AMBULATORY BLOOD GLUCOSE MONITORING

DRA. MARIELBA AGOSTO MUJICA, M.D.

History!
Crude self-blood glucose monitoring was initially developed in 1965. The first commercially available home blood glucose monitoring devices were sold in 1970, weighed over 3 lbs and cost over $350 per month to operate. In the US there are about 30 self-blood glucose meter manufacturers selling $2 billion worth of strips and meters annually.

However, these devices provide only a static reading of ones blood glucose levels rather than an indication of real time continuous trending.

Indications
SMBG in patients who take medications that can cause hypoglycemia and that need to be adjusted based on ambient glucose levels.
In order to avoid hypoglycemia achieve target glucose levels patients with type 1 diabetes who take pre-prandial rapidacting or very rapid-acting insulins should usually test

before meals to adjust doses, based on meal size and content, anticipated activity levels, and glucose levels.
Similar guidelines apply to insulin-treated type 2 diabetes, although their glucose levels are characteristically more stable and they may require less frequent monitoring.

Indications
Patients treated with sulfonylureas or meglitinides, which can also cause hypoglycemia, should be tested once to twice per day during titration of their doses, but after a stable dose and target glycemic targets are achieved, may only need to test several times per week, usually in the morning or before dinner. All insulin and sulfonylurea patients need to test more frequently before and during long car rides, during sick days, and when there are changes in diet and exercise patterns.

Indications
Self-monitoring of glucose may not be necessary at all, or only in unusual circumstances, for patients with type 2 diabetes who are diet-treated or who are treated with oral agents not associated with hypoglycemia.

Type 1
SMBG is an integral part of intensive therapy in type 1 diabetes, which is widely accepted as recommended therapy owing to its benefits.

Self-monitoring allows adjustments of doses and timing of insulin and of timing and content of meals and snacks based on immediate feedback of glucose results and allows timely intervention for low or decreasing glucose levels to avert serious hypoglycemic events.
Self-monitoring of blood glucose is also important for patients with type 1 diabetes who are not managed with intensive insulin, although they may require somewhat less frequent testing

Type 1
The American Diabetes Association (ADA) recommends that patients with type 1 diabetes monitor blood glucose at least three times daily For most patients with type 1 diabetes, testing blood glucose levels more frequently is necessary to safely achieve A1C targets without hypoglycemia. Testing blood glucose levels before and at intervals after meals; before, during, and after exercise; and occasionally during the night will provide useful information for adjusting insulin and carbohydrate intake

Patients with hypoglycemia unawareness may need to test more frequently, particularly prior to driving or operating any machinery, watching small children, and other activities where compromise of cognitive function may be dangerous.

Type 2
The effectiveness of SMBG in terms of improving glycemic control in patients with type 2 diabetes is less clear than for type 1 diabetes.
Multiple observational studies have evaluated SMBG in type 2 diabetes, with some showing benefits and others not There is no evidence that SMBG affects quality of life or long-term clinically important outcomes (eg, diabetes complications).

Type 2
Monitoring blood glucose is a tool, not a therapeutic intervention.
It provides important information with which motivated insulin-treated patients can modify their behavior and improve their A1C values safely. SMBG may also be useful for some type 2 diabetic patients who would take action to modify eating patterns or exercise, as well as be willing to intensify pharmacotherapy, based on SMBG results SMBG is expensive. -unlikely to be costeffective

Type 2
Self-monitoring of glucose may not be necessary at all, or only in unusual circumstances, for patients with type 2 diabetes who are diet-treated or who are treated with oral agents not associated with hypoglycemia.
It may be unnecessarily burdensome in frail elderly individuals with cognitive impairment or difficulty with fine motor skills from neurological or musculoskeletal conditions. In such patients, the target for glycated hemoglobin (A1C) should be somewhat higher (8 percent) than for younger and more fit elderly patients, and therefore, there is little role for regular self-monitoring of blood glucose, unless the patient is taking insulin.

Operator

Glucose strips

Other sugars

Site of testing

Sources of error

Blood Glucose Meter

Operator
Errors in SMBG are most frequently attributed to operator-error failure to use test strips appropriate to the meter calibrate the meter correctly

dirty meters
inadequate hand washing improper storage of the test strips.

The glucose meter and strips should be brought in for clinic visits. The patient's method of testing should be observed periodically and any technical mistakes corrected. Patients should be queried regarding storage of strips. If SMBG results do not seem consistent with expectations, we recommend that the patient bring the glucose meter in to be checked against meters of known accuracy or with a simultaneous lab value. Most meters can be downloaded so that the actual measurements (rather than reliance on patients self-report of frequency of testing and specific results) can be reviewed.

Patients who are motivated and test often usually get much more reliable results than those who are less interested or who test less often (such as non-expert clinicians) We also recommend the following steps to increase the accuracy of glucose monitoring:

Blood Glucose Meters

There are a variety of SMBG systems available. Most glucose meters are reasonably accurate (+/-10 percent) and require only a very small drop of blood. In an evaluation of the accuracy of 27 monitoring systems, 16 fulfilled minimum accuracy requirements. Accuracy during episodes of hypoglycemia and in patients with poor peripheral tissue perfusion may be less than optimal (1-4%) In the past, glucose meters reported whole blood glucose values, which made it difficult to compare finger stick results with results from a laboratory, which are always plasma. The majority of available glucose meters now provide plasma equivalent values rather than whole blood glucose values. Thus, results from most available glucose meters and commercial laboratories should now be comparable

Glucose Strips
Some glucose strips have considerable batch to batch variation and require recalibration to a meter every time a new batch is used. Many strips are packaged in groups (10, 25, 50, or 100) inside a can containing a desiccant to control humidity. Common errors include leaving the lid off for periods of time, with exposure to heat, moisture, and humidity, and mixing lots of strips into one can for convenience.

Patients may forget to match the code on the strip bottle to the meter code, with uncompensated batch variation causing erroneous glucose value readings.
Fortunately, most meters now have eliminated the need to code each bottle of strips. Many newer meters overcome this problem by automatically recognizing codes for strips

Site of testing
Several blood glucose meters are now available that use sites other than the finger to obtain blood samples in an effort to reduce the discomfort involved with fingersticks. A study of one device that can be used to obtain samples from the arm found that it provided accurate results and was less painful than fingerstick testing Monitoring from alternate sites, such as the skin of the forearm, may give slightly lower results than those taken at the fingertips, since they may sample venous blood rather than capillary blood.

In addition, during times when the blood glucose concentration is either rising rapidly (such as immediately after food ingestion) or falling rapidly (in response to rapidly acting insulin or exercise), blood glucose results from alternate sites may give significantly delayed results compared with fingerstick readings

Site of Testing

Other sugars
The FDA issued a safety alert in February 2006 that some glucose monitors (those using the enzyme glucose dehydrogenase pyrroloquinoline quinone or GDH-PQQ) will give falsely elevated readings in patients who have received treatments containing other sugars, including xylose as part of a d-xylose absorption test, maltose or galactose in IV solutions (IV immune globulin is formulated with maltose), or icodextrin in peritoneal dialysis fluid Most glucose meters do not use this enzyme and the test method used is identified in the package insert for the glucose strips. Several patient deaths were attributed to inappropriate insulin treatment for falsely elevated glucose strip readings New test strips have been designed to minimize interference with non-glucose sugars

Using the information

Regimen of SMBG will be effective only if the patient is able to use the information to make appropriate dietary or therapeutic adjustments. As an example, patterns of glycemic control can be most easily identified if the blood glucose values are entered in columns, corresponding to times of the day, and the relation to both food intake and exercise noted. Many glucose meters provide data management features that can be downloaded onto a computer, allowing graphic representation of glycemic variation by time of day or over a period of weeks, allowing calculation of means, and visualization of trends and variances. Unless results are reviewed on a frequent basis to detect and address blood glucose patterns, self-monitoring will not fulfill its purpose. Relying on the automatic data storage of the meters, without regularly reviewing the results, may detract from the clinical utility of monitoring.

Optimal use of the data obtained is best done in two stages:

Pattern identification

Insulin algorithms
Once a basic regimen of eating, exercise, and insulin dosing has been established, there will still be a day-to-day variability in blood glucose values due, among other factors, to the vagaries of insulin and food absorption. This can be effectively treated by an insulin algorithm in which the beforemeal dose of short-acting insulin is adjusted according to the blood glucose value and, for patients who use carbohydrate counting, anticipated carbohydrate content of the meal. The adjustments should be small in patients who are very sensitive to insulin or who are taking low doses of insulin (as with a continuous insulin pump)

Patterns, as opposed to intermittent problems, are best identified if there are a relatively large number of measurements. Thus, blood glucose values should be recorded four to seven times daily for several days and evaluated for patterns of variation, which allow adjustment of doses or types of insulin at different times of the day.

Using the information Type 2

The frequency of SMBG in patients with type 2 diabetes, while most often less than for patients with type 1 diabetes, is dependent on the glycemic targets set and the treatments used. If SMBG is initiated to improve glycemic control, patient education strategies are necessary to ensure successful management of SMBG feedback the frequency of testing decreases over time, often because patients did not know how to respond to high readings, and patients perceived that providers were more interested in A1C values than glucose logs Use of SMBG was successful in reducing A1C values when accompanied by training of patients and clinicians to collect and interpret SMBG profiles

Using the information

With a well-educated and motivated patient, therapeutic advice can often be given over the telephone or even via fax or e-mail. It is important not to recommend many changes at the same time. Having made a change, it is usually best to wait several days until the effect of that change can be assessed from further blood glucose measurements.

CONTINUOUS GLUCOSE MONITORING

What is a Continuous Glucose Monitoring (CGM) system?

It is an FDA-approved device that records blood sugar levels throughout the day and night. Originally introduced into clinical practice in 1999 for short term, retrospective analysis of glucose control, since 2006 CGM is now available for real time use and provides information on direction, magnitude, frequency and duration of glycemic oscillations on a moment to moment basis to aid control of diabetes by patients themselves. The system is used to measure an average blood sugar for 3 to 7 days (depending on the model), while the person with diabetes continues daily activities at home. Approved devices can measure blood sugar levels every 1 to 5 minutes, providing hundreds of blood sugar measurements every 24 hours.

Traditional Monitoring vs. CGM

Testing 6 times a day, this patient would see: average glucose 135 mg/dl readings within target 84% of the time only 1 hyperglycemic episode detected

With CGM, the same patient would see: average glucose 151 mg/dl readings within target 62% of the time several episodes of hypo and hyperglycemia

How does CGM works?

CGM devices have three components:
a disposable subcutaneous sensor, a wireless transmitter, and a monitor that displays data.

A computer is required to download, graph, and analyze the data.

What is the role of CGM in diabetes management?

It is intended to continuously record interstitial glucose levels and use this information to supplement, not replace, blood glucose information obtained using standard home glucose-monitoring devices.
Its main advantage is to identify fluctuations and trends that would otherwise go unnoticed with standard HbA1c tests and intermittent finger stick measurements. .

Classes of CGM devices

Professional CGM - The first class of FDA-approved CGM devices has been typically used diagnostically by health care professionals, since they store and subsequently display data retrospectively. While wearing the device, the patient can record activities and events, but the glucose values are not displayed.
The patient must keep a logbook with timing of insulin doses, exercise and meal information. Personal CGM - The second class of CGM devices are designed for carefully educated patient, since they display data in real time, thereby allowing the patient to monitor and respond to personal blood glucose values in real time.

Indications for Professional CGM*

Patients with type 1 or type 2 diabetes who:
*AACE Continuous Glucose Monitoring Task Force. AACE Consensus Statement on CGM. Endocrine Practice. 2010;16(5):730-744.

are not at their A1C target have recurrent hypoglycemia or hypo unawareness All pregnant women with type 1 diabetes.

CGM may also facilitate treatment adherence for women with type2 diabetes or insulin-requiring gestational diabetes. Youth with type 1 diabetes who are changing their diabetes regimen or are experiencing: nocturnal hypoglycemia dawn phenomenon hyperglycemia Hypoglycemia unawareness post prandial

Indications for Personal CGM*

*AACE Continuous Glucose Monitoring Task Force. AACE Consensus
Statement on CGM. Endocrine Practice. 2010;16(5):730-744.

Personal CGM is recommended for patients with type 1 diabetes with:

Hypoglycemia unawareness or frequent hypoglycemia above target or with excess glucose variability

A1C

Requires

lowering A1C without increased hypoglycemia During preconception and pregnancy

How does CGM works?

A small glucose-sensing device called a sensor has the enzyme glucose oxidase embedded at its surface that converts glucose into electronic signals. It is a disposable sensor inserted under the skin of abdomen or upper arm to measure interstitial fluid glucose.

How does Professional CGM works?

The sensor sends these signals: *through a cable to the monitor (in earlier models- Medtronic Minimed Gold), or

Minimed

* to an attached recorder (Medtronic iPro), or * through an attached transmitter (DexCom SEVEN PLUS) that sends the signals wireless to a receiver which can be set so that the patient is blinded to the data during the collection period.

iPro

SEVEN PLUS

How does CGM works?

Stored electronic signals in the monitor, recorder or receiver are converted to glucose concentrations that is downloaded to a computer and is viewed as graphs or charts. The monitor must be calibrated daily by entering 2 to 4 blood glucose readings obtained at different times, using a standard blood glucose meter.

How does Personal CGM works?

The receiver displays and stores glucose information. The information stored in the receiver is then converted into estimated mean values of glucose standardized to capillary blood glucose levels measured during calibration. The time of day, premeal glucose, timing and amount of bolus insulin, and physical activity can be electronically logged in some CGM devices or recorded on a paper log and considered when analyzing the data.

SEVEN PLUS

Guardian RT

Receiver Display
Arrows are displayed that let the patient know the trend of glucose levels, either in an upward or downward direction. This allows the patient to take corrective measures before an episode of hypo- or hyperglycemia occurs.

Alarms can be set to warn the patient when glucose levels reach a certain level.

Sensor-Augmented Pump Therapy MiniMed Paradigm REAL-Time Revel System

(the closest to an artificial pancreas!)

By fingerstick tests this patient appears fairly well controlled

When analyzing CGM reports: 1. Look at overnight period first. 2. Look at preprandial levels. 3. Look at postprandial levels.

Analyzing CGM Reports

Summary and Recommendations

Self-monitoring of blood glucose (SMBG) is an integral component of the intensive insulin regimen recommended for most patients with type 1 diabetes.
Patients with type 1 diabetes will usually require testing before meals; before, during, and after exercise; and occasionally during the night to adjust insulin doses for meals and avoid hypoglycemic events.

Similar guidelines apply to insulin-treated type 2 diabetes, although their glucose levels are characteristically more stable and they may require less frequent monitoring.

Summary and Recommendations

Patients with type 2 diabetes treated with sulfonylureas or meglitinides, which can also cause hypoglycemia, should be tested once to twice per day during titration of their doses, but after a stable dose and target glycemic targets are achieved, may only need to test several times per week, usually in the morning or before dinner.
All insulin and sulfonylurea patients need to test more frequently before and during long car rides, during sick days, and when there are changes in diet and exercise patterns.

Summary and Recommendations

SMBG may not be necessary or less frequent SMBG may be appropriate for patients with type 2 diabetes who are not taking medications associated with hypoglycemia
Errors in SMBG may result from poor technique, lower test sensitivity in measuring low blood glucose levels, improper storage of test strips, or interfering substances

Summary and Recommendations

Blood is usually sampled from the fingertips.
Monitoring from alternate sites, such as the skin of the forearm, may give slightly lower results than those taken at the fingertips, since they may sample venous blood rather than capillary blood. Alternative sites may also give less reliable results when there are rapid fluctuations in blood sugar.

Summary and Recommendations

With continuous glucose monitoring (CGM), blood glucose levels are reported to the patient in real time.
Consistent and reliable use of a continuous glucose monitoring (CGM) system can modestly improve glycemic control in adults with type 1 diabetes. Some studies have shown fewer periods of hypoglycemia with CGM, but there are concerns with reproducibility of glucose results, particularly in the lower glucose range, with currently available CGM.

CASE DISCUSSION
The following case illustrates the value of blood glucose monitoring in patients with type 2 diabetes, depending upon the time, treatment, and stage of the disease

Case
A 56-year-old woman who is a clothing sales assistant presents with thirst, fatigue, and a vaginal yeast infection.
HEIGHT: 5 4 and WEIGHT 265 lbs Random blood glucose value is 260 mg/dL A1C (HbA1c) value is 9.4 % She eats a diet high in fat and carbohydrates

Exercises little
She watches TV for several hours nearly every evening, during which time she often eats two or three sugarcovered donuts

Initial treatment
Appropriate initial management
arrange for education about diabetes, in the form of written material, videos, and follow-up in an education and support group with other obese patients with type 2 diabetes;

advise her to modify her eating habits (reducing caloric intake and eliminating refined carbohydrate)
encourage her to walk on a treadmill for at least 30 minutes at least five evenings a week at home. She should also be asked to measure fasting blood glucose every morning. Metformin 500mg BID started

BG monitoring
Her thirst, fatigue, and vaginal infection subside soon thereafter. During the next three weeks, her blood glucose values during a typical week are as follows:
Day Before breakfast Mon 265 treadmillTue treadmillWed donuts!Thur exerciseFri treadmillSat donuts!Sun 184 175 305 280 190 174 Comments Exercised on Exercised on No exercise, 2 No Exercised on 3-mile walk. No

Interpretation and approach

Daily fasting blood glucose values provide this woman with immediate feedback about the consequences of her behaviors. She can see that when she strays from her diet, her blood glucose values are higher the next morning, and when she exercises they are lower. After three weeks, she increases her exercise program to 45 minutes five evenings per week, and she rarely eats snacks in the evening. Her weight falls to 238 lbs, her mean fasting blood glucose concentration is 148 mg/dL Her A1C value is 8.1 percent. She has learned a lot about diabetes and its possible future consequences from her reading and support group meetings, and has made her goal an A1C value below 7.0 percent She is congratulated on the good lifestyle choices she has made and is encouraged to continue metformin is optimized, to 2 grams daily in divided doses.

Follow-up
Follow-up During the next month, her blood glucose values during a typical week are as follows: Day s Before Before breakfast lunch meal Before Before Comment evening bedtime Evening 184 Evening Ev Ate 172

Mon 156 167 exerciseTue 141 Wed 178 Thur 160 exerciseFri 157 ening exerciseSat 159 late, no exerciseSun 204

Interpretation and approach

Her mean fasting blood glucose concentration is now 145 mg/dL, and the concentrations are higher later in the day. Her A1C value is 7.6 percent. She is congratulated on her progress, and is given several options. She could add a sulfonylurea, add a dose of NPH insulin at bedtime, or add a GLP-1 agonist like exenatide or liraglutide She elects to continue with lifestyle measures and metformin but to add bedtime insulin. She is encouraged to reset her goal for HbA1c to below 7.0 percent. She is taught to take 12 units of NPH insulin at bedtime (10 pm) every evening, while continuing her other treatment. She is asked to measure fasting blood glucose every day and to report the values to you every week.

F/U monitoring
During the next few weeks her bedtime dose of insulin is increased as follows:
Week NPH 1 204 140 Mean fasting blood glucose 168 163 148 286 134 Bedtime dose of 122 154 245 133 165

327
32

Interpretation and approach

By measuring fasting blood glucose daily and averaging the values each week the dose of bedtime NPH insulin can be adjusted to an appropriate level.
Over the next year her A1C values are between 6.5 and 7.5 percent. She is asked to continue measuring fasting blood glucose every day and occasionally at other times.

During the following year her A1C value rises to 8.4 percent, despite fasting blood glucose concentrations <130 mg/dL She is asked to measure blood glucose more often before lunch and dinner and at bedtime.

BG Monitoring
During the next three months, her blood glucose concentrations during a typical week are:
Day Before breakfast 119 128 147 123 130 Before lunch 198 251 236 Before evening meal 235 Before bedtime

Mon Tue Wed Thur Fri

266 241

Interpretation and Approach

Although her fasting blood glucose concentrations remain within the target range, they are rising steadily throughout the day. This is probably due to progression of type 2 diabetes, so that her pancreatic beta-cells are making less insulin than they used to.

She is advised to continue metformin and NPH insulin at bedtime.

Because the target A1C has not been achieved, the insulin regimen should be intensified. She could add a second dose of NPH insulin before breakfast and take short acting insulin before her evening meal. She starts to measure blood glucose before breakfast, lunch, and dinner and at bedtime, and starts to use an algorithm to select premeal doses of insulin

Summary
In this case (based on an actual clinical case) we are trying to show how testing blood glucose at different times of the day and in different situations can help in making treatment decisions. There are several aspects of this case that are currently managed somewhat differently than in the past. While everyone would advocate vigorous support of healthy lifestyle change for a woman like this, many clinicians would recommend adding drugs and/or insulin at an earlier stage in an effort to get her HbA1c well below 7.0 percent as quickly as possible. One of the most common reasons for patients having an HbA1c that is too high is "clinical inertia" where additional treatments in a stepped protocol are not added soon enough.