Middle East Journal of Family Medicine

Ali A. Rizvi, MD, FACP
Diabetes Unit Division of Endocrinology, Diabetes, and Metabolism
University of South Carolina School of Medicine
Two Medical Park, Suite 502 Columbia, South Carolina 29203, USA
Ph: 803-540-1071 Fax: 803-540-1050 email: arizvi@gw.mp.sc.edu
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ABSTRACT

Diabetes mellitus is a chronic, costly, and increasingly prevalent disorder that carries a huge burden of complications. Blood glucose monitoring is critical to achieving glycemic goals and standards of care. An integral part is self-monitoring with glucose meters that are user-friendly and accurate while minimizing patient discomfort. Minimally invasive continuous monitoring is available for physician-directed retrospective review of 3 days of data, while a subcutaneous sensor that transmits frequent readings to be viewed on the screen of an insulin pump in real time has recently been launched. Graphs and trends of blood glucose with the help of software that analyzes and reports them through meter downloads and sophisticated data management features provide valuable feedback regarding the state of glycemia. The development of completely noninvasive blood glucose monitoring promises to aid in configuring a 'closed-loop' system that delivers insulin in a semi-automated fashion. Ongoing research and its translation to the bedside through the proper education and training of both clinicians and patients will be the key to successfully harnessing these exciting technological advances for optimizing diabetes care in the future.

Key words: diabetes, glucose monitoring, glucose meters, continuous monitoring
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INTRODUCTION

The prevalence of diabetes has witnessed a relentless increase in modern times, accompanied by its enormous toll in complications and cost [1]. Attainment of optimal glucose targets by monitoring of daily, monthly, and long-term glycemic control is an integral part of an effective strategy to improve diabetes management. The field has witnessed remarkable advances in the ease and accuracy of glucose monitoring techniques recently in order to assist in improving diabetes management. The American Diabetes Association (ADA) standards of care [2] include parameters pertaining to both self-monitored blood glucose and glycosylated hemoglobin (HbA1c) (Table 1). This provides valuable feedback on the effectiveness of treatment and guides the clinician and patient in making appropriate daily and long-term adjustments with the ultimate aim of sustaining optimal glycemic control.

Recent research that points to glycemic variability as a risk factor for endothelial dysfunction, oxidative stress, and vascular complications independent of the HbA1c level [3]. The new paradigm is to aim for blood glucose concentrations in persons with diabetes as close to those found in non-diabetic individuals as is safely possible. The frequency and timing of SMBG should be dictated by the particular circumstances, needs and goals of the patient. The ADA's Consensus Statement [4] list the following indications for SMBG: (a) achieving and maintaining glycemic control (b) preventing and detecting severe hypoglycemia (c) avoiding and treating episodes of significant hyperglycemia (d) adjusting to changes in lifestyle, and (e) determining the need for initiating insulin therapy in gestational diabetes mellitus. SMBG allows patients to evaluate their individual response to therapy, assess whether glycemic targets are being achieved, and can be useful in preventing hypoglycemia and adjusting medication doses. This becomes crucial when intensive insulin regimens with multiple-dose injections or pump therapy are employed.

Clinical studies reveal that SMBG is performed by patients much less frequently than recommended [5]. For type 1 patients, SMBG is recommended three or more times a day, especially when tight control is the aim [4]. The optimal frequency of SMBG for patients with type 2 diabetes on oral agents should be sufficient to facilitate reaching glucose goals; twice daily or more frequent monitoring may be desirable in patients treated with sulfonylureas, other secretagogues, or insulin, particularly when therapy is initiated or changed [4]. To achieve postprandial glucose targets, SMBG 2 hours after meals (one hour post-meal in gestational diabetes) is appropriate [6]. Routine evaluation of the patient's technique and ability to use data to adjust therapy is recommended.

Accurate and user-friendly meters for home use provide the autonomy and flexibility of checking glucose levels with minimum hassle and discomfort. The worldwide market for glucose monitors is $2.7 billion per year, with annual growth estimated at 10-12% [7]. At least 25 different meters are commercially available [8]; however, a large variability in their performance exists because many factors can interfere with glucose analysis. Only half of all analyses meet the ADA criterion of <5% deviation from reference values [9].

The accuracy of SMBG is both instrument- and user-dependent. Several technologic advances that decrease operator error in the last few years include "no touch" technique, "no wipe" strips, timing when both the sample and the strip are in the meter, smaller sample volume requirements, an error signal if sample volume is inadequate, barcode readers, and the ability to store up to several hundred results in memory. Together these improvements have led to superior performance by new meters. Patients should be instructed in the correct use of glucose meters and their monitoring technique evaluated at regular intervals [10]. Optimal use of SMBG also requires proper interpretation of the data. Patients should be taught how to use the information to adjust food intake, exercise, or pharmacological therapy to achieve specific glycemic goals. Ongoing education at clinic visits, comparison of SMBG with concurrent laboratory glucose analysis, and home practice with meters improves the accuracy of patients' blood glucose results [11].

Alternate site testing (AST) may be useful in reducing the number of fingertip tests, reduce discomfort, and enhance the acceptability of self-monitoring in patients who check several times a day [12]. Not all glucose meters are approved for AST, although this feature is rapidly becoming a standard feature in most meters. The forearm is the usual site for AST and has been studied the most. The Advance Micro-draw System (Hypoguard USA, Inc.) received clearance from the Food and Drug Administration (FDA) for drawing a blood sample from the palm for measuring blood glucose, which may be a less painful site for testing than, but correlates well with, the fingertips. Studies show good correlation of forearm readings with results from fingertip checks in the fasting state. After meals, however, the fingertip readings tend to be higher than the forearm, where blood flow is slower. The fingertip is the recommended place for testing when accuracy is important, as in suspected hypo- or hyperglycemic situations. AST in the hypoglycemic range may potentially give misleading results.

Monitoring times merit comment (Table 2). Pre-meal measurements are needed to adjust the basal insulin dose and in determining the dose of short-acting insulin prior to meals in patients who use multiple-dose, flexible insulin regimens. Two-hour post-prandial readings are important to assess the level of post-meal hyperglycemia, and serve as a verification of meal coverage when a short-acting oral secretagogue or rapid-acting insulin is used. After fine-tuning of the insulin dose at mealtimes has been achieved, post-prandial monitoring should continue to be performed periodically but less frequently. The bedtime check is helpful in determining the efficacy of the dinnertime dose of insulin, and as a key safety component in preventing nocturnal hypoglycemia. A blood glucose test between 2 to 4 am once or twice a week can identify episodes of unrecognized nocturnal or overnight hyper- or hypoglycemia and is an important part of adjusting long-acting insulin dosage or the basal insulin rate during pump therapy. Importantly, blood glucose should be checked if symptoms of hypoglycemia are present, illnesses that can affect glucose control are present, and prior to driving and physical activity.

In spite of the availability of meter memory and download capabilities, maintaining a written log of blood glucose readings is very important. This enables the patient and the provider to look at various relevant parameters (like notes on food intake and timing, activity, stress, etc.), as well as trends of the readings over many days, weeks, or months, in order to facilitate necessary therapeutic adjustments (Figure 1).

The choice of a meter is influenced by patient preference, cost, insurance coverage, and physician recommendations. Certain unique meter characteristics may lend themselves to preferred usage by a particular patient. For example, meters may have a user-friendly design, single-strip system with no coding or calibration requirements, require a small blood sample size, have a quick 5-second result time, provide the option of alternate-site (forearm) testing, have electronic logbook or data download capabilities, show trend graphs on the screen, send glucose readings automatically to an insulin pump, or be able to organize readings into before-meal and after meal times for showing relationship of glucose to food intake. Certain 'talking" meters providing audible glucose reports, while voice-prompts can guide the visually-impaired step-by-step through the testing sequence.

The capability of storing blood glucose values that can be accessed by scrolling back is a convenient feature of many glucose meters. However, even though the readings give dates and times, it is difficult to assess a pattern and make appropriate treatment changes based on the scroll-back memory feature alone. Downloading data into a computerized database far pattern analysis and long-term storage is intended to circumvent this hurdle. These data management systems can store hundreds of test results and information such as time, date, insulin or medication types and doses, meals, and exercise times. Different time-segments can be designated as 'fasting', 'pre-meal', or 'postprandial' and the computer will group the readings into these categories for ease of analysis. It may be helpful to display or observe the SMBG results in one of the various graph or text formats or as a14-day summary provided by these computer software systems (Figure 2). Some blood glucose meters also have the capability of built-in data analysis and can display glucose averages, day graphs, and other helpful patterns; patients can detect trends in glycemic values and thus participate more actively in their own care. The MiniMed Solutions Software (Medtronic MiniMed, Northridge, California, USA) can integrate blood glucose values from the Paradigm Link meter with various parameters of insulin pump therapy - like amount of carbohydrates consumed and boluses of insulin given by the patient - thus assisting in fine-tuning of pump settings.

Despite the phenomenal advances in blood glucose meter technology, self-monitoring as it currently exists has real and inherent limitations. Fingerstick testing shows a snapshot of the glucose level at a single point in time, representing the sporadic measurement of a continuous and changing variable. It does not give an idea of the degree and direction of change in glucose. With more frequent or continuous monitoring, information can be used to adjust treatments in a more measured, anticipatory, and meaningful manner, thus safely intensifying control [13]. The downsides include having to learn, navigate, and troubleshoot the new devices, the need for educating providers and patients, increased cost, "information overload", and the imperfections of the nascent technology itself.

The Continuous Glucose Monitoring System Gold (Medtronic MiniMed, Northridge, CA) has the advantage of providing very frequent glucose readings - up to one every 5 minutes or 288 readings a day for 3 days at a time. A tiny sensor is inserted just beneath the skin of the abdomen for 'continuous' recordings that can be downloaded and retrospectively analyzed. Patients can note events like insulin administration, meals, and exercise times. It can be helpful in giving the clinician a more 'complete' picture and pick up unsuspected periods of glucose peaks and lows, uncover nocturnal hypoglycemia, detect hypoglycemia unawareness, and show glycemic elevations as in the post-prandial state or the dawn phenomenon [14] (figure 3). The Guardian RT can sound an auditory or vibratory alarm for both hypo- and hyperglycemia in real-time according to a preset glucose range [15]. The increased realization and emphasis on the benefits of tight glycemic control in hospital patients, especially in critical care, the peri-operative period, and cardiac bypass surgery, has spurred the development of continuous blood glucose recording in the inpatient setting [16] although none are approved or available for clinical use yet.

The MiniMed Paradigm REAL-Time System (Medtronic Minimed, Northridge, California, USA), which consists of two components: a continuous glucose monitoring system and an insulin pump (figure 4). A sensor, inserted under the skin by the patient and replaced every three days, measures interstitial fluid glucose. A recent advancement is the MiniLink sensor that is smaller and runs on rechargeable batteries. A transmitter then sends this information to an insulin pump (the Paradigm 522 or 722 brands) where it is displayed on the screen as a real-time glucose value as well as 3-hour and 24-hour trend graphs. The device can be programmed to trigger an alarm for readings outside the desirable range - both hyper- and hypoglycemia - that can be confirmed by a fingerstick test. Glucose trends can be spotted and anticipatory steps taken in order to prevent glycemic excursions. It is hoped that this 'sensor-augmented' insulin pump may prove to be a prelude to completely noninvasive glucose sensing coupled with automatic insulin delivery - a closed-loop system that may function as a true 'artificial pancreas'.

The DexCom STS (DexCom Inc, San Diego, California, USA) is a patient-insertable sensor that transmits blood glucose readings wirelessly to a hand-held receiver. A long-term sensor (LTS) is available for subcutaneous implantation as an outpatient procedure under local anesthesia.

The hemoglobin A1c (HbA1c) test enables health providers to ascertain a patient's average glycemia over the preceding 2-3 months and thus assess treatment efficacy. It should be performed routinely in all patients with diabetes in order to document the degree of glycemic control at initial assessment and subsequently as part of continuing care. It is recommended that the HbA1c test be done at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients whose therapy has changed or who are not meeting glycemic goals [2]. Note that glycemic control is best judged by the combination of the results of the patient's SMBG testing and the HbA1c; the two complement each other. Point-of-care HbA1c testing with rapid turn-around in the office has been shown to be effective in making interventions, changing therapies, and improving general management strategy immediately in the ambulatory setting [17]. Physician-patient discussions regarding treatment changes can be done face-to-face and more efficiently without an unnecessary delay in instituting adjustments (figure 5). Several home HbA1c test kits, most requiring mail-in for results, are also available.

Due to its shorter half-life, glycated serum fructosamine provides an index of glycemic control over the preceding 10-14 days. This test gives two-week averages of blood glucose by measuring the glycosylation of the blood proteins albumin and globulin, and thus provides a clue to recent, short-term glycemic control [18]. This test may be useful during pregnancies, in the presence of hemoglobinopathies and hemolytic anemias, and for the short-term evaluation of therapeutic interventions.

GlycoMark is an FDA-approved blood glucose testing system that is purported to bridge the gap between fingerstick monitoring and HbA1c by measuring levels of the compound 1,5-anhydroglucitol. It is marketed as a test of short-term to intermediate glycemic control, reflecting predominantly post-meal glucose excursions [19]. As an index of postprandial hyperglycemia, GlycoMark should prove useful as treatment targets are lowered and management of post-meal glucose spikes becomes increasingly important.

The science of glucose monitoring has seen vast improvement s in the past decade, helping patients and providers to implement intensive control with the promise of reducing the burden of diabetes-related morbidity and mortality. It is hoped that the next breakthrough in this area will be the advent of completely noninvasive testing that is risk-free, accurate, convenient, and affordable. In addition, for insulin-treated patients, a feedback system based on the latest monitoring technology to calculate and automatically deliver the appropriate amounts of insulin will be a major and exciting therapeutic advancement. Maintaining excellent glycemic control through minimizing day-to-day glucose variations seems to be the standard of care for diabetes management for the future. With the current state and pace of technological progress, this goal appears more achievable than ever before.