As of 2012, an estimated 371 million people worldwide are affected by diabetes. This number is expected to rise to 552 million (or one in 10 adults) by 2030. In Canada, more than three million people are living with diabetes and this number is expected to reach 3.7 million by 2019. The rise in type 1 diabetes has been linked to changing environmental factors, while the rise in type 2 diabetes is strongly associated with increasing rates of obesity.
In people with normal glucose tolerance, blood glucose levels are automatically monitored and controlled by the body. After eating, the body releases enough insulin to keep the plasma glucose within a normal range that rarely rises above 7.8mmol/L and usually returns to pre-meal levels within two to three hours. In people with impaired glucose tolerance or diabetes, the body has little or no automatic control of blood glucose levels. After eating, they often experience extended periods of elevated blood glucose levels.
The chronic hyperglycemia of diabetes is associated with both micro- and macrovascular complications such as blindness, end stage renal disease, cardiovascular disease and non-traumatic amputation, resulting in significant increases in morbidity and mortality. Improving glycemic control in diabetic patients has been shown to reduce these complications. The main goal of treatment is to keep blood glucose levels in the normal or near-normal range.
Checking one’s blood glucose is one of the best ways to know how well the diabetes treatment plan is working. What follows are some of the blood glucose monitoring techniques available in Canada today.
GLYCATED HEMOGLOBIN TESTING
The Diabetes Control and Complications Trial (DCCT ) and the UK Prospective Diabetes Study (UKPDS ) demonstrated that glycated hemoglobin (also called A1C, hemoglobin A1C, or HbA1C) and the development of long-term complications are correlated in both type 1 and type 2 diabetes, respectively. Therefore, hemoglobin A1C testing is the most widely used measurement of glycated hemoglobin, and laboratories are encouraged to use standardized assay methods for this test.
Hemoglobin formed in new red blood cells enters the circulation with minimal glucose attached. However, red cells are freely permeable to glucose. As a result, glucose becomes irreversibly attached to hemoglobin at a rate dependent upon the prevailing blood glucose concentration. Approximately one percent of erythrocytes are destroyed every day, while an equal number of new ones are formed. Thus, the average amount of A1C changes in a dynamic way and indicates the mean blood glucose concentration over the life span of the red cell. Although the A1C reflects mean blood glucose over the entire 120-day life span of the red blood cell, it correlates best with mean blood glucose over the previous eight to 12 weeks. Hence A1C should be measured every three months when glycemic targets are not being met and when diabetes therapy is being adjusted. A1C is now also being used for diagnosis of diabetes. However when glycemic targets are consistently achieved, A1C may be tested every six months.
In Canada, the A1C continues to be reported using the National Glycohemoglobin Standardization Program (NGS P) units (%).
The recommended target A1C value is 7 percent or lower for most adults with type 1 or type 2 diabetes. A six percent or lower A1C is also recommended for some adult diabetics without causing significant hypoglycemia, to further lower the risk of neuropathy and retinopathy. The goal should be set higher, between 7.1 and 8.5 percent, for patients with limited life expectancy, high level of functional dependency, multiple co-morbidities or with history of coronary artery disease, in whom the risk of hypoglycemia may outweigh the potential benefit.
Studies suggest that A1C values may also be helpful in the diagnosis of impaired glucose tolerance or overt diabetes mellitus, being simpler to perform and to repeat than the oral glucose tolerance test.
There are a number of uncommon circumstances that may affect the A1C accuracy:
- In case of low red cell turnover, resulting in disproportionate number of older red cells can give a false high A1C value. Such problems can occur in patients with iron or vitamin B12 deficiency, hyperbiliruminemia, as well as in patients with chronic opiate or alcohol use.
- On the other hand, rapid cell turnover results in a greater proportion of younger red cells and hence falsely low A1C values. These problems will occur in patients with hemolysis and those treated for iron, vitamin B12, or folate deficiency, and patients treated with erythropoietin. It also occurs in patients with chronic liver disease or with elevated triglycerides.
- A1C values may be falsely elevated or decreased in those with chronic kidney disease and in people on hemodialysis.
As an integrated measure of fasting, premeal, and post-meal glucose levels, A1C does not fully represent the risks that diabetic patients face on a daily basis, as it does not readily reflect the degree of glycemic variability that a patient may experience during a given day.
Optimal diabetes management involves control of fasting, pre- and post-meal glucose levels. A1C alone cannot be used to identify whether a particular patient’s abnormal glycemic patterns are due to high fasting blood glucose levels or high post-meal blood glucose levels. In fact, the relative contributions of fasting blood glucose and post-meal blood glucose to A1C vary according to A1C levels, with post meal blood glucose measurements becoming increasingly important as A1C decreases toward target levels.
SELF MONITORING OF BLOOD GLUCOSE
Awareness of all measures of glycemia, including self-monitoring of blood glucose (SM G) results and A1C, provide the best information to assess glycemic control. SMBG can help both patients and their healthcare professionals better adjust to therapy and assess the responses to therapy.
Potential benefits of SMBG include improvement in A1C, identification, prevention or management of hypo- and hyperglycemia. Furthermore, SMBG can help minimize fluctuations in blood glucose levels that have been shown to signal imminent occurrence of severe hypoglycemia in majority of cases and may independently contribute to diabetic complications. In addition, when adjusting oral agent or insulin doses, it is important to know the pattern of blood glucose values, i.e., when during the day the levels are high, in the targeted range, or low, since the design of the treatment regimen may differentially affect glucose concentrations at various times after drug ingestion or injection.
SMBG profiles help healthcare providers better plan individualized antihyperglycemic regimens and provide an educational feedback tool to inform patients of the effects of modulating their diet, physical activity, or intake of oral antidiabetic agents or insulin. Such active involvement in their care helps empower patients and has been shown to facilitate the achievement of glycemic targets.
SMBG is currently recommended for all people with type 1 and type 2 diabetes being treated with insulin. SMBG should be determined individually, and be part of a total treatment regimen that includes diet, exercise, weight loss and insulin or oral medications when indicated. The optimal frequency and timing of SMBG depends on many variables, including diabetes type, level of glycemic control, management strategy and individual patient factors. Healthcare professionals will also need to modify SMBG regimens to accommodate changes in therapy and lifestyle.
For people with type 1 diabetes, SMBG is an essential component of daily diabetes management and it has been shown that testing three or more times a day was associated with a statistically and clinically significant 1 percent reduction in A1C levels. Furthermore, blood glucose measurements taken post-lunch, post-dinner and at bedtime have demonstrated the highest correlation to A1C. Frequent daily SMBG pre- and post-meals will provide useful information for adjusting insulin and carbohydrate intake. In addition, 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. The results of multiple testing each day provide information that is better correlated to A1C than fasting results alone.
The effectiveness of SMBG for patients with type 2 diabetes is less clear than for those with type 1 diabetes. Multiple observational studies have evaluated SMBG in type 2 diabetes, with some showing benefit and others not. However, for people recently diagnosed with type 2 diabetes, regardless of treatment, SMBG has been demonstrated to be of benefit. For those with type 2 diabetes using insulin, the Canadian Diabetes Association 2013 Clinical Practice Guidelines recommend to test at least three times a day, which is associated with improved glycemic control. In those with type 2 diabetes on once-daily insulin as well as oral antihyperglycemic agents, testing at least once a day at variable times is also recommended. For individuals treated with antihyperglycemic agents or lifestyle changes only, the frequency of SMBG should be individualized, depending on glycemic control and type of therapy and should include both pre- and post-meal measurements. However, SMBG 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 A1C should be somewhat higher (eight percent or lower) than for younger and more fit elderly patients, and therefore, there is little role for regular SMBG, unless the patient is taking insulin.
Target fasting, pre-meal and post-meal glucose values
The levels of plasma glucose that should result in A1C in the target range are between 4 to 7 mmol/L for fasting and pre-meal levels. If these targets are met but A1C remains above the desired target, glucose levels measured two hours after a meal should be checked as well. They should range between 5 to 10 mmol/L or more ideally 5 to 8 mmol/L.
Accuracy of SMBG
Since patients and their healthcare providers rely on SMBG results to identify hyper- and hypoglycemia and modify treatment accordingly, it is important for glucose meter readings to be accurate and reliable. Despite the increasing simplification of blood glucose meters over the years, they are still not foolproof. SMBG readings can vary from their true value by more than 20 percent. At above 4.2 mmol/L blood glucose reading, a difference of less than 20 percent between fingertip sampling of capillary blood glucose and simultaneous venous fasting blood glucose levels is considered acceptable. However, less variation is recommended for blood glucose readings of 4.2 mmol/L or less.
Since variability exists between blood glucose results using self-monitoring devices and laboratory testing of fasting blood glucose, meter results should be compared with laboratory measurements of blood glucose at least annually and also when indicators of glycemic control do not match meter readings. In addition, errors in testing techniques are also common. Problems arise from:
- using the wrong test strips for the meter
- incorrect calibration of the meter
- dirty meters
- inadequate hand washing
- improper storage of the test strips.
To increase accuracy
- Patients should be encouraged to bring their glucose meter and strips in for every clinic visit.
- The patient’s method of testing should be observed periodically and any technical mistakes corrected.
- Patients should be queried regarding storage of strips. Periodic re-education on correct monitoring technique may improve the accuracy of SMBG results.
If SM BG results do not seem consistent with expectations, it is recommended that the patient bring the glucose meter in to be checked against meters of known accuracy or with a simultaneous lab value.
Most meter readings 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.
Alternate site 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 finger sticks. Monitoring at alternate sites, such as the forearm, palm of the hand or thigh, may give slightly lower results than those taken at the fingertips, since they may sample venous blood rather than capillary blood. While this should not be a problem if the patient uses one or the other site exclusively, the between-test variability will increase if numerous sites (such as fingertips and forearm sites) are used. 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, during exercise or while experiencing hypoglycemia), blood glucose results from alternate sites may give significantly delayed results compared with finger stick readings. In comparison, blood samples taken from the palm near the base of the thumb (thenar area), demonstrate a closer correlation to fingertip samples at all times of day, and during periods of rapid change in BG levels.
Measurement of urinary ketones is less subject to error because any positive value suggests the presence of ketonemia. In patients with type 1 diabetes, the urine should be tested for ketones if the blood glucose concentration is above 14.0 mmol/L for unexplained reasons, especially if the person feels generally unwell at the time. Testing for ketonuria should also be performed during periods of acute illness or stress, or if there are symptoms compatible with diabetic ketoacidosis (DKA) such as nausea, vomiting or abdominal pain. If all of these conditions are present in a person with type 2 diabetes, ketone testing should also be considered, as DKA can also occur in these individuals. The presence of ketones in the urine does not always mean that the person has impending ketoacidosis. Ketonuria indicates that the person is in a catabolic state and is breaking down fat, and can occur in anyone who has a negative caloric balance while dieting. However, in the absence of purposely trying to restrict calories, the presence of urine ketones along with hyperglycemia is more serious than hyperglycemia alone. Ketoacidosis can lead to serious complications such as diabetic coma.
Urine ketone testing is done with a dipstick, available in pharmacies without a prescription. If the patient has moderate to large ketones, they should immediately call their healthcare provider to determine the best treatment. They may need to retest every two to three hours, stay well-hydrated, and take extra insulin if indicated.
People with type 1 diabetes who use an insulin pump may prefer blood ketone testing over urine ketone testing, as it has been associated with earlier detection of DKA. Interruption of insulin delivery can result in rapid onset of DKA.
CONTINUOUS GLUCOSE MONITORING SYSTEMS
A continuous glucose monitoring system (CGMS ) measures blood glucose in the interstitial fluid every few minutes. Two types of devices are available:
- newer systems that display “real time” (also called “personal”) glucose results directly on the monitor system
- earlier “non-real time” (sometimes referred as “professional”) devices that do not have a result display capability and results are only available for retrospective viewing and analysis when data are downloaded to a computer by a healthcare provider.
A typical “real-time” system consists of: a disposable glucose sensor placed just under the skin, which is worn for a few days until replacement, a link from the sensor to a non-implanted transmitter which communicates to a radio receiver, an electronic receiver worn like a pager (or insulin pump) that displays blood glucose levels on a practically continuous manner and also monitors rising and falling trends in glycemic excursions.
Real time CGM has been consistently shown to reduce A1C in both adults and children with type 1 diabetes, and to reduce A1C in adults with type 2 diabetes. It also reduces times spent in hypoglycemia state. The professional CGM has shown to reduce A1C in adults with type 2 diabetes and in pregnant women with type 1 or type 2 diabetes.
Continuous monitoring allows examination of how the blood glucose level reacts to insulin, exercise, food and other factors. The additional data can be useful for setting correct insulin dosing ratios for food intake and correction of hyperglycemia. Monitoring during periods when blood glucose levels are not typically checked (i.e. overnight) can help identify problems in insulin dosing (such as basal levels for insulin pump users or long-acting insulin levels for patients taking injections). Monitors may also be equipped with alarms to alert patients of hyper- or hypoglycemia so that a patient can take corrective action(s) (after finger stick testing, if necessary) even in cases where they do not feel symptoms of either condition. While the technology has its limitations, studies have demonstrated that patients with real-time continuous sensors experience less hyperglycemia, hyperglycemia, nocturnal hypoglycemia and even improvement in A1C levels.
Because CGMS does not directly measure glucose levels in the blood, but rather the glucose level of interstitial fluid, there are two disadvantages compared to traditional blood glucose monitoring.
1. Using current technology, continuous systems must be calibrated with a traditional blood glucose measurement and therefore do not yet fully replace “finger stick” measurements.
2. Glucose levels in interstitial fluid temporally lag behind blood glucose values. The lag time has been reported to be five minutes in general. This lag time is insignificant when blood glucose levels are relatively consistent. However, blood glucose levels, when changing rapidly (rising such as after a meal, or dropping in case of hypoglycemia), may read in the normal range on a CGMS while in reality the patient is already experiencing symptoms of an out-of-range blood glucose value and may require treatment.
For these and other reasons related to this first generation technology, patients using CGMS are typically advised to take traditional finger stick measurements at least twice a day (for calibration), to verify that the sensor readings are accurate, and whenever they wish to self-treat their diabetes.
Currently available CGMS continue to be relatively expensive. Not all continuous glucose meters and supplies are covered by insurance companies. Initial costs are approximately $700 for the device that directly samples subcutaneous fluid, with additional costs for supplies at $200 per month. Insurance companies have improved reimbursement over the years, and more companies are covering part, if not all, depending on the specific plan.
GLUCOSE SENSING BIO-IMPLANTS
Longer term solutions to continuous monitoring, not yet available but under development, use a long-lasting bio-implant. These systems promise to ease the burden of blood glucose monitoring for their users, but at the trade off of a minor surgical implantation of the sensor that lasts from one year to more than five years depending on the product selected.
Products under development include: The Senseonics Continuous Glucose Monitoring System, Glysens ICGM system, The Dexcom LTS (long term system), The Animas Glucose Sensor (Dexcom G4 Platinum, Animas Implanted
Some new technologies to monitor blood glucose levels will not require access to blood to read the glucose level. Non-invasive technologies include near IR detection, ultrasound and dielectric spectroscopy. These will free the person with diabetes from finger sticks to supply the drop of blood for blood glucose analysis.
Most of the non-invasive methods under development are continuous glucose monitoring methods and offer the advantage of providing additional information to the subject between the conventional finger stick, blood glucose measurements and over time periods where no finger stick measurements are available (i.e. while the subject is sleeping).
Products under development include: Fovioptics retinal glucose analyzer, Inlight Solutions, NIR glucose sensor, NIR Diagnostics, NIR glucose sensor, Sinsys Medical GTS , Sontra Ultrasonic Symphony Diabetes management system and Solianis Monitoring AG.