Diabetes Mellitus - Targets for Control

By Prof. Dr. Leslie Charles Lai Chin Loy   Clinical Consultant (Clinical Biochemistry)  Diabetes mellitus is a pandemic and its prevalence is increasing worldwide with dire health consequences for those afflicted with the condition. Around 50% of diabetics die of myocardial infarction and 25% die of cerebrovascular accident. In addition, diabetes is the commonest cause of blindness, end-stage renal disease and amputations in the world. The risk of macrovascular (coronary heart disease, stroke and peripheral vascular disease) and microvascular (retinopathy, nephropathy, peripheral and autonomic neuropathy) complications can be reduced by treating blood glucose, lipids and blood pressure to target. At the 6th International Diabetes Federation Western Pacific Region Congress in Bangkok, 22nd till 26th October 2005, the 4th Edition of 'Type 2 Diabetes Practical Targets and Treatments' was launched. The targets for control are shown in Tables 1 and 2. Table 1. Targets for Control Parameter Target HbA1c <6.5% (DCCT-aligned assay) Blood Pressure <130/<80 mmHg Total Cholesterol <4.5 mmol/L (<174mg/dl) LDL Cholesterol <2.5 mmol/L (<97 mg/dl) HDL Cholesterol >1.0 mmol/L (>39 mg/dl) Triglycerides <1.5 mmol/L (<133 mg/dl) Urinary albumin:creatinine <2.5 mg/mmol in men <3.5 mg/mmol in women Table 2. Recommended Targets for Glycaemic Control HbA1c Fasting plasma glucose / prepandial plasma glucose 2 hour postprandial plasma glucose <6/5% (DCCT-aligned assay) 4.4-6.1 mmol/L (80-110 mg/dl) 4.4-8.0 mmol/L (80-145 mg/dl) While we should attempt to treat people with diabetes to target, it is important to realise that failure to reach a target should not be seen as failure to achieve a benefit for the patient. All improvements are beneficial, whether or not a target is reached. The gold standard for assessment of long-term glycaemic control is HbA1c which reflects the glycaemic control over the previous two to three months. HbA1c should be used as the prime determinant of success of glycaemic control and of the need to change therapy. Where red cell turnover is shortened, e.g. in patients with haemoglobinopathies such as thalassaemia, the HbA1c is unreliably low. The urine microalbumin:creatinine ratio should preferably be done on the first void urine in the morning. There is considerable intra-individual variation (biological variation) in urine microalbumin levels even in healthy adults. In healthy individuals, the coefficient of variation (CV = mean/SD x 100%) of microalbumin to creatinine ratio in early morning urines (first void urine) is 31% whereas the CV is 103% on random spot urine samples obtained from healthy individuals. In diabetics, the CV of microalbumin to creatinine ratio on early morning urine specimens is 39%. 24-hour urine microalbumin excretion rate has a CV of 70% in healthy individuals (Howey, et al., Clinical Chemistry 1987,33: 2034-2038). There is now a global initiative to standardise HbA1c using the reference material, calibrators and primary reference methods developed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). An International Diabetes Working Group (IDWG) has been established comprising representatives from the International Diabetes Federation (IDF), European Association for the Study of Diabetes (EASD), American Diabetes Association (ADA), IFCC and the National Glycohemoglobin Standardisation Program (NGSP; DCCT-aligned). The IDWG has recommended that the IFCC-HbA1c should be used worldwide but implementation of this may be after 2008. The current direct comparison method used in the NGSP standardisation (method used in Direct Control and Complications Trial) is not very specific. Existing methods for measuring HbA1c (DCCT-aligned) have CVs (measure of imprecision) of around 3-4%. If an assay has a CV of 3% we cannot differentiate between an HbA1c value of 7.0% and 7.9%! IFCC-HbA1c values will be true HbA1c values. Methods for measuring HbA1c which are calibrated using the IFCC calibration materials have better precision than the DCCT-aligned methods, with intra-assay and inter-assay CVs of less than 2.0%. This improved precision may make it possible to use HbA1c to diagnose diabetes. Since the IFCC-HbA1c values are 'true' values they will be lower than the DCCT-aligned HbA1c values. The relationship between NGSP-HbA1c and IFCC-HbA1c is given by the master equation below and a comparison of NGSP-HbA1c and IFCC-HbA1c values is given in Table 3. Master Equation: NGSP-HbA1c = 0.915(IFCC-HbA1c) + 2.15% r2= 0.998 Table 3. Comparison of NGSP-HbA1c and corresponding IFCC-HbA1c values NGSP %HbA1c IFCC %HbA1c 4 2.1 5 3.1 6 4.2 7 5.3 8 6.4 9 7.5 10 8.5 11 9.6 12 10.7 Since the IFCC-HbA1c values are lower than the NGSP-HbA1c values there could be some confusion when the IFCC-HbA1c values are introduced. As such, the IDWG has recommended that the IFCC-HbA1c values should be reported as mean blood glucose levels. Studies are currently underway to assess the robustness of the relationship between IFCC-HbA1c and mean blood glucose level and to assess the dispersion of mean blood glucose values around the regression line. I will give a more detailed account of the global standardization of HbA1c in a future issue of the newsletter.