GLYCAEMIC CONTROL

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CHAPTER 3 GLYCAEMIC CONTROL

OVERVIEW

To achieve and maintain the targets (Table 3.1) of optimal glycaemic control can be difficult because of the progressive deterioration of pancreatic insulin secretion. Success is more likely if the patient, in collaboration with the professional and guided by monitoring of glycaemic control, masters the complex task of balancing the three key components of diet, physical activity and blood glucose-lowering medication dosage.

TABLE 3.1 Targets for optimal glycaemic control

Target Who monitors Action
Avoiding hypoglycaemia Patient Recognises warning signs
  Balances regular meals, correct dose of therapy and physical activity
Able to correct promptly
Professional Assesses needs and educates
Fasting blood glucose of 4 to 7 mmol/l Patient Able to do and interpret tests
Adjusts therapy accordingly
Professional Assesses needs and educates
Glycated haemoglobin of less than 7.0%* Patient Understands significance of test result
Adjusts therapy accordingly
Professional Repeats regularly
Advises on appropriate therapy changes

* Individualised HbA1c targets should be set between 6.5 and 7.5%; the lower value is preferred for patients at significant risk of vascular complications, the higher may be more appropriate for those with limited life expectancy or at risk of iatrogenic hypoglycaemia

This chapter discusses self-monitoring and blood glucose-lowering medication. Diet and physical activity are discussed in Chapter 2.

MONITORING

Glycaemic control can be assessed in three complementary ways:

GLYCOSYLATED HAEMOGLOBIN (OR FRUCTOSAMINE)

Glycosylated haemoglobin, or HbA1c, is formed by the non-enzymatic glycation of part of the β-chain of haemoglobin. HbA1c levels correlate to the mean plasma glucose over the preceding 9–10 weeks. The relationship between HbA1c and mean plasma glucose levels is shown in Table 3.2. A recent HbA1c result should normally be available at the full periodic review. HbA1c should be checked more frequently when control is poor or glycaemic management has been altered. The estimation of HbA1c requires expensive equipment and stringent quality control: it is generally not feasible in primary care and is best done by a hospital laboratory.

TABLE 3.2 Correlation between HbA1c level and mean plasma glucose levels (Rohlfing et al 2002)

HbA1c (%) Mean plasma glucose level (mmol/l)
6 7.5
7 9.5
8 11.5
9 13.5
10 15.5
11 17.5
12 19.5

Serum fructosamine levels, if available, correlate to the mean plasma glucose over the preceding 1–2 weeks and may serve as an alternative if the HbA1c is not “valid”, such as in the presence of anaemia or a haemoglobulinopathy.

PATIENT SELF-MONITORING

Achieving and maintaining good glycaemic control usually requires effective patient self-monitoring and/or monitoring by his carer. Health education is an essential component of self-monitoring. The patient needs to be motivated and able to test accurately, interpret the results correctly and act upon them appropriately: this can only be achieved by regular patient education. Self-monitoring results should be recorded and brought to any diabetes review where glycaemic control is discussed.

Blood testing

Blood glucose testing is recommended for diabetics treated with insulin (both types 1 and 2), but may be desirable in patients on diet alone or oral medication, who require accurate blood glucose estimations. Blood glucose testing is more expensive than urine testing, and requires the correct use of a properly calibrated blood glucose meter and appropriate education to develop self-confidence in interpreting and acting upon test results.

Many varieties of finger-pricking lancets, blood glucose machines and test strips or sensors are now available, but only the lancets and strips/sensors can be prescribed on the NHS. Each different make of blood glucose machine has its own unique test strips. The current issue of the Monthly Index of Medical Specialities (MIMS) lists each make of test strip and the machine(s) with which it is compatible. There have been significant technical advances in machines, with sensors allowing the blood drop to be analysed outside the machine. A rigorous evaluation of the different blood glucose meters and lancing devices now available on the UK market was published in 2005 by the Department of Health’s Medicines and Healthcare products Regulatory Agency (details can be downloaded from its website, www.mhra.gov.uk). This useful source should assist in selecting the most suitable machine or device. Recently the MHRA has identified a safety problem with some blood glucose meters, where units of measurement may change and mislead the user.

Although blood glucose machines are not currently available on prescription, many are inexpensive, often costing less than £20 (the manufacturers’ main profit is in the sale of the test strips or sensors). If the GP writes a letter simply confirming the diagnosis of diabetes in a named patient, then that patient is exempt from paying Value Added Tax (VAT) when purchasing his machine, provided that the machine is intended for that patient’s personal use. Lancets need to be disposed of safely; preferably using either a needle clip or a sharps bin (both can be prescribed).

Most official guidance and Diabetes UK advocate regular home blood glucose monitoring, even in type 2 diabetics, but there is not yet a clear consensus on how frequently to test. The latest ADA guidelines recommend 2 to 3 times daily in patients with type 1 diabetes, but possibly more often in patients with type 2 diabetes on insulin (ADA 2007). However, an editorial in the British Medical Journal challenged the conventional advice given about frequency of testing; it suggested that regular monitoring is not always necessary and that properly conducted large-scale studies need to be done to determine whether more frequent testing will improve glycaemic control (Reynolds 2004). It is sensible to test more frequently if control is poor or if the patient is unwell.

Plasma glucose values are 11% higher than whole blood glucose values. Machines will be calibrated to either of these. The blood glucose targets for good control are 4–7 mmol/l pre-meal and < 10 mmol/l post-meal. If glycosuria or raised blood glucose is found, an increased dose of either the oral blood glucose-lowering drug or insulin may be appropriate. Dietary energy intake, if excessive, should be reduced. If the medication is given in divided doses, the dose that covers the tested time of day must be adjusted accordingly. However, if after stabilisation and despite adjustment of treatment, the blood glucose becomes > 20 mmol/l for more than 4 days, or if the patient becomes ill, then he should seek medical help urgently. Persistently abnormal levels should prompt a review of the balance between medication, diet and physical activity.

BLOOD GLUCOSE-LOWERING MEDICATION

In patients with type 2 diabetes, there is likely to be a progressive deterioration over time of pancreatic β-cell function, resulting in most patients eventually requiring insulin to achieve acceptable glycaemic control. The main classes of oral blood glucose-lowering medication act by improving either insulin secretion (insulin secretagogues) or insulin action. For a drug to stimulate insulin secretion, it is necessary for the pancreatic β-cells to still be functioning. Further details about the drug classes discussed below can be found in the British National Formulary (BNF, section 6.1.2).

A stepped approach to achieving and maintaining metabolic control is sensible. Starting with lifestyle changes and the early introduction of monotherapy, it moves progressively onto logical and effective combinations of different agents if the HbA1c remains greater than 7.0%. This is summarised in Table 3.3, with more than one option at some numbered steps, choice depending upon the clinical circumstances and patient preference (ADA 2007). It is the authors’ personal view that, in primary care, basal insulin is best introduced only when maximal oral therapy (including triple therapy, if feasible) cannot achieve good metabolic control.

TABLE 3.3 Summary of the stepped treatment of raised blood glucose in type 2 diabetes

At each numbered step, letter “a” is first choice option, subject to drug contraindications, clinical circumstances and patient preference.
Step Evaluation Intervention
1 HbA1c <7.0% Lifestyle advice (diet and physical activity)
2a

Metformin 2b Insulin secretagogue (usually sulphonylurea) or glitazone (alternative in renal impairment) 3a HbA1c ≥7.0% on first-line drug (maximum tolerated dose) Combination of: metformin and insulin secretagogue (usually sulphonylurea) 3b Combination of: metformin and glitazone 4a Combination of metformin and sulphonylurea and rosiglitazone 4b Add basal insulin* 5 HbA1c ≥7.0% on combination of basal insulin and oral agent(s) Intensify insulin regimen (consider adding rapid-or short-acting)

* Of the two glitazones, only pioglitazone currently has a licence to be prescribed in combination with insulin.

Changes to treatment should be guided not only by a recent HbA1c, but also self-monitoring results, opportunities to optimise lifestyle and the patient’s well-being and concordance. The interval between any dose changes must allow sufficient time for their effect to be seen, but prompt action is indicated in the event of repeated hypoglycaemia or significant hyperglycaemia. Ideally, additional medication should be introduced only after the maximum recommended dose of current medication has failed to achieve reasonable glycaemic control or is not tolerated.

Other medical problems must be managed appropriately. If uncertain about any aspect of management, it is sensible to seek specialist help.

INSULIN SECRETAGOGUES (DRUGS THAT IMPROVE INSULIN SECRETION)

Currently, there are two main groups of drugs that increase insulin secretion:

NICE’s Clinical Guidelines in 2002 recommended that “a generic sulphonylurea should normally be the insulin secretagogue of choice” (NICE 2002).

Sulphonylureas

This class of drugs acts by stimulating insulin secretion from pancreatic β-cells (although there is less stimulation of first-phase secretion than by the PPRGs), but do not affect insulin resistance. In the absence of ketonuria, sulphonylureas are indicated in nonobese patients whose blood glucose is not controlled by diet. Sulphonylureas can be combined with either metformin, a glitazone, basal insulin or acarbose. The following agents are available: tolbutamide, glibenclamide (glyburide), gliclazide (also available in a modified-release formulation), glimepiride, gliquidone, glipizide and chlorpropamide. Sulphonylureas should be introduced slowly with the dose titrated according to self-monitoring and HbA1c results.

The different sulphonylureas appear to have a comparable effect upon blood glucose-lowering, but with different durations of action. Although both once-daily and twice-daily dosing are associated with better concordance, once-daily preparations have the advantages of reducing the total number of tablets that a patient needs to take and of potentially simplifying the drug regimen.

Sulphonylureas are contraindicated in severe hepatic and renal impairment, porphyria, during breast feeding and pregnancy, or when ketoacidosis is present. The short-acting tolbutamide can be used in renal impairment, as can gliclazide and gliquidone, which are metabolised mainly in the liver.

The two main drawbacks associated with sulphonylureas are that they can induce hypoglycaemia and can encourage weight gain. Glibenclamide is associated with the rare but potentially fatal occurrence of nocturnal hypoglycaemia in the elderly. Weight gain was recorded with both chlorpropamide and glibenclamide (but less than with insulin) in the intensively treated group of patients in the UKPDS (UKPDS 1998). However, hypoglycaemia and weight gain are not inevitable with sulphonylureas, and the risks of either occurring may be minimised by:

The side-effects of sulphonylureas are mild and infrequent, and include gastrointestinal disturbances and hypersensitivity reactions (a skin rash that usually appears within 6–8 weeks of initiation).

Post-prandial regulators of glucose (PPRGs)

These drugs are also known as meglitinide analogues or rapid-acting insulin secretagogues. The two available drugs in this group are repaglinide and nateglinide. Both can be used in combination with metformin, but nateglinide is not currently licensed for monotherapy.

The main action of PPRGs is to increase (more than sulphonylureas) the first-phase insulin secretion in response to rising plasma glucose levels by pancreatic β-cells, with the effect of reducing the mealtime “glucose spike”. PPRGs are best initiated at an earlier stage in the disease process, when pancreatic β-cells have more capacity to secrete insulin. PPRGs have a quicker onset (usually within 15 minutes) and shorter duration of action (up to 3 hours) than sulphonylureas. Nateglinide appears to have a slighter quicker onset and shorter duration of action than repaglinide. PPRGs may be preferable to sulphonylureas in a patient who either wishes or needs to fast (e.g. during Ramadan), or whose meal times are unpredictable and/or irregular.

PPRGs should be avoided in patients with severe liver disease or on dialysis, and in pregnancy, breast feeding and ketoacidosis. Their side-effects include hypoglycaemia, particularly in elderly patients and in those with adrenal or pituitary insufficiency (probably less risk than with sulphonylureas) and hypersensitivity reactions. Weight gain is also possible, although less so than with sulphonylureas. Other side-effects reported with repaglinide include gastrointestinal disturbances, rash and visual disturbances. Nateglinide interacts with ACE inhibitors, diuretics and corticosteroids.

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