alone or in any combination, insulin degludec administered once daily with the main evening meal was noninferior to insulin glargine administered once daily in reducing A1C from baseline (adjusted mean change from baseline = -1.10 and -1.18 for insulin degludec and insulin glargine, respectively; estimated treatment difference [95% CI] = 0.08 [-0.05;0.21]).

Comparison of Insulin Glargine U-300 and Insulin Degludec U-100 Efficacy Using TIR as the Primary Endpoint and Glycemic Variability and the Main Secondary End Point

The efficacy of insulin glargine U-300 was compared to that of insulin degludec U-100 in InRange, a 12-week, randomized, active-controlled, open-label, head-to-head comparison trial. A total of 343 patients with T1D (A1C above 7% and below 10%, on once-daily basal insulin and rapid-acting insulin analogs for at least one year) were randomized (1:1) to receive either insulin glargine U-300 (172 patients) or insulin degludec U-100 (171 patients). The primary efficacy endpoint was time-in-range (TIR; the amount of time spent in the target blood glucose range, expressed as a % of CGM readings within that range) of ≥70 to ≤180 mg/dL (≥3.9 to ≤10 mmol/L) at week 12 (assessed using blinded CGM). Patients receiving insulin glargine U-300 had a mean TIR of 52.74% (95% CI: 51.06, 54.42), compared to a mean TIR of 55.09% (95% CI: 53.34, 56.84) for those receiving insulin degludec U-100; with a mean difference of 3.16% (95% CI: 0.88, 5.44), insulin glargine U-300 was shown to be noninferior (P_{noniferiority} = 0.0067). Superiority was not demonstrated (P_superiority = 0.0548). The non-inferiority of insulin glargine U-300 with regard to the main secondary endpoint, the glucose total coefficient of variation (CV), was also demonstrated. Total glucose CV was 39.91% (95% CI: 39.20, 40.61) in the insulin glargine U-300 group, compared to 41.22% (95% CI: 40.49, 41.95) in the insulin degludec U-100 group (mean difference: –5.44% [95% CI: -6.50, -4.38]; P_{non-inferiority} <0.0001). There was no difference in the safety profile between the two treatment group, and no new safety signals were noted.

In addition to demonstrating the noninferiority of insulin glargine U-300 to insulin degludec U-100 with respect to its primary and main secondary endpoints, InRange was the first large randomized controlled trial to use CGM-based TIR as a primary efficacy endpoint, which may herald a shift toward incorporating CGM-based metrics into clinical trials.

Considerations for Patients Starting or Switching to Insulin Degludec

Insulin-naïve patients initiating treatment with insulin degludec should start at a dose of 10 units once daily. Insulin-experienced patients switching to insulin degludec should initiate therapy using the same total dose they used with their long- or intermediate-acting insulin.

Safety

The safety of insulin degludec was evaluated in nine treat-to-target clinical trials of 6 to 12 months in duration that enrolled patients with T1D or T2D. The most common adverse events occurring in ≥5% of patients with T2D receiving insulin degludec were hypoglycemia, nasopharyngitis, headache, upper respiratory tract infection and diarrhea. Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin degludec. In individual clinical trials, the risk of hypoglycemia was similar between insulin degludec and comparators.

Although insulin degludec and insulin glargine have comparable efficacy in reducing A1C, meta-analysis has demonstrated that insulin degludec is associated with significantly lower rates of nocturnal hypoglycemia, regardless of how hypoglycemic events are defined. According to the ADA definition of a nocturnal hypoglycemic event (symptoms + PG <70 mg/dL between 12 and 6 am), insulin degludec and insulin glargine were associated with 73.8 and 100.5 events per 100 patient years of exposure in insulin-naïve patients with T2D, respectively. In insulin-experienced patients, insulin degludec and insulin glargine were associated with 167.0 and 233.4 events per 100 patient years of exposure, respectively. Patients in clinical trials who achieve A1C <7% also experience significantly less overall confirmed hypoglycemia (defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance) with insulin degludec than insulin glargine (estimated rate ratio IDeg:IGlar, 0.86; 95% CI, 0.76 to 0.98).

Premixed Formulations

Premixed insulins contain a combination of a short- or rapid-acting insulin with a long- or intermediate-acting insulin. These insulins are sometimes referred to as biphasic because they provide two peaks of insulin activity from a single injection. Several of the insulin types discussed previously are available in combination as premixed suspensions:

• Humulin 50/50 and 70/30 (human insulin isophane suspension + human insulin injection [Humulin])
• Novolin 70/30 (human insulin isophane suspension + human insulin injection [Novolin])
• Humalog 50/50 and 75/25 (insulin lispro protamine suspension + insulin lispro injection [Humalog])
• Novolog 50/50 and 70/30 (insulin aspart protamine suspension + insulin aspart injection [Novolog])
• Ryzodeg 70/30 (insulin degludec + insulin aspart injection [Ryzodeg])

The rapid onset of action of some of these mixtures allows them to get given around the same time as a meal. Whereas Humulin 70/30 should be administered 30-45 minutes before a meal, Ryzodeg is administered at the same time as the meal and Novolog 70/30 and can be administered 15 minutes before or after a meal. With the exception of Novolin 70/30, these new mixtures are available in easy-to-use disposable insulin pens, which simplifies the injection process.

Compared with adequately titrated basal and bolus insulin, premixed insulins provide some advantage in terms of glycemic control. This has been demonstrated by meta-analysis, which demonstrated that premixed rapid-acting insulin preparations were more effective at reducing A1C than regular/NPH insulin, long-acting insulin and non-insulin oral agents (pooled difference of -0.4% compared with long-acting insulins and -0.5% for oral agents). Meta-analysis has also demonstrated that premixed insulin is more effective at lowering PPG, but less effective at reducing FPG and more often associated with minor hypoglycemia and weight gain than long-acting insulin or oral agents.

In a clinical trial longer in duration than those included in the previously discussed meta-analysis, patients with T2D suboptimally controlled with metformin and a sulfonylurea were administered either premixed biphasic insulin aspart twice-daily, basal insulin detemir once or twice daily, or prandial insulin aspart three times daily. After 2 years of treatment, more patients in the basal and prandial groups achieved the ≤6.5% A1C target. The basal insulin group experienced the fewest number of hypoglycemic episodes.

A disadvantage of premixed insulin is that the ratio of fast-acting to intermediate-acting insulin is fixed, so a patient cannot use carbohydrate counting or a correction factor to adjust the dose. Patients with T2D new to insulin therapy may be considered good candidates for these mixtures. In addition, patients on NPH insulin alone, or oral agents but who remain out of control or who have delayed hypoglycemia may benefit from premixed formulations.

Ryzodeg 70/30

Ryzodeg 70/30 is a mixture of the long-acting insulin degludec and the rapid-acting insulin aspart. Ryzodeg 70/30 was approved by the FDA for the improvement of glycemic control in adults with diabetes mellitus. It is administered once or twice daily with any main meal.

Efficacy

The efficacy and safety of Ryzodeg 70/30 for the treatment of patients with T1D or T2D were evaluated in one 26-week active controlled clinical trial, and four active controlled 26-week clinical trials, respectively. Ryzodeg 70/30 provided reductions in A1C equivalent to reductions achieved with other, previously approved long-acting or pre-mixed insulins (insulin glargine U-100, insulin detemir, or Novolog 70/30).

Considerations for Patients Starting or Switching to Ryzodeg 70/30

Insulin-naïve patients with T2D who are starting therapy with Ryzodeg 70/30 should initiate therapy with 10 U once-daily. Patients who are switching from once- or twice-daily basal insulin alone, or as part of a regimen of multiple daily injections, should follow these guidelines:

• In patients with T2D switching from a regimen of only a once- or twice-daily basal insulin, Ryzodeg 70/30 should be initiated at the same dose and injection schedule. Due to the rapid-acting insulin component of Ryzodeg 70/30, these patients should monitor their blood glucose after starting therapy.
• In patients switching from a multiple daily injection regimen that includes a basal and short- or rapid-acting insulin at mealtimes, Ryzodeg 70/30 should be initiated once daily with the main meal at the same unit dose as the basal insulin. Continue short- or rapid-acting insulins at the same dose for meals not covered by Ryzodeg 70/30.

Patients switching from a once- or twice-daily premix (or self-mix) insulin regimen alone, or as part of a regimen of multiple daily injections, should initiate treatment with Ryzodeg 70/30 at the same unit dose and injection schedule as for the premix or self-mix insulin. If these patients also use short- or rapid-acting insulins at mealtime they should continue doing so for meals that are not covered by Ryzodeg 70/30.

Safety

The safety of Ryzodeg in patients with T2D was assessed in four clinical trials of 6 to 12 months in duration enrolling 998 patients. The most common adverse events were hypoglycemia, nasopharyngitis, upper respiratory tract infection, and headache. Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Ryzodeg 70/30.

Complications of Insulin Therapy

Weight gain and hypoglycemia are the most frequently reported complications of insulin therapy. Both can be minimized with appropriate preventive measures and dosage adjustments. It is important to emphasize that the benefits of improved glycemic control far outweigh any adverse effects of weight gain in a patient with poorly controlled diabetes.

Weight Gain

Hyperinsulinemia caused by large amounts of exogenous insulin can lead to marked increases in weight, which is a real concern in T2D. Obesity itself is an insulin-resistant state that contributes to a cycle of worsening insulin resistance, increasing insulin requirements and further weight gain. Some patients, particularly those with obesity, may require large doses of insulin to normalize glycemia in order to overcome the insulin resistance that is typical of T2D. The additional exogenous insulin can result in hyperinsulinemia and an average increase in body weight of 3% to 9%. Excessive weight gain can be minimized by using the lowest possible dose of insulin to achieve target glycemic goals and encouraging the patient to decrease caloric intake and increase exercise. Of note is that the GLP1-RA class of agents help to reduce or minimize insulin requirements.

The UKPDS trial found that the average weight gain was approximately 7 kg in patients with T2D after 10 years of insulin therapy, with the greatest gains occurring when first initiated. After 3 years of treatment, metformin monotherapy resulted in no weight gain, compared with gains of 3.5 kg to 4.8 kg with either insulin or a sulfonylurea. Despite increased weight gain, UKPDS found that insulin monotherapy decreased the incidence of microvascular complications.

Studies of patients with T2D have reported less weight gain with insulin detemir (up to 2.6 lb) than with NPH insulin (up to 6.2 lb). Premixed rapid-acting preparations are also associated with increased weight gain compared with long-acting or oral agents. In the HEART2D trial, prandial insulin was associated with greater weight gain than basal insulin (4.8 kg vs 3.1 kg).

Hypoglycemia

The incidence of hypoglycemic reaction increases with insulin therapy, particularly intensive regimens and the thin and the elderly are most affected by such episodes. Patients with T1D are also more likely to experience hypoglycemia compared with patients with T2D. Severe hypoglycemia is rare in patients with obesity and T2D and is usually related to causal factors such as:

• Overinsulinization
• Underfeeding
• Unplanned strenuous physical activity
• Excessive alcohol
• Incorrect dose of insulin or oral agents taken by patient.

Among basal insulins, insulin glargine and detemir are associated with less symptomatic and nocturnal hypoglycemia than NPH insulin. In individual clinical trials, insulin degludec is associated with numerically fewer hypoglycemic events (overall and nocturnal) compared with insulin glargine, with meta-analysis revealing a significant difference. Compared with basal insulin, prandial insulin is associated with a greater risk of hypoglycemia. Frequent SMBG monitoring by the patient with adjustment in the dose or type of insulin can significantly reduce the likelihood of hypoglycemia.