Assessment of the Treatment Regimen

Introduction

Certain key clinical and metabolic parameters should be monitored during office visits:

• To assess glycemic control:
  • glycosylated hemoglobin (A1C) level
  • Plasma glucose values
• To assess cardiovascular (CV) risk:
  • Lipoprotein analysis
  • Blood pressure
  • Body weight
• To assess for evidence of diabetic complications
  • Kidney test
  • Dilated eye examination
  • Foot examination.

The metabolic goals for these parameters are shown in Table 21-1.

Glycemic control is assessed during office visits with determinations of plasma glucose levels and assays for glycated hemoglobin. Patients can evaluate the effects of their treatment regimen on a day-to-day basis between office visits by using self-monitoring of blood glucose (SMBG) at home. A combination of physician and patient assessment methods are used to obtain the most accurate information about the degree of metabolic control.

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Measuring Plasma Glucose Concentrations

Day-to-day glycemic control is reflected in measurements of plasma glucose concentrations. However, because this measurement is an isolated finding at a single point in time, it may not represent a patient’s usual metabolic state. Some limitations of plasma glucose measurements include the following:

• It is difficult to know the meaning of a single random or fasting plasma glucose determination.
• Random determinations may reflect peak, trough, or values in between because of the wide daily variations in glucose levels.
• The stress of an office visit may result in higher than usual glucose values.
• Some patients may become atypically adherent to their treatment regimen or use extra insulin before an office visit, resulting in an uncharacteristically low glucose level.
• The presence of an intercurrent illness at the time of an office visit can alter blood glucose levels.

Home glucose monitoring data are appropriate for assessing glycemic control and making changes in the therapeutic regimen of patients being treated with diet, oral agents and insulin therapy. Inaccurate or suspicious results would be revealed by a glycated hemoglobin assay, which reflects the level of glucose control for the preceding 2 to 3 months. Because a single plasma glucose measurement does not provide an adequate assessment of any type of therapy, other corroborating data, such as symptoms of hypoglycemia or uncontrolled diabetes, a glycated hemoglobin value and repeated plasma glucose measurements, are needed.

The timing of plasma glucose measurements has an impact on the significance of the findings:

• A postprandial sample obtained 1 to 2 hours after a patient has eaten is the most sensitive measurement because glucose levels are the highest during this time; total carbohydrate content of the meal will be reflected in this glucose value.
• A preprandial or fasting plasma glucose level reflects how efficiently carbohydrates from a meal have been cleared from the plasma.

Measuring Glycated Hemoglobin

Assays of HbA₁, A1C and glycated hemoglobin are used extensively to provide an accurate time-integrated measure of average glycemic control over the previous 2 to 3 months and to correlate plasma glucose measurements and patients’ SMBG results. Because these assays do not reflect the glucose level at the time a blood sample is tested, measurements of glycated hemoglobin are not useful for making day-to-day adjustments in the treatment regimen.

Glycation refers to a carbohydrate-protein linkage. This irreversible process occurs as glucose in the plasma attaches itself to the hemoglobin component of red blood cells. Because the life span of red blood cells is 120 days, glycated hemoglobin assays reflect average blood glucose concentration over that time.

The amount of circulating glucose concentration to which the red cell is exposed influences the amount of glycated hemoglobin. Therefore, the hyperglycemia of diabetes causes an increase in the percentage of glycated hemoglobin in patients with diabetes; A1C shows the greatest change, whereas the remaining glycated hemoglobins are relatively stable.

Levels of A1C and HbA₁ correlate best with the degree of diabetic control obtained several months earlier. Regardless of which assay is used, however, certain conditions can interfere with obtaining accurate results:

• False low concentrations are likely in the presence of conditions that decrease the life of the red blood cell, such as:
  • Hemolytic anemia
  • Bleeding
  • Sickle cell trait
• False high concentrations are likely in the presence of conditions that increase the life span of the red blood cell, eg, patients without a spleen. Other conditions that produce falsely elevated glycated hemoglobins include:
  • Uremia
  • High concentrations of fetal hemoglobin
  • High aspirin doses (>10 g/day)
  • High concentrations of ethanol.

Regular monitoring of glycated hemoglobin (e.g., every 3 to 6 months) is essential for all patients with diabetes, regardless of their type of therapy. On a daily basis, patients typically measure capillary blood glucose levels before meals, postprandially and at bedtime, particularly with intensive insulin regimens in which near-normal glycemia is being actively pursued. Even when preprandial levels seem satisfactory, patients’ glycated hemoglobin results often are higher than expected. This finding would not have been evident through glucose measurements alone, and the need for further efforts to control blood glucose would not have been apparent without obtaining a glycated hemoglobin measurement. Home A1C testing is now available (Becton-Dickinson). The patient applies a drop of blood to a reagent card, which is mailed to a central laboratory. The results are then mailed back to the patient. A disposable test kit for glycosylated A1C is now available for home testing by patients with diabetes.

Measuring Other Glycated Proteins

Enhanced glycation of other proteins occurs in diabetes and has been proposed as another method of assessing average glucose control. Because of the shorter half-life of serum proteins (17 to 20 days) compared with hemoglobin (56 days), measurement of serum fructosamine reflects a shorter period of average glucose control (2 to 3 weeks) (Figure 21-1). Traditionally, fructosamine measurements are particularly useful for following patients with gestational diabetes mellitus (GDM).

New devices that are available or soon to be released will have the capabilities of measuring serum ketones, lipoproteins, microalbumin and other important clinical measurements that traditionally could only be obtained by venipuncture or urine collection and measured in a laboratory.

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Self-Monitoring of Blood Glucose

This method of self-evaluation using capillary blood samples has become one of the more important tools for monitoring and improving glycemic control and making adjustments in the diabetes therapeutic regimen. SMBG is a relatively painless procedure that involves pricking the fingertip with a lancet to obtain a drop of blood that is placed on a test strip. Reagents on the test strip contain an enzyme that causes glucose to react with a dye to produce a color change. The color intensity is proportional to the amount of glucose present.

The test strip is placed in a small, hand-held meter that quantifies the glucose concentration using reflectance spectrometry. Some test strips can be read visually; other systems measure the electrical current produced by the glucose oxidation reaction to quantify the glucose concentration. Results obtained by SMBG tend to have good agreement with plasma glucose concentrations obtained by clinical laboratory procedures if done properly. Patient technique tends to be the source of most dis­crepancies. Typically, plasma venous glucose measure­ments are within 15% of the results of whole blood capillary glucose determinations.

SMBG is not a goal in itself but rather a means of achieving the goal of normal or near-normal glycemic control. It should be considered an important part of a comprehensive treatment regimen that includes:

• Diabetes education
• Counseling
• Management by a multidisciplinary team of health care providers.

Goals of treatment and thus the reason for performing SMBG must be clearly defined for the patient. Patients must be motivated and capable of learning the proper technique of SMBG and committed to applying the results to modify their treatment. Health care providers must be able to discuss SMBG results in a non­derogatory, helpful way that provides encouragement through open, honest communication and an atmosphere of support.

Reasons for Performing SMBG

The following reasons for performing SMBG have been outlined in a consensus statement by the American Diabetes Association (ADA):

To achieve or maintain a specific level of glycemic control—As evidenced by results of the DCCT and UKPDS, intensive therapy that is closely monitored using SMBG can help patients achieve near-normo­glycemia and delay the onset and slow the progression of diabetic complications in T1D and T2D. Therefore, SMBG at least four times daily is essential for evaluating and adjusting insulin doses in patients on intensive insulin regimens and, with lesser frequency, for patients on less-complex insulin or combination regimens or those using oral agents and diet, directed toward achieving near-normo­glycemia.

To prevent and detect hypoglycemia—Hypogly­cemia is a major complication of treatment regimens, particularly those involving intensive application of pharmacologic therapy to achieve near-normoglycemia. The elderly are particularly susceptible to hypoglycemia, and certain oral antidiabetic agents, such as the SFUs, can produce hypoglycemia. Therefore, appropriately timed SMBG is the only way to detect asympto­matic hypoglycemia so that appropriate action (adjusting insulin/oral agents, modifying diet/exercise) can be taken to prevent it from becoming severe.

To avoid severe hyperglycemia—Illness and certain drugs that alter insulin secretion (eg, phenytoin, thiazide diuretics) or insulin action (eg, prednisone) can increase the risk of severe hyperglycemia and/or ketoacidosis. SMBG should be initiated or used more frequently in all of these situations to detect hyperglycemia before it becomes severe. In addition, patients on insulin therapy can use SMBG data to adjust their insulin doses to avoid severe hyperglycemia.

To adjust care in response to lifestyle changes in patients on pharmacologic therapy—Glucose levels change in response to variations in diet, exercise, and stressful situations. SMBG can help identify patterns of response to planned exercise and daily activity and help modify pharmacologic therapy during times of increased or decreased caloric consumption.

Advantages and Disadvantages of SMBG

SMBG enables the patient to be involved in self-management and provides immediate feedback regarding the impact of diet, exercise and pharmacologic therapy on blood glucose levels. Patients who are educated about SMBG, how to use the results and how to make self-adjustments of insulin doses using algorithms (for insulin-requiring type 2 patients and type 1 patients) can achieve better daily glycemic control and have a better sense of self-control and participation in their own care. SMBG also provides worthwhile feedback that the physician and other members of the diabetes health care team can incorporate into ongoing evaluation of the treatment regimen. However, health care professionals need to make a point of requesting and reviewing a patient’s SMBG data to provide helpful guidance and encouragement.

Advantages of SMBG include:

• Accurate, immediate results for detecting hypoglycemia and hyperglycemia
• Day-to-day assessment of glycemic control
• Follow-up information after changes in treatment to enhance accurate adjustments in pharmacologic therapy
• Enhanced patient independence, self-confidence and participation in their treatment
• Storage of test results.

Disadvantages of SMBG include:

• Discomfort of lancing the finger to obtain blood (many meters today allow alternate-site testing)
• Complexity of some testing procedures, requiring mental acuity and dexterity
• Potential malfunction of equipment that could lead to inaccurate results that may affect treatment decisions
• False results because of inaccurate technique that may affect treatment decisions.

SMBG Systems

A combination of factors affect the overall performance of SMBG systems:

• The analytic performance of the meter
• The ability of the user
• The quality of the test strips
• The downloading capacity of home and office computers.

Analytic error can range from 4% to 33%; a goal of future SMBG systems is an analytic error of ± 5%. User performance is most affected by the quality and extent of training, which currently is hindered by reimbursement policies for diabetes education. Initial and regular assessments of a patient’s SMBG technique are necessary to assure accurate results. Patients need to be advised that test strips can be adversely affected by environmental factors. In addition, cautious use of generic test strips is warranted because of the complex process of calibrating test strips to specific meters.

A listing of available blood glucose meters, along with their features and capabilities, are compared in the annual Diabetes Forecast Consumer Guide and can be found at www.forecast.diabetes.org/consumerguide. The ADA Consensus Panel advises periodic comparisons between a patient’s SMBG system and a sample obtained simultaneously and measured by a referenced laboratory. Remember that whole blood glucose values are generally 15% lower than plasma values.

Who Should Perform SMBG?

Virtually all patients with diabetes should perform SMBG because of the value of this evaluation tool in promoting improved glycemic control and reinforcing adherence to therapy. The frequency of SMBG is dictated by the complexity of the therapeutic regimen. For example, insulin-using type 2 diabetics (particularly those on an intensive regimen) would need to perform more daily SMBG evaluations than patients who are achieving acceptable glycemic control with diet, exercise and oral agents.

Recommended Frequency of SMBG

The frequency of SMBG varies considerably based on the complexity of the therapeutic regimen and the clinical situation of the individual. In addition to guiding therapy, SMBG also has educational and motivational advantages. For example, intermittent measurements 1 to 2 hours after meals can provide an assessment of glycemic response to various types of foods, thus helping patients learn which foods have the greatest and least impact on blood glucose, as well as how the size of a meal affects glucose levels. SMBG also can help motivate patients (especially obese patients trying to lose weight), because they can observe immediate decreases in their blood glucose levels in response to dietary modifications, exercise and oral therapy.

Patients who demonstrate consistent, acceptable glucose results may require fewer tests (ie, one to three tests per week). However, testing requirements may increase when metabolic control worsens.

SMBG for Patients Who Do Not Take Insulin

Traditionally, SMBG was viewed as not necessary for type 2 patients on diet therapy or oral agents because glucose levels remained relatively stable on these treatment regimens. For these patients, SMBG was recommended only for monitoring short-term adjustments in therapy or for patients at risk for hypoglycemia. Because better glycemic control has been shown to be associated with a greater frequency of SMBG, this evaluation measure now is recommended for all patients, including those not taking insulin. The frequency of testing depends on how stable the patient is. Patients with less than optimal control should monitor their levels more frequently.

SMBG recommendations for patients on diet therapy:

• Prebreakfast—two to three tests per week
• 1 to 2 hours postdinner—two to three tests per week.

Monitoring glucose values from these two important time points, in addition to an A1C or fructosamine value every 3 to 6 months, is an efficient way to follow patients on diet and oral agents.

SMBG recommendations for patients using oral agents alone or combination therapy (daytime oral agents, evening insulin):

• Prebreakfast—four to seven tests per week
• Prelunch—two to three tests per week
• 2 hours postdinner—two to three tests per week.

Patients in this category generally require one to three tests per day when SMBG values are consistent. Patients can make nonpharmacologic changes in their diabetic regimen depending on the results (Table 21-2).

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SMBG for Patients Who Take Insulin

SMBG is critical for all patients who take exogenous insulin, particularly those on intensive insulin regimens or on combination therapy. The type of insulin regimen used should dictate the frequency of SMBG, with attention to insulin pharmacokinetics and the timing of insulin injections. The best time to evaluate the effectiveness of a dose is at the peak time of action of a particular type of insulin (Table 18-1).

Frequent SMBG is necessary to fine-tune an insulin regimen to the needs and responses of a given patient. Ideally, SMBG should be performed four to six times per day (before each meal, at bedtime and occasionally after meals and at 3 am, which is the approximate time of early morning glucose nadir). A more intensive SMBG schedule would be a preprandial and 2-hour postprandial measurement and at bedtime, depending on the frequency of insulin doses.

SMBG recommendations for patients on insulin therapy include:

• One injection per day—two tests per day; no less than one to three depending on metabolic control.
• Two injections per day—four tests per day (before each meal and at bedtime)
• Intensive regimen (multiple injections, external pump)—four to seven tests per day.

Results should be recorded in a logbook that is brought to each office visit so the physician can evaluate the effectiveness of the insulin regimen and determine the most appropriate insulin dosage adjustments (Figure 21-2). Selected patients should be instructed to apply their SMBG results as the data become available. Making immediate dosage adjustments based on SMBG feedback is evidence of the true benefit of this self-assessment tool. Additionally, most meter logs can be downloaded directly to a personal computer.

When SMBG reveals premeal hyperglycemia, a number of different methods can be used in addition to adjusting the dose of insulin to reduce daily glycemic excursions (Table 21-2).

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Applying SMBG Results to Adjust Insulin Doses

Patients can be taught how to analyze and use SMBG data to effectively make adjustments in their insulin doses so that they can maintain and improve glycemic control. Insulin algorithms can be used with SMBG to make appropriate day-to-day changes in insulin dosing and to guide long-term treatment.

The insulin algorithm shown in Figure 21-3 is used for patients receiving intensive insulin therapy. Self-adjustment guidelines for patients on a split-mixed regimen are shown in Table 21-3; insulin unit changes are provided by the physician on an individualized basis.

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Advances in Glucose Monitoring

Over the past several years, home glucose monitoring devices have become smaller, faster and easier to operate with data analysis capabilities. Computer-generated data analysis can assist the care­giver and the patient in many different areas, including data collection from blood glucose meters, certain insulin pumps and other new devices. Computer software programs can also create charts and graphs that reveal trends and patterns in blood glucose values for easier evaluation by the patient and the caregiver. There are many software programs that are not only user-friendly for the patient, but are easy to read and analyze by the caregiver. Several programs can generate one-page summaries of a person’s diabetes monitoring data intended for optimal presentation of information. Information typically provided includes the standard day plot, before and after meals, pie graphs, the preceding 14 days in a combination graph format (where diet, exercise and medication are shown with blood glucose levels) and a glucose line plot. The goal ranges and usual insulin doses are usually printed on the bottom of the page if applicable for that patient.

Advances in Devices for Bloodletting

The fingerstick devices used to get a drop of blood for testing from the patient have improved with depth-adjustable and sharp, thin lancets. There is a meter that has the capability of getting blood from areas other than the fingertips, such as the forearm, for patient comfort and convenience. Other companies have developed bloodletting devices that can be used on the fingertips and other areas with special attachments to the “finger sticker.” An all-in-one device manufactured by Intuity Medical has the lancet and glucose strip in a cartridge, making it easy for the user to avoid having to carry a finger sticker device and a can of glucose strips around in addition to the meter itself. Making life simper and easier is the key in T2D. In addition, laser technology has also been designed to facilitate the bloodletting for these home devices.

Advances in Continuous Glucose Monitoring

SMBG is a fundamental part of diabetes management. It is mandatory for acceptable glucose control. Intermittent measurement of capillary blood glucose via fingersticks has long been the only method other than urine testing for self-monitoring. However, such measurements provide isolated glucose values at one point in time, which do not reflect variations occurring throughout the day and night. In addition, this approach is dependent on patient education, diligence and consistency - not to mention pricking their own fingertips! Hence systems monitoring blood glucose concentrations on a continuous basis have been developed. These devices allow for frequent and automatic glucose measurements, and thus can detect and track changes in glucose levels over time. This has tremendous implications for achieving near normalization of glucose control while avoiding the most serious complication of intensive glucose management, hypoglycemia. Several such devices are currently available. The benefits are primarily for the person living with T2D and secondarily for the HCP who can look at a CGM download and make clinical therapeutic decisions fairly quickly.

Devices for CGM can be categorized into three types: real-time CGM (rtCGM) systems, which continuously measure and display glucose levels; intermittently scanned CGM (isCGM) systems, which measure glucose continuously but require scanning to visualize and store the data; and professional CGM systems, which are put in place by a healthcare professional and worn for a prespecified period. The first two types are personal devices (ie, owned by the user) and are intended to be used indefinitely, while professional CGM devices are clinic-based and are intended to provide blinded or unblinded data for a discrete period (typically 1-2 weeks). Devices for CGM are composed of three basic parts: a sensor, a transmitter, and a receiver or monitor. The sensor may be disposable (usually worn for 7-15 days, depending on the device, and then replaced) or implanted. A disposable sensor is placed just under the skin and is attached to a plastic sensor mount with adhesive to adhere to the skin. The small transmitter snaps into the sensor mount (or may be integrated into the sensor) and sends glucose information wirelessly to the pager-sized receiver, which can be worn on the belt or carried in a handbag. The data can also be sent to a smart phone, smart watch, or smart pen. The sensor measures glucose every 1 to 5 minutes (frequency varies according to the device). The readings are displayed over time. High and low glucose level alerts and alarms warn the user in advance of trending values toward hypoglycemic or hyperglycemic levels as determined by both the patient and the physician. These systems also store up to 90 days of data locally, which can be analyzed by the patient or physician. Engaging patients who acquire a CGM to look at their numbers and trends in response to their lifestyle habits as well as medication/insulin dose and injection time and adherence is crucial for success. Teaching patients how to respond to their alerts and trend arrows is also of tremendous importance.

Several personal CGM devices based on electrochemical glucose detection methods have received FDA approval and are currently (as of May 2024) available on the market. These include Abbott FreeStyle Libre 2 (and FreeStyle Libre 2 Plus), FreeStyle Libre 3 (and FreeStyle Libre 3 Plus), Dexcom G6, Dexcom G7, and Medtronic Guardian 3 and Guardian 4. Of these CGM systems, FreeStyle Libre 2, FreeStyle Libre 3, Dexcom G6, and Dexcom G7 have been classified as integrated CGM (iCGM) devices by the FDA, allowing them to be linked to other digitally connected devices. Until 2024, all CGM systems required a prescription; however, in March 2024, the FDA approved Dexcom Stelo, an iCGM device that is the first CGM system to be available over the counter. Another device, the Senseonics/Ascensia Eversense E3 CGM system, relies on fluorescence-based glucose detection instead of electrochemical methods (a fluorophore-linked divalent boronic acid interacts with glucose). It is the only under the skin-implantable biosensor on the market, receiving FDA approval in February 2022 for the use of up to 180 days. In April 2024, the FDA granted the iCGM designation to Eversense E3. Insertion is an office-based 15-minute procedure. The continuous glucose data goes to a smart phone or watch, can be shared with caregivers and HCPs, and has software for data analysis in a similar fashion to the other transcutaneous CGM devices.

It is important to note that these systems measure interstitial glucose, a distinct physiologic space when compared with blood glucose. However, clinical trials with various devices have shown there is an adequate correlation between interstitial and capillary blood glucose measurements. Nevertheless, the use of such systems adds information on PPG excursions, nocturnal hypoglycemia or hyperglycemia not previously detected by fingerstick monitoring, thereby facilitating the tailoring of treatment regimens for the individual patient.

The 2024 ADA Standards of Care recommend an rtCGM or an isCGM device be offered for diabetes management to adult patients and youths on multiple daily injections (MDI), continuous subcutaneous insulin infusion (CSII), or basal insulin, if the patient is able to safely use the device (with or without the aid of a caregiver). The individual patient’s preferences and needs should inform the choice of CGM system. The Standards of Care also recommend that rtCGM devices be used daily, and that isCGM devices should be scanned every 8 hours, if possible.

A large body of evidence, including multiple randomized clinical trials (RCT), supports the efficacy of CGM devices in reducing A1C levels and hypoglycemic episodes. A 2024 systematic review and meta-analysis of 12 RCTs (8 on rtCGM and 4 on is CGM systems) involving a total of 1248 participants with T2D, found that, compared to SMBG, CGM device use resulted in significantly lower A1C levels (P <0.00001). However, this meta-analysis included only open-label studies.

In addition to the devices developed for measuring interstitial glucose, devices that use sweat, saliva, or tears for monitoring glucose levels throughout the day are being developed. Several studies have found a significant correlation between glucose levels in the blood and in other body fluids, similar to the correlation observed for interstitial and blood glucose. The goal is to develop sensors for integration into wearables, including clothing, bracelets, patches, and tattoos; however, the challenges of providing real-time signal correction, long-term stability for continuous monitoring, and reproducibility between sensors and patients, are still just being met.