A Conversation on an Effective, Straightforward, Quantitative Approach to the Outpatient Use of Insulin

There is no one right way to use insulin, but there are general principles that underlie an effective approach. Adjust insulin around patients’ usual eating patterns rather than giving them an insulin regimen and having them change their eating patterns to accommodate the regimen. It is very difficult for people to change their eating behavior. This is not to say that one should not educate patients to eat more healthily, but one must adjust insulin doses around their actual meal patterns.

Inconsistent meal patterns (timing and content) are the largest challenge to adjusting insulin doses. Educate patients to eat as consistently as possible with regard to the amounts of carbohydrate, protein, and fat in their meals, as well as the timing of their meals. Protein and fat have an important effect on the postprandial rise in blood glucose in addition to the more obvious effect of carbohydrate (4–6). Advising consistency does not mean that there have to be similar amounts of each nutrient at each meal throughout the day. It means that on each day, breakfasts, lunches, and suppers should each have their own consistent nutrient levels. (Supper will be used instead of “dinner” throughout this article because “dinner” means the largest meal, which is sometimes eaten in the middle of the day in some populations.) Regardless of the consistency of meal content and eating patterns, insulin doses must be adjusted based on glucose values that reflect the patient’s usual lifestyle.

This approach is consistent with the guidance from a recent American Diabetes Association (ADA) expert panel, which recommended that insulin dosing decisions “should not be based solely on carbohydrate counting,” but rather “continuous glucose monitoring . . . or self-monitoring of blood glucose . . . should guide decision-making” (7). If carbohydrate counting is used to calculate premeal insulin doses, the doses are based on insulin-to-carbohydrate ratios, and adjustments require changing these ratios, which is not covered by this approach.

The other challenge to adjusting insulin doses is the 20–30% intraindividual variability in patients’ responses to insulin injections (8,9). This variable response occurs to the same dose of insulin injected at the same site by the same nurse or investigator in the same patient from day to day, independent of meals. Fluctuations in eating and in responses to insulin mean that insulin doses must be adjusted based on glycemic patterns over time, given the patient’s current eating (and exercise) routines. Basing a long-term insulin dose adjustment on one or even several glucose values is inappropriate and can be dangerous. Changing a dose to treat a glucose value at a single time is appropriate, but only for that moment. Longer-term insulin dose changes are based on glycemic patterns over time, which reflect the patient’s current lifestyle.

Testing blood glucose preprandially is convenient and will usually suffice. Postprandial testing (1–2 hours after eating) requires patients to remember the timing and stop what they are doing to check their glucose. This process is usually inconvenient, and often not possible, in many situations. Before meals, people stop what they are doing to prepare to eat and sometimes to inject insulin, so checking glucose is usually easier and more convenient at this time point.

If preprandial glucose targets are reached, longer-term A1C targets are usually achieved as well. Sometimes, A1C levels remain above target when patients have reached preprandial glucose targets. This occurrence signifies that postprandial glucose values are high enough to keep A1C levels elevated, usually in situations with longer times between meals so that glucose values have more time to reach preprandial targets. In such cases, one must substitute (not add) postprandial testing for preprandial testing (e.g., checking glucose after breakfast instead of before lunch, after lunch instead of before supper, and after supper instead of before bedtime).

A small (100- to 150-kcal) bedtime snack that includes some protein to sustain the small rise in glucose is strongly recommended. The longer a patient does not eat, the greater the risk is for hypoglycemia. Decreasing the amount of time without eating overnight with a small bedtime snack is an important and effective way to minimize overnight hypoglycemia. Hypoglycemia can be a disincentive for patients to increase insulin doses when necessary and can even lead to their discontinuing insulin. For this reason, initial insulin doses are almost always less than what patients need and are gradually increased to minimize the risk of hypoglycemia.

The argument against a small bedtime snack is that >80% of patients with type 2 diabetes have obesity, so why recommend extra calories? One should instruct patients to reduce the calories they consume at supper to accommodate the calories in a bedtime snack. Obesity is a risk for macrovascular disease. Even if this swapping of calories from supper to snack does not occur, a gain of an extra 5 lb or so (e.g., from 250 to 255 lb) does not increase that risk very much.

Another argument that is sometimes offered is that a bedtime snack might increase fasting plasma glucose (FPG) levels. Even if that is so, a slightly higher basal insulin dose would achieve target FPG levels. As with meals, bedtime snacks need to be taken consistently to avoid overnight hypoglycemia should the snack be missed. If patients refuse to increase their insulin doses when necessary, and certainly if insulin is discontinued, glycemic control will worsen. Because hyperglycemia has a profound effect on the risk of developing microvascular complications of diabetes, in the author’s view, consistently ingesting a small bedtime snack outweighs the arguments against doing so.

There are both microvascular and macrovascular complications of diabetes. The microvascular complications include diabetic retinopathy (the leading cause of blindness in working-age people [10]), diabetic nephropathy (>50% of patients on dialysis receive this treatment secondary to diabetes [11]), and diabetic neuropathy (ultimately responsible for ∼85% of lower-extremity amputations, which are eightfold more common in people with diabetes [12]). None of these microvascular complications need to occur. The Diabetes Control and Complications Trial (13) showed that the development or progression of microvascular complications in people with type 1 diabetes seldom occurred if A1C levels were kept to <7.0%. With A1C levels between 7.0 and 8.0%, the relative risk of microvascular complications began to increase, but the increase became exponential with values >8.0% (13).

Regarding the macrovascular complications, myocardial infarctions are increased twofold in men with diabetes and fourfold in women with diabetes. About three-fourths of patients with type 2 diabetes die of heart attacks. Ischemic strokes are twice as common, and peripheral arterial disease also greatly increased. Studies have shown that tight diabetes control soon after diagnosis may be beneficial, but once cardiovascular disease has developed, tight control probably is not as important.

Based on the results of the Diabetes Control and Complications Trial, the ADA recommends an A1C target of <7.0% in most patients (14). There are certain patients, however, in whom tight diabetes control, with its increased risks for hypoglycemia in those receiving a sulfonylurea or insulin, is not indicated. These include patients with 1) a short life expectancy, 2) advanced microvascular complications that are not reversed with tight control, 3) social or educational issues, 4) cognitive dysfunction, 5) psychiatric issues, or 6) frailty associated with older age (14). In such patients, an A1C target of <8.0% is appropriate.

Although different diabetes organizations recommend other blood glucose targets, the ADA-recommended targets (14) will be used in this discussion. These are a preprandial target of 70–130 mg/dL and a postprandial target of <180 mg/dL. The ADA defines three levels of hypoglycemia: level 1 is 55–69 mg/dL, level 2 is <54 mg/dL, and level 3 is any severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia.

Although the ADA does not address a postprandial glycemia level that might be considered low (14), one must be identified for adjusting insulin doses. The rapid first-phase insulin release that occurs in people without diabetes retards the postprandial rise of glucose concentrations. This first-phase insulin secretion is lost when one develops diabetes, allowing greater increases in postprandial glucose. These postprandial glucose levels are even higher in patients whose insulin secretion is so diminished that they require insulin. For this reason, a value of <120 mg/dL was empirically selected because it was felt that if the peak glucose concentration, which occurs 1–2 hours after eating, were less than this value, there would be an increased risk for the injected preprandial insulin to cause subsequent hypoglycemia before the next meal.

There are >20 different insulin products, which are listed in Table 1. Most insulins are designated U-100, which denotes the concentration (i.e., 100 units/mL). Therefore, a 10-mL vial contains 1,000 units. Recently, some insulin preparations have become available in more concentrated forms (e.g., U-200 and U-300). The highly concentrated U-500 regular insulin has been available for decades. The larger the volume of insulin being injected, the more variable is its absorption. Thus, the advantage of using a more concentrated form of insulin is that there is less volume in the injectate, which has become more important with the progressive increase in obesity that requires higher doses of insulin.

Regular and NPH insulin are human insulins (i.e., their amino acid structure is identical to the insulin molecule secreted by pancreatic β-cells). All of the other insulins are analogs (i.e., their amino acid structures have been altered and, in some cases, complexed to other molecules, both of which somewhat alter their pharmacokinetic [PK] and pharmacodynamic [PD] characteristics). However, human and analog insulins are equally effective (15). The only clinical difference found between them is that overnight hypoglycemia is slightly, but significantly, less with basal insulins compared with bedtime NPH. However, in none of the >50 studies examined were bedtime snacks routinely recommended (15). Analog insulins cost two- to three fold more than human insulins. Patients for whom cost considerations are an issue can purchase human insulins at Walmart without a prescription for $25–30 per vial.

Three PK/PD characteristics of insulin injections are important for their clinical use: onset, peak, and duration of action (Table 2). These PK (time of appearance of insulin in the blood after injection) and PD (time-dependent changes of blood glucose after injection) properties are measured after injection, usually in subjects without diabetes. Because of the intraindividual variability of response to insulin (8,9) and patients’ variable eating patterns, small PK/PD differences are not clinically important. For example, because of the 30-minute lag period after the injection of short-acting (regular) insulin before its onset of action, injecting 20–30 minutes before eating has been taught to generations of medical students and house officers. Yet, a crossover study in which preprandial and postprandial glucose readings were measured at home seven times per day for 6 weeks after injecting regular insulin either 20 minutes or immediately before eating in the same patient revealed virtually identical values (16).

A straightforward approach for adjusting insulin doses depends on the principle that each component of an insulin regimen has a maximal effect on one of four periods throughout the 24-hour cycle (i.e., overnight, morning [between breakfast and lunch], afternoon [between lunch and supper], or evening [between supper and bedtime]). Glucose patterns during those periods determine whether that component of the insulin regimen needs to be adjusted. The relationships between types of insulin, timing of injection, time period maximally affected, and timing of glucose checks that reflect that period are shown in Table 3.

If a glucose pattern is high (i.e., if the number of values above the preprandial target of 130 mg/dL plus the number of values above the postprandial target of 180 mg/dL minus the number of unexplained preprandial values of <70 mg/dL and the number of unexplained postprandial values <120 mg/dL comes to ≥50% of all of the available values during the time period), increase doses in patients with overweight/obesity by 4 units or 10% of the current dose, whichever is greater, and in lean patients by 2 units or 10% of the current dose, whichever is greater. Overweight/obesity is defined as a BMI ≥27 kg/m² (≥25 kg/m² for Asian patients), and lean patients are defined by a BMI of <27 kg/m² (<25 kg/m² for Asian patients) for the purposes of these dose adjustments.

If a glucose pattern is high, determine whether it is very high by evaluating only the high values. If a combination of preprandial high values >200 mg/dL plus postprandial high values >250 mg/dL is ≥50% of all of the high values, the pattern is very high. In that case, increase doses in patients with overweight/obesity by 8 units or 15% of the current dose, whichever is greater, and in lean patients by 4 units or 15% of the current dose, whichever is greater. This may seem like too large a dose increase to many providers, but in the author’s experience, if more than half of the high values are >70 mg/dL above the target range, patients seldom experience hypoglycemia after a dose increase of this size. The reason for making an increase this large is that, in busy primary care practices, patients are usually seen approximately every 3 months. If lower dose adjustments are made to treat very high glucose patterns, it will take an inordinate amount of time to achieve glycemic control in these patients.

If a glucose pattern is low (i.e., if the number of unexplained preprandial values <70 mg/dL plus the number of unexplained postprandial values <120 mg/dL minus preprandial values >130 mg/dL and postprandial values >180 mg/dL comes to ≥30% of all of the available values during the time period), decrease doses in patients with overweight/obesity by 4 units or 10% of the current dose, whichever is greater, and in lean patients by 2 units or 10% of the current dose, whichever is greater.

Do not change the dose of a component of the insulin regimen if the glucose pattern in the period maximally affected by that component is neither high nor low or if the glucose pattern is too few (i.e., based on too few glucose readings, defined as glucose readings available during the period maximally affected by the component of the insulin regimen on at least one-third of the days being analyzed. The reason to require this proportion of readings for dose adjustment decisions is that the glucose pattern must reflect the patient’s usual lifestyle. A potential problem when there are too few glucose readings is that patients preferentially test when they think the values may be low or high, which would not reflect their usual lifestyle; consequently, wrong decisions could be made. This is why only unexplained hypoglycemic values are used to determine glucose patterns. Explained hypoglycemic values are usually secondary to missed meals or eating either later or less than usual and are the usual reasons for hypoglycemia episodes. These episodes require lifestyle changes rather than insulin dose adjustments.

The stepwise evaluation of glucose patterns in each period is shown in Table 4, and the amounts and conditions under which insulin doses are adjusted are summarized in Table 5.

Because only 70–75% of the insulin in premixed insulin preparations is intermediate-acting and 25–30% is short- or rapid-acting, dose changes are different for premixed insulins and mirror the dose changes of the intermediate-acting insulin component if it had been taken separately (Table 5). (The 50/50 premixed insulin formulation is used so rarely that it will not be addressed here.) If a glucose pattern is high, the dose changes should be 6 and 3 units, or 10% of the current dose, whichever is greater, in patients with overweight/obesity and lean patients, respectively. If a glucose pattern is very high, the dose changes should be 10 and 6 units, or 15% of the current dose, whichever is greater, in patients with overweight/obesity and lean patients, respectively. If a glucose pattern is low, decrease the dose of the premixed insulin that affects that period by 6 units or 10% of the current dose, whichever is greater, in patients with overweight/obesity and by 3 units or 10% of the current dose, whichever is greater, in lean patients. A very important principle in adjusting insulin doses in patients using premixed insulin is that hypoglycemia takes precedence. If the glucose pattern in any period is low, reduce the dose of the premixed insulin that affects that period even if the other period affected is at target, high, or even very high.

Note that changes in the short- or rapid-acting insulin component are much smaller than those in the intermediate-acting component. Because the two components cannot be changed independently of each other, this limits the ability of patients taking premixed insulin preparations to achieve glycemic targets. As premixed insulin doses are titrated upward, the 70–75% intermediate-acting insulin component allows the overnight and afternoon periods to reach target, but the evening and morning periods usually remain high. Further increases of the premixed insulin doses risk hypoglycemia in the overnight and afternoon periods. The ability to change these doses independently of each other in a self-mixed/split insulin regimen (described below) gets around this problem.

Type 2 diabetes is characterized by insulin resistance and diminished insulin secretion. On average, at the time of diagnosis, patients with type 2 diabetes have lost ∼50% of their insulin secretion. Over time, insulin secretion progressively falls, and currently there is no therapy that retards this decrease (17). Initially, glycemia in patients with type 2 diabetes can be easily controlled with one or possibly two noninsulin drugs. As insulin secretion continues to decrease, patients require the addition of more noninsulin therapies—sometimes as many as five different drug classes. Eventually, a significant proportion of patients with type 2 diabetes (currently 25–30%) will require insulin in spite of the combination of a number of noninsulin drugs.

When this point is reached, either bedtime NPH or a basal insulin is started. The starting dose is usually 0.2 units/kg of body weight. This is almost always less than the dose required and follows the principle that, when any insulin preparation is started, it should be at less than the dose that will eventually be required. This strategy avoids hypoglycemia. As previously mentioned, fear of hypoglycemia can lead to patients refusing to increase insulin doses when necessary and sometimes refusing to take insulin altogether. Starting with a lower dose and gradually titrating upward usually avoids hypoglycemic episodes.

Because the most important determinant of postprandial glucose concentrations is the preprandial glucose level, FPG concentrations are very important determinants of glucose levels throughout the day. Thus, one cannot conclude that the addition of bedtime NPH or basal insulin for patients with uncontrolled glycemia while taking a combination of noninsulin drugs has failed until target FPG levels are achieved. When that occurs, the question is whether the noninsulin drugs that the patient has continued to take can control glucose levels throughout the day. However, thiazolidinediones are one class of drugs that is often discontinued when insulin is started. Sodium retention, occasionally leading to heart failure, is a well-recognized adverse effect of the drugs is this class. Initiating insulin therapy also causes sodium retention, and the combination of the two drugs would exacerbate sodium retention and increase the risk of heart failure.

One reason for the underdosing of bedtime NPH or basal insulin alone is the fear of “overbasalization.” Overbasalization does not mean exceeding an arbitrary dose of insulin, e.g., 0.5 units/kg (18). Doses above this amount are just as effective as lower doses (19,20) and do not increase hypoglycemia (20). Rather, clinical overbasalization is the titration of bedtime NPH or basal insulin alone beyond the dose that has achieved FPG targets. This practice occurs when appropriate bedtime NPH or basal insulin doses are increased even further in an attempt to control daytime hyperglycemia, which often leads to hypoglycemia, especially occurring overnight. Moreover, these larger doses of basal insulin are not very effective in controlling postprandial hyperglycemia, which requires acute increases in insulin (either endogenous or exogenous) that bedtime NPH and basal insulin formulations cannot provide. Clinical overbasalization can result in hypoglycemia with persistent postprandial hyperglycemia.

Appropriate bedtime NPH or basal insulin doses are the amounts necessary to achieve FPG targets. When this has occurred, there are two ways to evaluate whether the patient’s continued noninsulin drugs have been able to control daytime hyperglycemia. One is to wait 3 months and measure A1C. If the value is >7.5%, glycemic control is inadequate, and the insulin regimen must be intensified. A value of 7.5% is used instead of 7.0% because the relative risk of the microvascular complications is only mildly increased at this level (13), but the lifestyle disruptions of an intensified insulin regimen (i.e., two or more injections of two different insulin preparations) are considerable and include the need to check blood glucose two to four times daily, less flexibility in meal patterns, and a higher risk of hypoglycemia. For patients with the less stringent target of <8.0%, this value is used to decide whether the insulin regimen should be intensified. A second and faster way to determine whether the insulin regimen needs to be intensified after the FPG target has been reached is to measure blood glucose levels before supper. If they are >180 mg/dL, signifying rising glycemia throughout the day, it is unlikely that daytime glycemia is being controlled well enough for the patient to achieve target A1C levels. In this case, the insulin regimen should be intensified.

There are three possible intensified insulin regimens: basal-bolus, self-mixed split, and premixed insulin. For all three, discontinue the noninsulin drugs because endogenous insulin secretion is so diminished that they are ineffective, and glycemic control must now be achieved with exogenous insulin that covers the three periods that require an increased postprandial insulin effect. There are three exceptions to stopping all of the noninsulin drugs, however. Bringing patients into glycemic control with insulin can lead to a small weight gain during the first 6 months or so of insulin therapy (∼2–4 kg depending on how poorly their glucose control was before insulin was intensified). After the first 6 months, patients do not progressively gain weight secondary to insulin therapy. Metformin mitigates this weight gain and therefore should be continued in patients with overweight/obesity. However, metformin does not contribute much to improving glycemic control, as it has already failed to do so. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 inhibitors significantly reduce cardiovascular disease events (21), and the latter also markedly reduces hospitalizations for heart failure (22). If patients are taking medications from either of these two drug classes for cardiovascular complications, these drugs should be continued when the insulin regimen is intensified.

Because FPG targets have been achieved before insulin needs to be intensified, the bedtime NPH or basal insulin dose should be maintained at the time of intensification. Add short- or rapid-acting insulin before each meal at doses of 4–6 units in patients with overweight/obesity and 2–4 units in lean patients. These doses are almost always less than what is eventually needed, but as with starting bedtime NPH or basal insulin, starting smaller doses with gradual up-titration avoids hypoglycemia.

Because using this intensified insulin regimen increases the number of injections from one to four, recently, a so-called “basal + 1” regimen has been tried in which the short- or rapid-acting insulin is added only before the largest meal of the day. When the glucose pattern in the period after that injection has reached target, the A1C level 3 months later determines whether overall glycemic control has been achieved. If not, preprandial injections are started before the next largest meal of the day. Three months after the glucose pattern in the period after that second-meal injection has reached target, if the A1C level is still not at its target, adding preprandial injections before the third meal of the day will be necessary. Unfortunately, two-thirds of patients require more than a single preprandial injection, which accounts for the much longer time it takes for patients to reach their A1C targets using this stepped approach compared with starting with preprandial injections before all three meals from the outset of insulin intensification (23). Because of this delay in achieving A1C targets, which can be exacerbated in many busy practices because patients are seen only at 3- to 4-month intervals, we routinely start our patients who need insulin intensification on preprandial injections before all three meals and only use the basal +1 approach if they initially refuse the increase from one to four daily injections.

In this regimen, separate NPH and short- or rapid-acting insulin preparations are mixed together in the same syringe and injected before breakfast and before supper. Almost all patients can be taught how to mix insulins if enough time is taken to do so. If used appropriately, the self-mixed split insulin regimen can control glycemia as well as a basal-bolus regimen (24,25). However, patients using this regimen have less flexibility with their eating and exercise, especially with the timing of lunch because the maximal action of the pre-breakfast NPH injection occurs in the afternoon. Therefore, this regimen cannot be used if patients do not eat lunch every day.

To switch from bedtime NPH or basal insulin alone, 80% of the total dose becomes the total daily NPH dose in the new regimen, with two-thirds given before breakfast and one-third given before supper. To avoid hypoglycemia, the maximal initial NPH dose is 40 units before breakfast and 20 units before supper (which corresponds to a bedtime NPH or total basal insulin dose of 75 units). Finally, a short- or rapid-acting insulin should not be added before lunch in response to a high afternoon glucose pattern. Instead, the morning NPH insulin dose should be increased to cover that period rather than having two components of the insulin regimen covering the same period. This avoids the need for a third injection and simplifies the decision for treating a high afternoon glucose pattern.

Because almost all patients require short- or rapid-acting insulin to achieve their A1C target, a small amount of one of these insulin formulations (2–4 units in lean patients and 4–6 units in those with overweight/obesity) is added to each NPH injection. Given that the peak effect of NPH insulin taken before supper occurs 8–12 hours later, as one increases this dose to control the FPG concentration, hypoglycemia may occur overnight before the fasting target is reached. Decreasing the pre-supper NPH insulin dose may well avoid the overnight hypoglycemia but will work against achieving the FPG target. If the patient is already taking a bedtime snack, this option is not available to avoid overnight hypoglycemia. In that event, moving the NPH insulin to bedtime will almost always take care of the problem because the peak effect of the bedtime intermediate-acting insulin moves closer to breakfast, when the patient is about to eat. This step converts the two-injection self-mixed split insulin regimen to a three-injection regimen. However, it is often the only way to both avoid overnight hypoglycemia and reach the FPG target without converting to a basal-bolus regimen with four daily injections.

Patients on basal-bolus and self-mixed split insulin regimens have the opportunity to add small amounts of extra short- or rapid-acting insulin to their usual preprandial doses if they have checked their glucose and found that it is high. A commonly accepted schedule is to add 1 unit for lean patients or 2 units for those with overweight/obesity for each 50 mg/dL their current glucose level is above 150 mg/dL. The largest amount added should be 4 units and 8 units in lean patients and those with overweight/obesity, respectively, for preprandial glucose values >300 mg/dL. For hypoglycemic preprandial glucose values, lean patients would subtract 1 unit and those with overweight/obesity would subtract 2 units from their mealtime dose.

Switching from an NPH or basal insulin only regimen to a premixed insulin regimen is more complicated because converting high doses of bedtime NPH or basal insulin to premixed insulin leads to pre-breakfast doses of short- or rapid-acting component (which makes up 25–30% of the premixed formulation) that may be high enough to risk hypoglycemia. Therefore, the highest dose of premixed insulin to be started should be 50 units before breakfast and 25 units before supper, which caps the short- or rapid-acting insulin component in the pre-breakfast injection at 15 units. To arrive at doses below these, different percentages of total bedtime NPH or basal insulin doses are used to calculate the conversions.

The first step in converting the bedtime NPH or the basal insulin dose to a premixed insulin regimen is to determine the amount of the dose to be used for the conversion. Use 100% if the current NPH or basal insulin dose is <60 units, 80% if it is 60–90 units, and 60% if it is >90 units. The second step is to allocate two-thirds of the resultant dose to the pre-breakfast injection and one-third to the pre-supper injection. Note the admonition mentioned above that it is more challenging to achieve target levels of glycemia because the doses of the intermediate-acting and short- or rapid-acting insulins cannot be adjusted independently of each other. Also, note that one cannot move the pre-supper premixed insulin injection to bedtime to address overnight hypoglycemia because giving short- or rapid-acting insulin at this time will likely exacerbate this problem.

It is not uncommon for patients with type 2 diabetes and obesity with a very high BMI to require hundreds of units of insulin to achieve satisfactory glycemic control. Some people, despite checking their glucose appropriately and increasing doses as recommended, are unable to achieve A1C levels <8.0% because, as described previously, large volumes of injectate impair insulin absorption. Patients receiving >200 total units of insulin per day can be switched to injections of U-500 regular insulin before breakfast and before supper. Also, as described previously, the time and course of action of U-500 regular insulin is similar to that of NPH insulin. Initial doses and dose adjustments are shown in Figure 1.

Glucose testing is only necessary initially before breakfast and before supper, as the regimen consists of just two injections of an intermediate-acting insulin. When FPG values reach target levels, testing before lunch should be introduced to determine whether a separate injection of a short- or rapid-acting insulin before breakfast would be helpful. Similarly, when before-supper glucose values reach target, testing before bedtime (snack) should be introduced to determine whether a separate injection of a short- or rapid-acting insulin before supper would be helpful.

These additional injections convert the U-500 regular insulin regimen from two to three or four injections per day. The injections of short- or rapid-acting insulin could be reserved for patients whose A1C levels remain ≥7.5% after the pre-breakfast or pre-supper glucose values reach target levels. Start with 10 units of a short- or rapid-acting insulin and increase the doses as described above for patients with obesity because, inexplicably, many of these patients respond to much lower doses of these U-100 insulins. With this approach, A1C levels can often be lowered to <8.0% and some to <7.5% after switching to the U-500 regular insulin regimen. As with NPH insulin, for the occasional patient who suffers from overnight hypoglycemia before achieving target FPG levels as the pre-supper U-500 regular insulin dose is increased (and is taking a small bedtime snack), moving the injection to bedtime can be helpful. In this situation, however, the patient must have a bedtime snack because the U-500 regular insulin has a small postprandial effect.

The key principle of this straightforward approach to adjusting insulin doses is that each component of the insulin regimen maximally affects a different time period depending on when it is injected and, thus, the glucose pattern during that period determines whether that component needs to be adjusted. This approach has been shown to be effective when used by a registered nurse in patients visiting a family medicine clinic (26), by a nurse practitioner in patients doing remote glucose monitoring (27), and by a clinical pharmacist in patients using continuous glucose monitoring (28). Nine illustrative cases are available online (2) for those interested in testing their understanding of this straightforward, effective approach for adjusting insulin doses.

No potential conflicts of interest relevant to this article were reported.

M.B.D. is the sole author and guarantor of this work and takes full responsibility for its contents.