HISTORICAL REVIEW OF HYPERGLYCEMIA
The first documentation of type 2 diabetes mellitus (T2DM) dates back to ancient Egypt as early as 1500 bc. Demetrius of Apamea (1st or 2nd century bc) has been credited with introducing the term “diabetes,” which means to “pass or run through” as in a siphon.1 It referred to how large volumes of urine passed through the body unchanged as if through a tube. The Greek physician, Aretaeus of Cappadocia (ad 2nd century), first suggested the term “Diabetes Mellitus.” He described it as “an infrequent affliction characterized by melting down of the flesh and limbs into the urine, short life, disgusting and painful, unquenchable thirst and the kidneys and bladder never stop making water.”2 Diabetes, in Greek, means “siphon” or “pipe-like” and Mellitus, in Latin, means honey. “Diabetes Mellitus” has also been called “Madhumeha” (“Madhu” meaning “honey”) in ancient Indian Ayurvedic Medicine. Indian texts, dated back to the 5th century bc, referred to cases of excessive urine, thirst and emaciation, in 2which the urine was described as ksaudra (sweet) or madhu (honey) meha (urine), to be associated with an illness said to affect the rich who consumed large quantities of rice, cereals, and sweets.3,4 Galen (ad 129−200), a famous anatomist countered what Aretaeus proposed and suggested that it is a disease primarily of the kidneys. It is a very rare disease, of which he had observed only two subjects. He stated, ‘The condition impressed him as an ailment of the kidneys, whereas other physicians called it “dropsy of the chamber pot” and “urinary diarrhea”;’ some others called it “dipsakos” (violent thirst).5 Avicenna (980−1037) in the first book of Canon states, “the urine of diabetics when left to stand in ambient air, leaves a residue that is particularly sticky and tastes sweet as honey.” Avicenna termed the disease “aldulab” or water wheel and “zalkh el kuliah” or diarrhea of the kidneys.6 The first paradigm shift in the conceptual evolution of diabetes came from the studies of Paracelsus (1493−1541) who described it as a constitutional disease that “irritates the kidneys.” Later, in 1674, reports of Thomas Willis (1621−1675) showed that the urine was sweet “as if imbued with honey (quasi melle) and sugar.” He evaporated the urine of diabetics, which he then tasted and came to the conclusion of “honey urine.”2 In 1776, a British physiologist named Matthew Dobson in his book “Experiments and Observations on the Urine of Diabetics” found that the urine of a diabetic was sweet because of increased sugars. He drew the blood of patients with diabetes, allowed it to stand, and then by tasting the sweet serum proposed that the hyperglycemia was a multisystem disease. He described the color as “common cheese whey.” After evaporating a number of urine samples to dryness, he noticed a white residue that smelled like brown sugar which fermented when yeast was added.7 The sugar in the blood and urine was identified as glucose by Michel Eugene Chevreul (1786−1889) in 1815.6 In 1838, George Rees (physician) isolated sugar from the blood serum of a patient with T2DM.8 In the early 19th century, glucose was identified as the sugar present in urine. In 1841 and 1848, respectively, Trommer and Fehling developed qualitative tests to measure glucose in urine9,10 using the reducing properties of glucose which on reacting with alkaline cupric sulfate reagents produced colored cuprous oxide indicating the presence of sugar. In Paris, Edme Jule Maumené (chemist) produced the first test strips using merino sheep wool containing stannous chloride (SnCl2) which turned black if a drop of urine containing sugar was added to it and heat applied. In 1908, Stanley Benedict developed a reagent containing copper sulfate, sodium citrate, sodium carbonate, and distilled water to help identify the presence of sugar in the urine.11 In 1919, Otto Folin and Hsien Wu modified the method by using a phenol reagent to react with a weakly alkaline copper tartrate solution.12 In 1940, Nelson modified this further by using arsenomolybdate reagent.13 The disadvantage of using the older screening tests was that the technique could detect any sugar that would reduce copper (nonspecific). It could react with other reducing substances present in the urine besides glucose, such as fructose, galactose, uric acid, ascorbic acid, ketone bodies, and salicylates.14 In 1959, an ortho-toluidine method was developed. It was based on the reaction between the aldehyde groups of aldoses and aromatic amines such as o-toluidine in hot glacial acetic acid which is specific for the detection of aldoses. The reaction results in the formation of a blue-green product with an absorption maximum at a wavelength of 635 nm. The reaction, however, used a strong, noxious, and corrosive acid.15 The current methods use an enzymatic method which is usually 3more specific, and the most frequently used method is the glucose hexokinase method to detect and measure glucose in urine, blood, and cerebrospinal fluid.
IS THERE A GLYCEMIC THRESHOLD FOR MORBIDITY AND/OR MORTALITY?
There is abundant data to prove that hyperglycemia causes harm to multiple organs. A meta-analysis of 38 prospective studies confirmed that hyperglycemia [both fasting and 2-hour postglucose (2h-PG)] in the nondiabetic range was associated with an increased risk of fatal and nonfatal cardiovascular (CV) disease. From 12 studies reporting on fasting plasma glucose (FPG) levels and six studies reporting on post-challenge glucose, CV events appeared to increase in a linear fashion with 2-hour post-challenge plasma glucose even in the range below diagnostic levels of diabetes without a threshold; however, for FPG, there was a possible threshold at 99 mg/dL (5.5 mmol/L).16
The Paris Prospective Study showed J-shaped relationships for all-cause mortality with both fasting and 2h-PG concentrations, with the lowest observed death rates for FPG centered around 99 mg/dL (5.5 mmol/L) and for 2h-PG levels around 90 mg/dL (5.0 mmol/L). For ischemic heart disease, death was associated in a liner fashion with fasting glucose; however, it was a J-shaped curve for 2h-PG with the lowest observed death rate for plasma glucose centered around 108 mg/dL (6.0 mmol/L).17
The DECODE (Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe) study, after adjusting for CV risk factors, reported a J-shaped relationship between mortality and glucose (both fasting and 2h-PG) with the lowest rates for FPG between 81 and 109.6 mg/dL (4.50–6.09 mmol/L) and for 2h-PG between 81 and 99 mg/dL (4.51–5.50 mmol/L). There was a graded relationship between CV mortality and 2h-PG with the lowest rates of mortality seen at the lowest levels of 2h-PG distribution.18
The Whitehall study was a 33-year follow-up study (n = 17,869 male civil servants aged 40–64 years). It was seen that coronary mortality rose in a linear fashion from a threshold 2h-PG of 82.8 mg/dL (4.6 mmol/L). At a 2h-PG of 200 mg/dL (11.1 mmol/L), it was seen that there was a 3.6-fold increase in CV mortality compared with a level of 82.8 mg/dL (4.6 mmol/L). The graded relationship persisted but was attenuated by 45% after adjustment for other CV risk factors [baseline ischemic heart disease, body mass index (BMI), systolic blood pressure, blood cholesterol, smoking, physical activity, lung function, and employment grade].19
A Korean study (n = 12,455,361 adults) analyzed the association of fasting glucose with mortality and found that for each 18 mg/dL (1 mmol/L) increase in fasting glucose, there was an increased mortality of 13%. In individuals with a fasting glucose between 100 and 125 mg/dL, each 18 mg/dL increase in fasting glucose was associated with a 30% increased risk for mortality in those aged 18–34 years, 32% increased risk in those aged 35–44 years, and a 10% increased risk in those aged 75–99 years. Fasting glucose that was associated with the lowest mortality was 80–94 mg/dL regardless of sex and age. Prediabetes (100–125 mg/dL) was associated with higher mortality, and a stronger association of hyperglycemia with mortality was seen at a younger age.204
A meta-analysis of 11 articles (consisting of 129 prospective cohort studies, n = 2,674,882 without diabetes and CV disease at baseline) showed an increased risk of all-cause mortality (56%) among people with a fasting glucose <72 mg/dL (4.0 mmol/L), as compared with people with normal fasting glucose. A fasting glucose level of <82.8 mg/dL (<4.6 mmol/L) was not associated with increased risk of any CV endpoints.21
DIAGNOSTIC CRITERIA FOR TYPE 2 DIABETES MELLITUS AND “HIGH RISK” FOR DEVELOPING DIABETES
Diabetes may be diagnosed based on the following criteria:
- Fasting plasma glucose: FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours (in the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or two separate test samples); OR
- Two-hour plasma glucose value ≥200 mg/dL (11.1 mmol/L) during an oral glucose load [oral glucose tolerance test (OGTT)] containing the equivalent of 75-gram anhydrous glucose dissolved in water as recommended by the World Health Organization (WHO); OR
- Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia (polyuria, polydipsia, or polyphagia) or hyperglycemic crisis; OR
- Glycated hemoglobin (HbA1c): A1c ≥6.5% (48 mmol/mol) standardized to the DCCT (Diabetes Control and Complications Trial) assay.22 While the American Diabetes Association (ADA) advocates using HbA1c as a diagnostic measure, the American Association of Clinical Endocrinologists (AACE) recommends using HbA1c primarily for screening purposes only as it can be misleading or inaccurate in some ethnic populations and clinical situations.23 HbA1c represents an average blood glucose over 2−3 months (lifetime of an erythrocyte); however, rates of erythrocyte turnover, cell membrane permeability to glucose, and hemoglobin glycation and deglycation may all lead to an altered relationship/interpretation between HbA1c and mean glycemia.24
People who are at “high risk” for diabetes can be included in the following groups as per ADA and AACE:
- Impaired fasting glucose (IFG): Defined as FPG ≥100–125 mg/dL
- Impaired glucose tolerance (IGT): Defined as 2h-PG ≥140–199 mg/dL
- HbA1c 5.5–6.4%. (The diagnosis of prediabetes, which may manifest as either IFG or IGT, should be confirmed with a glucose test challenge.)25 The ADA recommends defining prediabetes as HbA1c 5.7–6.4%.
The WHO defines high risk for diabetes as follows:
- IFG: FPG >110 mg/dL (6.1 mmol/L) and <126 mg/dL (7 mmol/L) and
- IGT: 2h-PG >140 mg/dL (7.8 mmol/L) and <200 mg/dL (11.1 mmol/L) following an oral glucose load.26
The diagnosis of T2DM requires two abnormal test results from the same sample or two separate test samples unless there is a clear clinical diagnosis 5such as hyperglycemic crisis or presence of classic symptoms of hyperglycemia with a random plasma glucose ≥200 mg/dL (11.1 mmol/L).27 It is recommended that the second test be either a repeat of the initial test or a different test, which must be performed without delay. If two different tests (such as HbA1c and FPG) suggest the diagnosis, analyzed from the same sample or from two different test samples, it would also confirm the diagnosis. However, if a patient has discordant results from two different tests, then the test result that is above the diagnostic cut-point should be repeated, with consideration of the possibility of HbA1c assay interference. The diagnosis is made on the basis of two confirmed tests even though a third different test may be normal [e.g., two elevated HbA1c results ≥6.5% (48 mmol/mol)] but normal FPG [<126 mg/dL (7.0 mmol/L)]. Because of the potential for preanalytic variability, plasma glucose samples must be spun and separated immediately after they are drawn. If patients have test results near the margins of the diagnostic threshold, then in the absence of signs and symptoms the test must be repeated in 3–6 months.
COMPARING THE GOLD STANDARD DIAGNOSTIC TEST (OGTT) WITH GLYCATED HEMOGLOBIN
Even though international guidelines in the diagnosis of diabetes suggest a cutoff of HbA1c ≥6.5% (48 mmol/mol), it has not been validated. An HbA1c ≥6.5% was set to define the point when hyperglycemia changes into a multisystem disease, an inflection point at which the risk of retinopathy increases in the general population. In 2010, the ADA established a diagnostic set point of HbA1c ≥6.5% (48 mmol/mol) based on its correlation with retinopathy.28 What is consistent is
that the cutoff point of HbA1c of 6.5% is same across the globe supported by a study of 12 publications from Eastern countries (n = 59,735) and 13 from Western countries (n = 22,954), indicating that an HbA1c cutoff point of 6.5% had a pooled diagnostic sensitivity and specificity of 58.7% and 98.4% for Eastern countries and 65.5% and 98.1% for Western countries, respectively. In both populations, HbA1c levels >6.0% identified the population at high risk of diabetes, and HbA1c levels >6.5% identified clinically established diabetes.29 A study in Pima Indians found that the threshold for retinopathy based on HbA1c (80th percentile) corresponded to HbA1c ≥6.9% (52 mmol/mol).30 Since then, only one longitudinal study has validated the inflection point of HbA1c ≥6.5% (48 mmol/mol) for increased incidence of retinopathy,31 with most other longitudinal studies suggesting that an HbA1c of 6.5% (48 mmol/mol) may not represent an adequate reference point at which complications start. The DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) study which examined 700 subjects for development of retinopathy at 10-year follow-up found that the positive predictive values for retinopathy increased sharply at an HbA1c of 6.0% (42 mmol/mol) rather than at 6.5%.32 About 5,764 subjects without a prior diagnosis of diabetes from the National Health and Nutrition Examination Survey (NHANES) program were analyzed to review the effectiveness of using HbA1c in diagnosing T2DM compared to FPG and 2h-PG. Compared to the FPG, the sensitivity of HbA1c ≥6.5% was only 43.3% and compared to the 2h-PG criterion, the sensitivity of HbA1c ≥6.5% was only 28.1% suggesting that the HbA1c ≥6.5% detects <50% of 6diabetic patients defined by FPG and <30% defined by 2h-PG. Patients who were diagnosed as diabetic using 2hPG criterion but had an HbA1c <6.5%, were more likely to be older (64 ± 15 years vs. 60 ± 15 years), female (53.2% vs. 38.2%), leaner, and less likely to be current smokers (18.1% vs. 29.1%) as compared to those with an HbA1c ≥6.5%.33 Another South African study analyzed participants (n = 946) from a community-based study who were screened for diabetes using either a fasting blood glucose or OGTT and compared with an HbA1c cutoff of 6.5% to estimate its diagnostic accuracy. Using fasting blood glucose alone, 14% were diagnosed with diabetes of which <50% had an HbA1c value of ≥6.5% (48 mmol/mol). While using an OGTT, 18% were diagnosed with diabetes of which <46% had an HbA1c value of ≥6.5% (48 mmol/mol). An HbA1c of 6.1% (43 mmol/mol) was found to be optimal in both groups with sensitivities of 80% and 75% and specificities of 77% and 78%, respectively. It was concluded that although an HbA1c cutoff of 6.5% (48 mmol/mol) is a good diagnostic tool with its high specificity, its low sensitivity limits its use.34 In another South African study that analyzed Asian Indians, a diagnostic cutoff for HbA1c of 6.3% was found to be optimal for the diagnosis of diabetes and neither HbA1c nor the FPG approached adequate predictive accuracy for the diagnosis of diabetes.35 In an Indian study (n = 525), it was seen that the optimal HbA1c cut-point for newly diagnosed diabetes was 5.8% (sensitivity = 75%, specificity = 75.5%), the cut-point for IFG (ADA criteria) was 5.5% [sensitivity = 59.7%, specificity = 59.9%, area under the curve (AUC) = 0.628], and the cut-point for IFG (WHO criteria) was 5.6% (sensitivity = 60.7%, specificity = 65.1%).36
PITFALLS IN ASSESSING BLOOD GLUCOSE AND HbA1c
Fasting plasma glucose is highly vulnerable to a number of preanalytical variables such as sample storage, elevated within-subject biological variability, acute stress, diurnal variations, and common drugs which influence glucose metabolism (such as corticosteroids, fibrates, cyclosporine, beta-blockers, sulfamethoxazole, thiazide diuretics, and thyroid hormones).37 HbA1c has a lower diagnostic performance in specific populations such as pregnant women, the elderly, and non-Hispanic blacks. It can overdiagnose diabetes in the presence of iron deficiency anemia (i.e., hemoglobin <130 g/L in males and <120 g/L in females) and in subjects genetically predisposed to hyperglycation.38 HbA1c is also prone to error in subjects with increased red blood cell turnover (e.g., hemolytic anemia, major blood loss, athletes), end-stage renal disease, or heavy alcohol consumption. HbA1c estimation can be greatly imprecise when methods other than high pressure liquid chromatography (HPLC) are used. It is more expensive compared to blood glucose measurement. In the presence of genetic hemoglobin variants (hemoglobin S and C traits, elevated fetal hemoglobin, chemically modified derivatives of hemoglobin such as carbamylated hemoglobin as seen in patients with impaired renal function), HbA1c estimation accuracy can get substantially affected. The bias in HbA1c estimation is mainly dependent on the specific hemoglobin variant and the method used for measuring HbA1c.397
OTHER METHODS FOR MONITORING GLYCEMIC CONTROL
Glycated Albumin and Fructosamine
Human serum albumin accounts for 60–70% of the total serum proteins and has a serum half-life of approximately 20 days. The protein consists of a single polypeptide chain of 585 amino acid residues and serves as a protein reservoir, and it has the ability to bind, stabilize and transport metabolic products, regulatory mediators, nutrients, ions, and other proteins in the blood. Serum albumin has a high sensitivity to glycation and has shown to serve as a biomarker of hyperglycemia. Glycation is a nonenzymatic process, also known as Maillard reaction. The rate of nonenzymatic glycation of albumin is approximately 9- to 10-fold higher than that of human hemoglobin. Glucose and other sugars react spontaneously with the free amino terminal residues of serum proteins, specifically lysine and arginine.40 The free aldehyde group of the carbohydrate condenses with the N-terminal amino acid of the protein to form a reversible Schiff base product (the aldimine intermediate), which then is further reconverted to glucose and protein or undergoes an Amadori rearrangement to form a fructosamine. The term “fructosamine,” therefore, refers to all ketoamine linkages that result from glycation of serum proteins. Since albumin is the most abundant of serum protein, fructosamine is therefore a measure of glycated albumin. Other circulating proteins, such as glycated lipoproteins and glycated globulins, may contribute to determine the total concentration of fructosamine. Since the half-life of albumin is approximately 14–21 days,41 fructosamine or glycated albumin provides information on blood glucose control mostly limited to the previous 2 weeks. Glycated albumin allows for an earlier detection of rapid changes of blood glucose.42 Fructosamine and glycated albumin seem useful not only as biomarkers of glycemic control in conditions in which HbA1c is unreliable, but also for identifying impaired control of blood glucose before any noticeable changes in HbA1c may occur. Colorimetric-based assays are the most widely used assays. The use of nonionic detergent containing uricase has greatly eliminated the interference from uric acid and polylysine, allowing for more accurate and sensitive measurement.43 Due to the technical nature of the assay, molecules with reducing activity such as bilirubin and vitamins may interfere in the measurement, thus biasing test results, especially when present in large concentrations. The concentration of glycated hemoglobin can be directly measured by several methods, including boronate affinity chromatography, ion exchange chromatography, high-performance liquid chromatography and immunoassays, Raman spectroscopy, refractive index measurements, capillary electrophoresis, and other electrophoretic techniques, but their usefulness has been challenged by requirements for dedicated instrumentation and poor analytical performance. A user-friendly, highly accurate, and automated enzymatic assay (Lucica GA-L kit, Asahi Kasei Pharma, Tokyo, Japan) has been developed.44 Levels of fructosamine and glycated hemoglobin may be modified in patients with protein-losing states (nephrotic syndrome, hepatic cirrhosis, protein-losing enteropathy) and thyroid disease.45 Physiologic or pathologic conditions linked to hypoproteinemia (i.e., pregnancy or malnutrition) can affect the concentration of fructosamine and it is considerably influenced by 8elevated levels of immunoglobulins, especially immunoglobulin A (IgA), which are present in abnormal concentration in a broad range of clinical conditions.46 Given the higher specificity and accuracy, glycated albumin testing is preferred over that of fructosamine.47
SELF-MONITORING BLOOD GLUCOSE
Self-monitoring blood glucose (SMBG) involves self-monitoring/checking of capillary blood glucose (finger prick) using a glucometer device. According to the ADA, SMBG should be performed at least three times a day.48 The United States Food and Drug Administration49 recommends that 95% of all SMBG readings be within ±15% of a standardized laboratory method for blood glucose estimation and 99% of all SMBG readings within ±20% of a standardized laboratory method for blood glucose estimation. The International Standards Organisation 15197:2013 recommends that 95% of all SMBG readings should be within ±15% for blood glucose ≥100 mg/dL and within ±15 mg/dL for blood glucose <100 mg/dL.50
Types of SMBG include:
- Short periods of intense SMBG, before each meal, after each meal (six points if three main meals are consumed daily), 2–3 days per week.
- Staggered schedule SMBG (done at various times of day throughout the week).
- Preprandial and 2-hour postprandial SMBG which can give the patient an immediate feedback on his/her food choices 2–3 days a week.
A meta-analysis of 1,557 studies and 12 randomized controlled trials (RCTs) with a total of 3,350 patients (noninsulin-treated T2DM) showed that the use of SMBG 8–14 times per week correlated with a better HbA1c at 6 months (–0.46%) and 12 months (–0.20%) compared to those who did not perform SMBG. Up to seven measurements of SMBG per week, however, did not significantly affect glycemic control. SMBG performed between 8 and 14 times per week was also associated with improved BMI (–0.46 kg/m2).51
The advantages of SMBG include the following:
- It helps the patient understand the relationship of food with his/her blood glucose and make proper lifestyle choices.
- It helps the healthcare provider titrate the medication; for example, an elevated fasting glucose level can help the healthcare provider use medication that targets hepatic glucose output.
- It helps reduce the anxiety of hypoglycemia.
- It helps mitigate high or low glycemic levels during the performance of hazardous tasks such as driving or operating machinery.
The disadvantages of SMBG include the following:
- It requires a level of education and self-motivation which may not be present in patients, particularly from low-income countries.
- It only provides a single “point-in-time” estimation of blood glucose and may lead to inappropriate therapy decisions.
- It may increase anxiety regarding glycemic control.
- It often fails to detect nocturnal and asymptomatic hypoglycemia.
- It could be cost-ineffective in the short term but may be cost-effective in the long term as was seen in a Spanish study52 that showed that the average cost of T2DM complications per patient was estimated to be approximately €4121.54 (66% due to macrovascular complications), whereas the cost of the test strips accounted for approximately 2% of the expenditure.
When should Therapeutic Action be Taken Based on SMBG?
If >2 out of 5 readings for fasting glucose or postprandial blood glucose values remain outside the target range within a defined time period, then the following actions should be taken:
- For fasting hyperglycemia, drugs to target hepatic glucose output (maximum tolerated insulin sensitizers, failing which drugs that inhibit glucagon, such as gliptins or glucagon-like peptide 1 receptor analogs, may be considered, failing which oral secretagogues or basal insulin with the least risk of nocturnal hypoglycemia may be considered) can be used in various combinations.
- For postprandial hyperglycemia, either reduce the carbohydrate content of the meal to reduce post-meal glucose excursion or use drugs which particularly target postprandial hyperglycemia [gliptins, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glinides, alpha-glucosidase inhibitors (AGIs), glucagon-like peptide-1 (GLP-1) analogs, short-acting or ultra-short-acting prandial insulins].
- For hypoglycemia (glucose levels below 70 mg/dL), either increase the carbohydrate intake or reduce the dose of hypoglycemic drugs.
Benefits of SMBG
A study showed that patients who performed SMBG more than once per day showed a reduction in HbA1c of approximately –0.7%. SMBG was seen to help reduce HbA1c levels to <7%; however, it was necessary to carry out SMBG at least six times a day.53 The results of the St Carlos study in newly diagnosed T2DM patients (n = 130 for SMBG vs. n = 65 for HbA1c-based control group), followed for 3 years, showed that diabetes regression was 4.5 times more likely in the SMBG group and was associated with greater adherence to dietary and physical activity. The intervention group (SMBG) also showed weight loss of 4 kg.54 A meta-analysis of RCTs (n = 8) analyzed the use of SMBG (vs. no monitoring), structured SMBG (vs. unstructured), and SMBG-driven therapy adjustments in noninsulin-treated T2DM and showed that SMBG helped reduce HbA1c by –0.17% compared to no SMBG and the use of structured SMBG helped reduce HbA1c by –0.27% compared to unstructured SMBG.55
CONTINUOUS GLUCOSE MONITORING AND CONCEPT OF “TIME IN RANGE”
Continuous glucose monitoring (CGM) is a valuable tool for both T2DM patients and healthcare professionals to monitor ambulatory glucose in a continuous 10manner so that important therapeutic interventions may be exercised. Several diabetes organizations have concluded that CGM may be a useful educational and management tool, particularly for patients on insulin therapy. The future of CGM is evolving rapidly as are the indications for its use in T2DM. CGM warns users of hypoglycemia and/or hyperglycemia.56
Requirements
- Glucose sensor: This is inserted subcutaneously to measure glucose levels in interstitial fluid.
- Glucose reader: This records the glucose digitally/graphically by recording data from the sensor and creates visually attractive data that identifies time in range, above range, and below range.
Most CGM systems have Bluetooth-enabled services that involve applications on mobile phones/computers that create color-coded visually attractive data, thus helping the patient establish positive or negative relationships of food intake with therapy.
CGM may be either:
- Real-time CGM (rtCGM): Trends in glucose variation can be viewed real time and can warn users of hypoglycemia or hyperglycemia.
- Intermittent viewing CGM (iCGM) or flash glucose monitoring (FGM) system: This records trends of glucose variation that can only be viewed after physically scanning the sensor.
- Personal CGM: The CGM system owned by the patient and used at home with real-time glucose reading.
- Professional CGM: Clinic-based loaner distribution model for intermittent use.
Examples of CGM include the following:
- Libre Pro Flash Glucose Monitoring System (Abbott Diabetes Care): This system does not require any calibration and the lifespan of the glucose sensor is 14 days. The device may inaccurately indicate hypoglycemia. Results from a clinical study indicated that up to 40% of the time, when the device indicated hypoglycemia (blood sugar ≤60 mg/dL), the subject's glucose values were actually in the range of 81−160 mg/dL. It does not provide real-time results, and patients should be encouraged to adhere to their blood glucose monitoring routine while using the system. High levels of ascorbic acid (Vitamin C), salicylic acid (used in Aspirin), severe dehydration, or excessive water loss may give inaccurate glucose results. It is not approved for pregnant women, patients on dialysis, or critically ill people. Sensor placement is approved only for the back of the arm.57 The use of FGM was tested in the REPLACE trial58 in patients with insulin-treated T2DM and the study found no significant differences in HbA1c using either FGM or SMBG.
- Dexcom G4 Platinum (Dexcom) rtCGM: This system requires two daily calibrations and the lifespan of the glucose sensor is 7 days. It has a built-in Bluetooth wireless communication system. It monitors real-time glucose activity and uses a small sensor, transmitter, and a Dexcom Receiver. The sensor records glucose readings every 5 minutes. It provides high/low 11glucose alerts and alarms. The Dexcom G6 features a 10-day wear sensor and is water-resistant and easy to insert with an Auto Applicator.59 G4/5 systems are affected by acetaminophen blood concentration, but the G6 system is not.
- iPro2 Professional (Medtronic diabetes) rtCGM: This system is another example of rtCGM which records glucose readings every 5 minutes for up to 6 days. It does not require calibration. It is affected by acetaminophen blood concentration.60
- Eversense (Senseonics, Inc.) CGM 90 days system rtCGM: This system involves a sensor that is placed professionally under the skin by a trained healthcare provider and a receiver/transmitter which is rechargeable, removable, and water-resistant that receives glucose readings every 5 minutes (real time) from the sensor and provides alerts when the mobile phone is not nearby. It is not affected by acetaminophen blood concentration.61
Efficacy of CGM and Comparison with SMBG
A study analyzed the efficacy of rtCGM (2 weeks on, 1 week off for 12 weeks, using interstitial glucose measured every 5 minutes, giving a total of 288 data points over a 24-hour period) in 100 T2DM patients who were not on prandial insulin62 versus SMBG done four times per day. Patients were on therapies, including diet and lifestyle only, or on various combinations of antihyperglycemic therapies, including basal insulin. The rtCGM group showed a mean unadjusted HbA1c reduction of −0.5% compared to SMBG group at week 12, with reduction in HbA1c of −0.6% at week 52. The HbA1c reduction occurred in the absence of medication intensification or increased hypoglycemia, suggesting that behavior and lifestyle modification resulted in significant benefits. Intermittent use of rtCGM may help patients with T2DM to avoid burnout.63 A meta-analysis of four RCTs showed that the use of rtCGM in T2DM helped improve HbA1c by –0.31%.64 A systematic review and meta-analysis concluded that the use of CGM is beneficial and significantly reduces HbA1c (−0.25%) compared to the usual method of SMBG.65 Another meta-analysis of seven RCTs (n = 669 patients) that compared CGM with SMBG showed that patients who used CGM exhibited significantly lower HbA1c levels (–0.35%) and suffered from hypoglycemia for a short time compared to those who used SMBG.66
“Time in Range”
The International Consensus in Time in Range (IC-TIR) defines TIR based on the readings of glucose provided from interstitial fluid via CGM which are as follows:
- “TIR” for patients with T2DM refers to a standardized primary glucose range between 70 and 180 mg/dL and occasionally between 70 and 140 mg/dL as a secondary range (regulatory issues and comparability studies) with data extracted from sensors, for at least 10 days, though 14 days are preferred. For T2DM, glucose values are required to stay >70% within TIR over 24 hours and <25% in hyperglycemia, <4% time below TIR (<70 mg/dL, <1 hour in 24 hours; <1% below 54 mg/dL; <15 minutes in 24 hours). This has been associated with an HbA1c <7%, with minimum glycemic variability. For the frail T2DM, >50% of glucose values are to be within TIR and >90% below 250 mg/dL, <1% time below TIR (<70 mg/dL, <1 hour in 24 hours).12
- Hyperglycemia [time above range (TAR)]: It is classified as level 1 (alert level, >180 to <250 mg/dL), level 2 (clinically significant, >250 mg/dL), and level 3 (ketoacidosis or hyperosmolar hyperglycemic state).
- Hyperglycemic exposure is expressed as the percentage of time with glucose values >180 mg/dL.
- Hypoglycemia [time below range (TBR)]: It has major clinical significance and is classified as level 1 (between 54 and 70 mg/dL), level 2 (<54 mg/dL), and level 3 hypoglycemia assistance by a third party without a specific value of blood glucose.
- Hypoglycemic episode is defined when the sugar is <70 mg/dL and lasts for at least 15 minutes. The cessation of a hypoglycemic episode should be considered only 15 minutes after blood glucose reaches the normal range values.67
Correlation of Time in Range with HbA1c
A study compared articles that reported paired HbA1c and %TIR metrics (n = 1,137). There was an excellent correlation between the two (R = –0.84; R2 = 0.71). It was seen that for every absolute 10% change in %TIR, there was a 0.8% (9 mmol/mol) change in HbA1c.68 Data from four randomized clinical trials (n = 530, T1DM and insulin-requiring T2DM) showed that CGM-derived metrics (TIR) correlated strongly with HbA1c and percentage of glucose values >250 mg/dL, but weakly correlated with the percentage of glucose values <70 mg/dL or <54 mg/dL. It was seen that when >90% of participants had either a mean glucose <140 mg/dL or TIR >80%, the HbA1c was ≤7.0%. For participants with HbA1c ≥8.0%, the median TIR was 44%, with 90% of participants having a TIR <59%.69
Does TIR Correspond to Improved Clinical Outcomes in T2DM?
A study analyzed (n = 3,262 T2DM Subjects) the relationship of TIR (assessed by CGM) and diabetic retinopathy. It was seen that patients with more advanced diabetic retinopathy had significantly less TIR and higher measures of glycemic variability.70 Another study analyzed the relationship of carotid intima-media thickness (CIMT) in 2,215 T2DM patients with TIR and found that subjects with abnormal CIMT had significantly lower TIR and with each 10% improvement in TIR, there was a 6.4% lower risk of abnormal CIMT.71
CONCLUSION
Hyperglycemia represents the start of a vicious cycle that eventually leads to complications and multiple-organ dysfunction that is called diabetes mellitus. This is represented by an average blood glucose value of HbA1c ≥6.5% although it may be lower for certain ethnic communities (South Asians, etc.), and it is important to define the specific point at which diabetes develops. For now, even in South Asians, an HbA1c of 6.5% is considered diagnostic of diabetes 13mellitus. Optimal screening methods include the use of OGTT and HbA1c. Glycated albumin and fructosamine represent alternate short-term methods for assessing glycemic control. CGM with the concept of TIR seems most intriguing which may help patients not only achieve their HbA1c goals but also reduce glycemic variability. Coming back to the case, it is important to confirm the diagnosis of diabetes mellitus by subjecting the patient to a glucose tolerance test. On performing the test, we established his diagnosis as diabetes mellitus. We also found that his triglycerides were 450 mg/dL, highly sensitive C-reactive protein was 12.5 ng/dL, high-density lipoprotein cholesterol was 29 mg/dL, and liver enzymes were suggestive of biochemical transaminitis consistent with a fatty liver.
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