Glycemic Variability

Glycemic VariabilitySpeaker NameGlycemic VariabilityGlycemic Variability (GV) means swings in blood glucose levelGlycemic VariabilityDiminished glycemic auto-regulation or insulin shortage are hypothesized etiological factors for these glycemic bumps.

High Glycemic VariabilityLow Glycemic VariabilityDCCT & UKPDSDCCT - tight glycemic control is of paramount importance in preventing late-stage complications of T1DM, especially cardiovascular complications.

UKPDS - confirmed the positive effect of tight glycemic control in the prevention of micro-vascular complications in T2DM.

Both studies demonstrated good correlation between HbA1C and patient-relevant endpoints

DCCT- Diabetes Control and Complications Trial ; T1DM- Type 1 Diabetes MellitusUKPDS- United Kingdom Prospective Diabetes Study; T2DM- Type 2 Diabetes Mellitus

Patients with similar HbA1C levels can have different Glucose variability parametersKohnert KD, et al; Horm Metab Res 2009; 41: 137 141Glycemic VariabilityThere is a growing body of evidence that not only the average HbA1c values, but also short-term glycemic peaks and nadirs (lasting minutes or hours), represent an independent risk factor for complications of diabetes.

These short term glycemic peaks and nadirs represent glycemic variability

GV & its Risk FactorsCan be of 2 Types: within day variability- with differences between fasting and postprandial blood glucose values throughout 24 hoursbetween day variability- reflecting differences in blood glucose control from day to day

Risk Factors:Erroneous dosage and timing of anti-diabetic drugsInadequate medicationImproper adherence to the treatmentImproper dietLack of exercise

GV & Post-prandial GlucoseGV takes into account the intraday glycemic excursions including episodes of hyperglycemia & hypoglycemia.

Major contribution to GV by PPG as most time spent in the post-prandial state.

Also PPG correlates better with HbA1C as compared to FPG.

Variations in HbA1C is indicative of long term glucose variability.

Variation in intraday FPG and PPG is indicative of short term variability.

PPG- Post-prandial Plasma Glucose; FPG- Fasting Plasma GlucosePPG vs FPGPPG correlates better with HbA1C as compared to FPG.

HbA1CHbA1CAvignon A et al. Diab Care 1997;20:1822-1826

Hyperglycemic spikes following every meal induce oxidative stress, endothelial dysfunction and inflammatory reactionsNode K et al, Cardiovascular diabetology; 2009; 8:23

Weber C et al, Diabetes Technol Ther. 2009 Oct;11(10):623-33Measures of Glycemic Variability

SD- Standard Deviation; CV- Co-efficient of Variance; MAGE- Mean Amplitude of Glycemic Excursions;CONGA- Continuous Overall Net Glycemic Action; MODD- Mean of Daily Differences12Measures of Glycemic VariabilitySeveral methods to quantify glucose variability

No universally accepted gold standard

SD & CVEasiest way is to calculate SD (standard deviation) or CV (co-efficient of variation) from the glucose measurements

Possible to calculate SD and CV with seven-point glucose curve

But, in 7 point glucose curve some peaks and nadirs will be missed SD & CV less accurateMeasures of Glycemic VariabilityM-value Measure glucose excursions via six SMBG values per 24 hrs.The M-value is 0 in ideal controls which rises with increasing glycemic variability or poorer glycemic controlLimitations - Number of readings are less and makes it difficult to distinguish whether patient has high mean glucose or high glucose variability

MAGE (Mean amplitude of glycemic excursions)Most widely used methodHourly blood glucose sampling for 48 hrs, CGM data can also be usedGenerates a value for variation around a mean glucose levelIt ignores excursions less than 1 SDMay incorrectly disregard smaller excursionsSMBG- Self Monitored Blood Glucose; CGM- Continuous Glucose MonitoringContinuous Glucose Monitoring Systems (CGMS)Glucose measurements every 10 sec/Average level every 5 min

Sensor containing glucose oxidase

Electric current generated by oxidation of glucose

Electric current correlated with glucose level

Glucose is not displayed instantly

Continuous measurements for 72 hours

Measures of Glycemic VariabilityCONGA (Continuous overlapping net glycemic action)Developed specifically for CGM dataIt is calculated as the SD of the summated differences between a current observation and an observation n hours previously. Because CONGA does not require arbitrary glucose cutoffs or arbitrarily defined rises and falls, it seems to be a more objective manner to define glucose variability than M-value or MAGELimitation cannot be calculated on SMBG data & CGM data in daily practice is not feasibleMeasures of Glycemic VariabilitySerum measurement of 1,5-anhydroglucitol (1,5-AG)Its re-absorption in the kidney is inhibited by excessive excretion of urinary glucoseThe higher the plasma glucose concentration, the lower the plasma 1,5-AG concentrationUrinary glucose seen at 160-190 mg/dl.Hence, of little use in patients below this level

SD is the easiest way to quantify glycemic variability.

As easy to measure, it is the only measure which has demonstrated correlation between GV and patient-related outcomes i.e. mortality in ICU patients

Metabolic Effects of GVGV was significantly higher in the insulin treated group as compared to the diet only and oral drug treatment group.GV had a positive correlation with age, diabetes duration, HbA1C.GV had a negative correlation with HDL, weight, BMI and WC.GV showed no correlation with the lipid parametersGV significantly correlated with 10 year risk of CHD and fatal CHD.373 T2DM patientsGV was measured via MAGE, SD, MG, nMAGE For patients controlled on Diet, oral or insulin therapyCorrelated with age, diabetes duration, weight, BMI, WC, Cholesterol, LDL, HDL, TG &HbA1C Gribovschi et al. Appl Med Inform 2013; 32(1): 53-60.BMI- body mass index, WC- Waist Circumference,LDL- Low Density Lipoproteins, HDL- High density lipoproteins, CHD- coronary heart disease; MG- Mean interstetial glucose measurementsGV & Oxidative StressHyperglycemia drives production of reactive oxygen species (ROS) via 4 mechanisms:

the polyol pathwaythe hexosamine pathwayprotein kinase C activationformation of advanced glycation end-products

ROS defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of pro-inf ammatory genes even after glycemia is normalized

GV & Oxidative StressDifferent complications (eye, kidney, nerve, blood vessels) arise from a number of triggers perturbing a number of metabolic pathway(s)

The urinary excretion rate of 8-iso-PGF2, a reliable marker of oxidative stress, was found to be strongly, positively correlated (r = 0.86, p < .001) with glycemic variability assessed from the mean amplitude of glycemic excursions (MAGE) as estimated by continuous glucose monitoring systems (CGMS).Monnier et al, Diabetes Care 31 (Suppl. 2):S150S154, 2008Normo-insulinemic, hyperglycemic glucose clamp study

Different concentrations of glucose given as single spike or oscillating between basal and high levels over a 24 hr period

T2DM paitients and healthy controls were studied

Suggested that oscillating glucose levels enhances oxidative stress & has more deleterious effects on endothelial function as compared to constant high glucose levels

Ceriello et al, Diabetes 2008;57:1349-54GV and MicroangiopathyHyperglycemia has been known to cause endothelial apoptosis and arterial denudation.

This increased ROS d/t GV will augment the endothelial damage and dysfunction.

This endothelial dysfunction can lead to a number of micro- and macro-vascular complications.

In vitro, animal & some human studies consistently report a deleterious effect of intermittently high glucose as compared to constant high glucose levels

However, human studies performed are less consistent in their findings

GV & Diabetic ComplicationsMicrovascular and macrovascular complications are dependent on dysglycemia, which has two components:chronic sustained hyperglycemiaacute glycemic fluctuations from peaks to nadirs.

Hence, global antidiabetic strategy should be aimed at attacking different components of dysglycemia (i.e., HbA1C, FPG, PPG, as well as glucose variability).

GV & Microvascular ComplicationsBragd et al, GV was found as a independent predictor of peripheral neuropathyHowever, no relation was found with other microvascular complications like retinopathy or neuropathy

Oyibo et al, relation between painful neuropathy and M-value calculation

Gimeno-Orma et al, correlation was found between diabetic retinopathy and GV of FBGDiabetic retinopathy increased with a increased FBG variation

Zoppini G et al, GV of FBG significantly associated with diabetic retinopathyDiabetes Metab 2008;34:612-6Diabet Med 2002;19:870-3J Diabetes Complications 2003;17:78-81Nutr Metab Cardiovasc Dis 2009;19:334-9.GV & Macrovascular ComplicationsStudies produced controversial results for relation of GV & cardiovascular complications

Gordin et al, arterial stiffness was not correlating to GV but was positively associated with changes in SBP & DBP

Verona diabetes study in elderly T2DM, GV-FPG was found as an independent predictor of all-cause mortality

DIGAMI 2 Trial, assessed relation between GV & cardiovascular complications in patients with AMI & T2DMThe 1-year risk for death, reinfarction, or stroke did not relate to glycaemic variability in T2DM patients with AMIDiabetes Res Clin Pract 2008;80:e4-7Circulation 1997;96:1750-4Eur Heart J. 2013 Feb;34(5):374-9SBP- Systolic Blood Pressure; DBP- Diastolic Blood Pressure;AMI- Acute Myocardial Infarction; DIGAMI- Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial InfarctionGV & Critically Ill PatientsConvincing relation between short term GV and death in critically ill patients

Dossett et al, Egi M et al, Krinsley J, all concluded that that GV measured as SD was significant predictor of mortality in critically ill patients, irrespective of severity of illness

However, in the subgroup of diabetic patients, no correlation between GV and death was seen

Wintergerst et al, Hirschberg et al, showed similar correlation between GV & mortality in pediatric ICU patients.

Interventional studies are still lackingAm Surg 74: 67985Anesthesiology,105:24452Crit Care Med,36:300813Pediatr Crit Care Med, 9:3616Pediatrics 118: 1739ICU- Intensive Care Unit

Hospital mortality related to mean glucose and glycemic variability. Q1-Lowest quartile of glycemic variability; Q4-highest quartile of glycemic variabilityJ.S. Krinsley: Crit Care Med 2008;36:300813GV and Autonomic Neural ImbalanceChronic hyperglycemia is involved in the development of autonomic neural imbalance.

However, it has been suggested that acute fluctuations (GV) in glucose levels lead to an increased level of circulating cytokines and ROS.

Sustained hyperglycemia; cytokines & ROS (d/t acute fluctuations) can lead to destruction of the myelin sheath and nerve fiber damage leading to Diabetic Autonomic Neuropathy (DAN).

GV and Autonomic Neural Imbalance

Fleischer J et al, J Diabetes Sci Technol 2012; 6(5): 1207-15.GV and Autonomic Neural ImbalanceJamali et al, hypoglycemia affects more the somatic motor nerves whereas hyperglycemia affects only somatic sensory nerves.

Ohlsson et al, demonstrated that parasympathetic dysfunction was associated with increased glucose fluctuations in 20 diabetic patients.

Literature mentions DAN, can be an early risk marker for diabetic complications.

Fleischer J et al, cross sectional study, in 653 diabetic patients autonomic imbalance was associated proliferative retinopathy, micro- and macro-albuminuria and obesity.Fleischer J et al, J Diabetes Sci Technol 2012; 6(5): 1207-15.GV and Mood DisordersGV is also said to be associated with mood disorders and decreased quality of life.

Cox DJ et al, demonstrated that negative mood (depression, anxiety) and cognitive symptoms (difficulty concentrating, slowed thinking) were associated with within-day glucose variability in 60 T2DM patients.

Penckofer S et al, those with diabetes and co-morbid depression had higher anxiety, more anger, and reduced quality of life.

Also, higher anxiety traits were associated with steeper glucose excursionsCox DJ et al, Diabetes Care 2007; 30(8): 2001-2Penckofer S et al, Diabetes Technol Ther 2012;14:303-10

GV & Quality of LifeFrequent fluctuations in blood glucose with hypoglycemia and glycemic excursions are associated with a poor quality of lifePenckofer et al, demonstrated large GV was associated with low quality of life as compared to HbA1c and average BG.Glucose Triad vs Glycemic Pentad

FPGPPGHbA1CFPGPPGHbA1CGVQoLPenckofer S et al, Diabetes Technol Ther 2012;14:303-10BG- Blood Glucose; QOL- Quality of LifeMeasures to Minimize GVLife style measuresDiet & exercise induced weight loss can significantly improve insulin sensitivity & beta-cell functionReducing glucose excursions along with the average glucose levels

Alpha-Glucosidase Inhibitors

HbAlc and plasma glucose in the patients who had received voglibose were comparable to those of patients in the control group

M-value was lower in the patients treated with voglibose than in the control subjects

1,5-AG was higher in the patients treated with voglibose than in the control subjects

A statistically significant decrease in AUCinsulin occurred after treatment with voglibose

Insulin sensitivity was improved to a statistically significant level in the patients treated with vogliboseDiabetes Care 1998; 21(2): 256-60.1,5-AG- 1,5-anhydroglucitolAlpha-Glucosidase Inhibitors

Study using CGMS measures of glucose intraday variability, MAGE, SD, mean glucose levels, CONGA and interday variability, MODD. All were found to be significantly reduced when treated with acarbose + metformin in a 16 week intention-to- treat study in comparison to glibenclamide + metformin

Drugs like alpha-glucosidase inhibitors which target post-prandial Hyperglycemia, not only reduce the glycemic excursions but also reduces oxidative stress and improve endothelial function

Diabetes Technology & Therapeutics 2009,11(6): 339-44InsulinsIn T1DM & T2DM, treatment with long-acting analogs has been shown to diminish hypoglycemia and glucose variability.

Prandial insulins, and even more short-acting analogs, diminish postprandial hyperglycemia and consequently glucose variability specifically in type 2 diabetes patients.

Use of continuous sc insulin infusion is in type 1 diabetes associated with a decrease in glucose variability

Whether diminishing glycemic variability in these patient groups translates into improved outcome is unknownSc- Subcutaneous

ConclusionGV seems related to oxidative stress and endothelial dysfunction

Apart from the standard glycemic parameters, GV can also be a target for optimal glycemic control

Applicable in T1DM, T2DM, gestational diabetes and critically ill patients

Studies have shown, although not conclusively, improved outcome in micro- & macro-vascular complications

Inspite of all the formulas, a simple and standard formula is yet to evolve.

Various treatments like alpha-glucosidase inhibitors, GLP-1 agonists, basal and prandial insulins have shown to significantly improve GV

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