1

HbAlc <6.5%' Monitor for deterioration

Consider adding a DPP-4 inhibitior or a thiazolidinedione10 if metformin contraindicated or not tolerated

Metformin2 + DPP-4 inhibitor5,9 or a thiazolidinedione5,10

sulphonylurea + DPP-4 inhibitor' or a thiazolidinedione5,10

HbAlc <7.5%1 Monitor for deterioration

Metformin + sulphonylurea + sitagliptin , or metformin2 + sulphonylurea4 + a thiazolidinedione5,10, or metformin2 + sulphonylurea4 + exenatide6

HbAlc <7.5%1 Monitor for deterioration

HbA1c< 7.5% Monitor for deterioration

Start insulin2.

HbA1c < 7.5%1 Monitor for deterioration

With adjustment for other ethnic groups

Continue with metformin and sulphonylurea ( and acarbose, if used), but only continue other drugs that are licensed for use with insulin. Review the use of sulphonylurea if hypoglycaemia occurs. DPP-4 inhibitor refers to sitagliptin and vildagliptin. Thiazolidinedione refers to pioglitazone and rosig lita zone.

Figure 6.1 Treatment pathway to guide management of blood glucose in type 2 diabetes, adapted from NICE Clinical Guideline No. 87, May 2009. Reproduced with permission from Gaede P. N Engl J Med

2008;358:580-91

First line

The majority of patients and certainly those who are overweight (BMI >25kg/m-2) should start metformin first line. This should be started at 500 mg once or twice a day and the dose increased after 5-7 days (see Box 6.1). Increasing the dose gradually may offset the gastrointestinal side effects that many patients fail to tolerate (Box 6.2).

Box 6.1 Metformin

Metformin is now the only available biguanide. Earlier drugs in this group included phenformin, which was withdrawn in the 1970s as it caused lactic acidosis. The biguanides are related to galegine that was originally derived from the French lilac. This plant had been used for centuries to treat the symptoms of diabetes. Metformin is less lipophilic and safer than phenformin, rarely causing lactic acidosis, but is contraindicated in renal failure (see Chapter 12) forthis reason. Metformin has a number of beneficial actions in diabetes. It reduces hepatic gluconeogenesis, increases insulin sensitivity and reduces carbohydrate absorption from the gastrointestinal tract. It also improves circulating free fatty acids and very low density lipoprotein (VLDL) levels. The UKPDS study suggested that metformin improves cardiovascular risk independently of its effect on blood glucose levels. Very occasionally, metformin causes reduction in vitamin B12 absorption, and serum B12 levels should be checked in patients taking metformin who develop peripheral neuropathy.

Box 6.2 Advice from the American Diabetes

Association/European Association for the Study of Diabetes on gradual introduction of metformin to avoid side effects

Initiating metformin therapy (ADA/EASD advice)

1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner)

2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 or 1000 mg before breakfast and dinner

3. If GI side effects appear as doses advanced, can decrease to previous lower dose and try to advance dose at a later time

4. The maximum effective dose is usually 850 mg twice per day, with modestly greater effectiveness with doses up to 3 g per day. GI side effects may limit the dose that can be used

5. Based on cost considerations, generic metformin is the first choice of therapy. A longer-acting formulation is available in some countries and can be given once per day

Non-obese patients maybe insulin-deficient (particularly if they have actually lost weight) and could start a sulphonylurea first rather than metformin, but metformin has other benefits and so could be co-prescribed from the start in this situation. The sulphonylurea is titrated upwards according to fasting blood glucose levels if available, or HbA1c. Such patients may need insulin adding early on and their condition should be monitored closely.

Patients starting oral hypoglycaemic therapy in the UK are eligible for free prescriptions. They should be advised to inform the Driving and Vehicle Licensing Authority, who will provide advice on their future responsibilities. This is a legal requirement for patients starting insulin, or those on any sort of treatment who have complications affecting driving ability. Advice to patients about informing the DVLA should be recorded in the medical notes.

Second line

If the HbA1c is still not in target after 2-3 months, offer a second agent. This could either be a sulphonylurea, a glitazone, or a gliptin (see Table 6.1). Glitazones should be avoided in those with, or at risk of heart failure. The short-acting sulphonylurea gliclazide can be given at a dose of 40-320 mg per day (if the slow release version is used, 30-120 mg). Doses above 160 mg should be given as two divided doses. If the patient is unwell or actually losing weight then insulin should be started without delay. This may also be appropriate if the HbA1c is still very high (e.g. over 9%, 75 mmol/mol).

Third line

'Triple therapy' using metformin, a sulphonylurea and either a glitazone or sitagliptin is licensed, but many patients using this combination are candidates for insulin, and this should always be considered before starting a third oral drug. Patients starting insulin can continue their oral medication, but an intensive insulin therapy regimen may be simpler if the sulphonylurea is withdrawn, as the insulin is providing a similar effect exoge-nously. Patients starting insulin who continue a glitazone are at higher risk of fluid retention and this may precipitate heart failure in susceptible individuals. However, the combination may be beneficial as insulin sensitivity is increased. Glitazones take 8-12 weeks to be effective, and may be added in to improve control in a patient already taking insulin. Most type 2 patients should continue taking metformin unless they fail to tolerate it or develop renal impairment. The patient who is actually gaining weight needs more dietary advice. Insulin and sulphonylureas tend to promote weight gain, and the injectible incretin exenatide may be useful in this situation but is not licensed for use with insulin. It stimulates glucose-mediated insulin secretion and so does not on its own cause hypoglycaemia. However, the risk of sulphonylurea-induced hypoglycaemia is substantially increased by concomitant exenatide (or gliptin) therapy. See Chapter 19 for more on its mode of action.

Other drug therapies

Other treatment options include the metiglinides (repaglinide or nateglinide), which are taken before a meal to promote insulin secretion and reduce post-prandial hyperglycaemia. Repaglinide is not recommended for use in patients over 75 years old. The alpha-glucosidase inhibitor acarbose acts by delaying carbohydrate absorption and can be taken with other agents but is not well tolerated due to its gastrointestinal effects.

Table 6.1 Major classes of hypo-glycaemic agents and their current role in therapy.

Drug class and mode of action

Examples

Advantages

Disadvantages

Place in management

Biguanides:

Reduce hepatic gluconeogenesis Increases insulin sensitivity Reduces carbohydrate absorption from the GI tract Sulphonylureas: Increase endogenous insulin production

Glitazones:

Increase tissue sensitivity to insulin

Incretin mimetics:

Increase the release of endogenous insulin following carbohydrate ingestion

Reduce release of pancreatic glucagon

Delay gastric emptying

DPP-4 Inhibitors:

Delay the clearance of natural incretins

Meteglinides:

Stimulate the release of pre-formed endogenous insulin

Alpha-glucosidase inhibitors:

Delay the digestion and absorption of ingested carbohydrate

Insulin therapy:

Direct effect on tissues (particularly muscle and liver) to increase uptake of glucose from plasma

Metformin Weight neutral

No risk of hypoglycaemia Possible cardiovascular benefits beyond hypoglycaemic effects Inexpensive Gliclazide Generally well tolerated

Glimepiride Inexpensive Glibenclamide Effective at reducing HbAlc and blood glucose in symptomatic patients

Pioglitazone Usually well tolerated (Rosiglitazone) May be used in combination with other oral therapies and with insulin

Exenatide Actually reduce weight

Liraglutide Can be used with either metformin, a sulphonylurea, or both

Sitagliptin Weight neutral

Vildagliptin Sitagliptin can be used as triple therapy with metformin and a sulphonylurea Repaglinide Specifically aimed at Nateglinide post-prandial hyperglycaemia

Rapid action

Acarbose Reduces post-prandial hyperglycaemia Weight neutral

See Chapter 8 Effective at reducing HbA1c

Gastrointestinal side effects limit its usefulness

Risk of hypoglycaemia Weight gain

Take up to 12 weeks for maximum effect Risk of distal fractures in women May cause fluid retention and so precipitate heart failure in susceptible individuals Small degree of weight gain Injectable Expensive

Use with sulphonylurea substantially increases risk of hypoglycaemia Nausea and vomiting is common Relatively expensive Not always effective enough at reducing HbA1c

Multiple doses required -before each meal

Poorly tolerated due to gastrointestinal side effects including flatulence

Weight gain and need for high doses in insulin-resistant patients Require regular injection or a pump Risk of hypoglycaemia

First line in the majority of patients particularly those with insulin resistance

Usually second line in patients uncontrolled on metformin alone, but can be used alone in those unable to tolerate metformin or patients who are insulin-deficient

Usually second line in patients wishing to avoid the more significant weight gain with sulphonylureas, or third line in those still inadequately controlled on two agents (but insulin should be considered in such cases)

Could be used second line in a patient wishing to avoid weight gain but can also be added in to a combination of metformin and sulphonylurea

Can be added in second or third line (only sitagliptin licensed for triple therapy)

Repaglinide may be used as monotherapy Nateglinide only licensed for use with metformin

Can be used alone or in combination with metformin and/or sulphonylurea

Usually commenced when two oral agents have failed to achieve target, but should be considered wherever there are features of insulin deficiency, if control is very poor, or during intercurrent illness to maintain control

Cost effectiveness and other considerations

Treatment choices may be guided by other issues including cost and patient choice. All type 2 patients who can tolerate it should be offered metformin. This drug is inexpensive and was one of the most prescribed medications in the USA in 2006. Insulin therapy is generally the most effective option in terms of HbAlc reduction, but sulphonylureas are cheaper. Glitazones are also relatively expensive, but unlike the latter will not cause hypoglycaemia. This is also an advantage of exenatide and the gliptins, unless they are co-prescribed with a sulphonylurea. Table 6.1 describes some of the advantages and disadvantages of the individual agents (Figure 6.2).

Starting insulin in general practice

Insulin can be started in most type 2 patients in general practice. As described in Chapter 8, the usual preferred regimen is a twice daily dose of premixed insulin such as Novomix 30 or Mixtard 30

Figure 6.2 Self-monitoring of blood glucose is recommended in all patients taking insulin and may be justified in others on an individual basis.

given before breakfast and before the evening meal. It is usual to start at 6-8 u twice a day with home blood glucose monitoring. The monitoring technique should be taught prior to commencing (and not at the same time as) the insulin. The insulin can then be prescribed and a new appointment arranged to demonstrate the injection technique. In addition to the insulin device, needles (usually 6 mm but longer if the patient is particularly overweight), and a sharps disposal bin should be issued as repeat prescriptions. Needle clipping devices are also prescribable and reduce the volume of sharps requiring disposal. Patients need to be clear about disposal arrangements for their sharps bins when full. The insulin dose can be titrated upwards according to blood glucose levels, usually in increments of 2-4 units, as described in Chapter 8. An alternative is to start with a long-acting analogue such as glargine or detemir at 8 units in the evening, titrating upwards according to fasting glucose levels. Conversion to a more flexible regimen can be achieved later on, either through the addition of short- or rapid-acting insulins with meals to create a basal-bolus regimen, or by changing over to a premixed insulin twice or three times a day. By this time the patient has become accustomed to injections and any initial needle phobia will have hopefully been overcome. The initial management of a once daily long-acting analogue can usually be managed by general practice teams. Diabetes Specialist Nurses linked to the local hospital diabetes centre are very useful as a source of advice, guidance and patient education, particularly when insulin regimens become more complicated.

Unlike type 1 diabetes, type 2 is a progressive condition in which insulin requirements are likely to increase over time. This should be borne in mind when selecting appropriate intervals to review adequacy of control.

Hypoglycaemia

As discussed in Chapter 5, hypoglycaemia may be seriously detrimental to quality of life and employment prospects. Type 2 patients starting insulin for the first time may or may not have experienced hypoglycaemia before (usually because ofsulphonylureas). The risk of this happening is substantially greater with insulin and in some cases this may influence the decision to start insulin over other options, as discussed above. Patients should be counselled over the risk of hypo and given not only practical advice about how to correct it but also a supply of glucagel and glucagon to be used if needed. Risk of hypoglycaemia is the main reason why those taking insulin (unless such treatment is only temporary, i.e. less than 3 months) are legally obliged to inform the Driver and Vehicle Licensing Agency (DVLA). Advice to inform the DVLA should be recorded in the notes. DVLA regulations are revised from time to time and the latest guidance should be consulted.

Figure 6.3 Proportion of patients attaining treatment goals in UKPDS.

Figure 6.2 Self-monitoring of blood glucose is recommended in all patients taking insulin and may be justified in others on an individual basis.

Figure 6.3 Proportion of patients attaining treatment goals in UKPDS.

Difficulties in achieving targets

Despite concerns about over-treatment, the reality is that too few patients manage to achieve their target HbA1c. Even in the context of a well-organised clinical trial with intensive follow-up such as UKPDS, Figure 6.3 shows the proportion of patients meeting the target HbA1c of <7% (53 mmol/mol). However, patients should be encouraged that all reductions are beneficial.

Further reading

Bailey CJ, Day C. Glycaemic memory. Br J Diabetes Vasc Dis 2008;8:242-7. National Institute for Health and Clinical Governance. Type2 diabetes - newer agents: short guideline. Clinical Guideline No. 87, May 2009. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. NewEngJ Med 2007;356:2457. United Kingdom Prospective Diabetes (UKPDS) Group (49). JAMA 1999;281: 2005-12.

Witters LA. The blooming of the French lilac. J Clin Invest 2001;108:1105-7.

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