Type 2 diabetes mellitus

Type 2 diabetes accounts for approximately 90% of all cases of diabetes. Insulin resistance is the cardinal pathogenic factor and patients are therefore initially hyper insulinaemic although eventually beta cell failure intervenes. Diagnosis is often made on clinical grounds but can be confirmed by measuring C-peptide and/or insulin levels. Management is by a combination of lifestyle changes, oral hypoglycamics and eventually insulin therapy becomes unavoidable in the overwhelming majority of cases.

Approach

The management and treatment of T2DM should be conducted in a step wise manner. Although recommendations vary slightly around the world, and between different professional associations, the basic principles are consistent.

Lifestyle

Lifestyle modifications are the first step in managing newly diagnosed T2DM.

Specifically, the patient should be advised to try to lose weight, increase the amount of regular physical exercise in their daily life, stop smoking if they do and modify their diet.

Dietary management

Dietary modifications should be aimed at producing a negative caloric balance in order to aid weight loss, aiming for an ideal BMI (25kg/m2).

This will be an unrealistic aim in many patients and, in such cases, even a 10% reduction in body weight is associated with very significant health benefits.

Dietary advice for people with diabetes should be little different from general healthy eating advice. Specifically, avoidance of refined sugars, reduction of saturated animal fats, the majority of calories coming from complex carbohydrates, five portions of fresh fruit and vegetables per day and a caloric intake aimed at maintaining steady weight (~2,000 cal per day for women and ~2,500 for men).

Much of this advice is summarised on the eatwell plate.

Exercise

Again unrealistic targets should not be set.

Any increase in routine physical activity will be beneficial. For many people, half-an-hour walking each day on most days of the week will represent a significant increase in their physical activity and will have tangible benefits in terms of weight reduction and increase in insulin sensitivity.

Smoking cessation

The leading cause of premature mortality in T2DM is ischaemic heart disease.

Smoking cessation is therefore of paramount importance in people with T2DM. The potential benefits of smoking cessation should be promoted very strongly and patients should be offered professional help with smoking cessation which may take the form of group support, one to one counselling, pharmacological management of withdrawl symptoms and the like. 

Much of this support is now freely available on the NHS in the UK.

Oral hypoglycaemics

Metformin

The first line oral hypoglycaemic agent in all except those with an eGFR of <30 ml/min should be metformin.

Traditionally, metformin is not started until a 6-8 week trial of lifestyle modification has been undertaken. If the HbA1c is greater than 7% (53 mmol/mol) at the end of this period, metformin should be started.

Increasingly, however, it is started at time of diagnosis and this is now standard practice in some parts of the world. Metformin often causes dose limiting GI side effects and patients should be warned of this and encouraged to persevere, as they will often remit.

To avoid these side effects the dose should be gradually titrated up from 500mg od with food, increasingly gradually by 500 mg per day once a week aiming for a maximum dose of 2-2.5 g/day (typically 1 g with breakfast, 500 mg with lunch and 1 g with the evening meal).

Patients who experience GI side effects during titration should be advised to reduce their dose to the previous dose or the highest dose that is tolerable with out significant side effects. If side effects are still a problem then metformin S/R (maximum daily dose = 2 g) should be offered. In general, this has much greater tolerability than plain metformin although does carry a cost premium and therefore should not be offered as first line.

Metformin powder and solution are also available for those with swallowing difficulty.

Sulphonylureas

The sulphonylureas should normally be used as a second line, add-on therapy in addition to metformin, once the patient is on the maximum tolerated dose of metformin and has an HbA1c >7% (53 mmol/mol).

Sometimes, in very lean individuals or where there has been complete intolerance to all forms of metformin or where the patient is highly symptomatic at presentation, sulphonylureas may be used as first line oral hypoglycaemic therapy. The preferred drugs in this class are usually gliclazide or glipizide.

The maximum dose of the former is 160 mg bd and the latter 10 mg bd, usual starting doses being 80 mg and 5 mg od respectively. The sulphonylureas are potent hypoglycaemics and can cause severe and prolonged hypoglycaemia especially in the elderly and in those with renal impairment where they are prone to accumulation. They can also cause significant weight gain.

Despite these disadvantages, there is however a wealth of clinical experience with their use, they have significant evidence-base supporting their use (especially the UKPDS trial), their long term tolerability and safety has been well demonstrated and their cost is low.

Thiazoledinediones (glitazones)

Following recent growing awareness of potential risks associated with this class of drugs (osteoporotic fractures, worsening of heart failure, possible increased MI risk with rosiglitazone, risk of bladder cancer), these are now used either as third line OHAs, occasionally with insulin as insulin-sensitisers or not at all. They should not be used in patients with an active or a history of bladder cancer, and patients should be assessed for risk factors for bladder cancer and its symptoms, prior to initiation, and reviewed after 3-6 months. Similarly, they should avoided in patients with a history of heart failure, and patients monitored for its signs and symptoms.  

Rosiglitazone has now been withdrawn and therefore the only drug in this class that is used is pioglitazone.

Pioglitazone should be considered in those with T2DM who are on maximal tolerated doses of metformin and sulphonylurea and who do not have an HbA1c at or below target (i.e. 7-7.5%, 53-58 mmol/mol, in most cases), in whom significant insulin resistance is suspected (i.e. overweight and especially those with a predominantly centripetal weight distribution).

Initiating a thiazolidinedione in those who have had T2DM for more than 10 years and who are lean or rapidly losing weight (i.e. those who have reached beta cell failure and are now under-insulinised) is rarely an effective intervention. If the patient does not have a history of CCF or osteoporosis and is not at excessively high CHD risk, then pioglitazone should be started at 15 mg od and gradually increased as tolerated over two to three months to 45 mg od.

The patient should be warned that weight gain of 1-2 kg can be expected and that swelling of the ankles may occur. They should be assessed for signs of heart failure each time the dose is increased. If HbA1c does not fall by 0.5-1% (Approx' 5 - 10 mmol/mol) within the first few months on pioglitazone, it is questionable of there is any benefit in continuing with this treatment.

DPP-IV Inhibitors

DPP-IV (dipeptidyl peptidase) inhibitors such as sitagliptin, saxagliptin, alogliptin, linagliptin, and vildagliptin are orally active small molecule inhibitors of the main enzyme responsible for inactivation of endogenous GLP-1. Their therapeutic effects are therefore analogous to the GLP-1 agonists,although not as potent, increasing insulin secretion and reducing glucagon secretion. Where the GLP-1 agonists cause weight loss, the DPP-IV inhibitors are weight-neutral.

Their current place in therapy is widely regarded as third or second line oral hypoglycaemic. All five therapies are licensed for dual-therapy with metformin, and also in combination with insulin, with or without metformin. 

Sitagliptin, saxagliptin, alogliptin, and vildagliptin are licensed for dual-therapy with either a sulphonylurea or pioglitazone. 

Sitagliptin, saxagliptin, linagliptin and vildagliptin are licensed as mono-therapy if metformin is considered inappropriate, and also licensed as triple therapy with both metformin and sulphonylureas. 

Sitagliptin and alogliptin may also be used in combination with both metformin and pioglitazone. They are not licensed for use as part of a 'quadruple therapy' combination ie. metformin/sulphonylurea/glitazone/DPP-IV inhibitor.

They can reasonably be expected to produce an approximate 0.5% DCCT units / ~ 5 mmol/mol SI units reduction in HbA1c and may therefore delay insulin initiation. This is particularly useful in the elderly, the very obese in whom insulin often has limited efficacy, those who refuse insulin therapy and those who can not use insulin for occupational reasons.

Sitagliptin (Januvia) is used at 100 mg od. Vildagliptin (Galvus) is used at 50 mg bd, unless in dual therapy with a sulphonylurea when it is only used od. Saxagliptin (Onglyza) and Linagliptin (Trajenta) are used at 5 mg od. Alogliptin (Vipidia) is used at 25 mg od. 

DPP-IV inhibitors, with the exception of linagliptin, should only be used with caution in renal impairment, typically with half doses recommended when eGFR<50 ml/min, and further reductions if eGFR <30ml/min. Linagliptin, however, is excreted by a hepatobiliary route, and so can be used in moderate to severe renal failure without dose adjustment. 

 SGLT2 Inhibitors

These reduce glucose reabsorption by the kidney by reversibly inhibiting the sodium-glucose co-transporter 2 (SGLT2) channels in the renal proximal convoluted tubule. Products include canagliflozin (Invokana), dapagliflozin (Forxiga) and empagliflozin (Jardiance). 

They are licensed for mono-therapy or dual therapy with insulin or other anti-diabetic agents. NICE recommend the use of canagliflozin or empagliflozin as an option for triple therapy in combination with metformin and a sulphonylurea or thiazolidinedione. Dapagliflozin should not be used with pioglitazone. 

The MHRA have released a safety report highlighting the serious potential side effect of diabetic ketoacidosis (DKA), often with normoglycaemia, recommending they must be discontinued if DKA is suspected. They should also be avoided if eGFR is <60mL/min, and if over 85 years old or with cardiovascular disease due to a risk of hypotension. 

Canagliflozin is initiated at 100mg od, titrated to 300mg od max. Dapagliflozin is used at 10mg od. Empagliflozin is initiated at 10mg od, titrated to 25mg od max.

 Other OHAs

Alpha glucosidase inhibitors

There is only one licensed drug in this class at present, acarbose (Glucobay). It works by inhibiting the digestion of dietary starch and effectively lowering the glycaemic index of carbohydrates. It has modest potency as a hypoglycaemic agent and is not often used, partly because it causes flatulence. However, in combination with other OHAs and even with insulin, it can be a useful adjunct in those who are able to tolerate it.

It does have the advantage of being relatively side effect free other than flatulence, it is safe in renal impairment and has few drug interactions. The dose is between 50 mg od and 200 mg tds to be taken witht the first mouthfull of each meal.

Meglitinides

Two drugs are currently licensed in this class, nateglinide (Starlix) and repaglinide (Prandin). The meglitinides are, like sulphonylureas, insulin-secretagogues but  they bind to a differnet site on the ATP sensitive potassium channel from the sulphonylureas. Nateglinide is only licensed for use in combination with metformin. Repaglinide is can be used in combination with metformin or as monotherapy. The dose of nateglinide is 60-180 mg tds and the dose of repaglinide is 0.5 mg tds - 4 mg qds.

In practice neither drug is used a great deal in the UK as they provide little advantage for the majority of patients over sulphonylureas. They have not been exposed to the same rigorous trial evaluation as sulphonylureas and have a greater acquisition cost.

GLP1 agonist therapy

The GLP1 (glucagon like peptide 1) agonists include exenatide standard-release (Byetta), exenatide modified-release (Bydureon), liraglutide (Victoza), and lixisenatide (Lyxumia).

This is a novel class of injectable therapy for T2DM which utilises 'incretin' physiology to enhance post-prandial, glucose-dependent insulin secretion form the patient’s own beta cells, and decrease glucagon secretion. This class of drugs also induces early satiety thereby reducing caloric intake and thus weight.

At present this class of drugs is licensed for use as a third line, add-on therapy for T2DM typically at the point where a thiazolidinedione or insulin initiation would otherwise be considered. They are licensed for use in combination with sulphonylurea plus metformin and also with metformin plus thiazolidinedione. Standard-release exenatide, liraglutide and lixisenatide are also licensed for combination with basal insulin, however, lixisenatide should not be combined with both a sulphonylurea and a basal insulin as this may cause hypoglycaemia. 

A weight reduction in excess of 3% of initial body weight and an HbA1c reduction of up to 1%DCCT units / ~ 10mmol/mol SI units should be expected after six months of therapy.

They should not be started in people with an eGFR of less than 30 ml/min and there is a small but real risk of pancreatitis associated with their use which the patient should be warned about.

Exenatide standard-release is given at a dose of 5 micrograms bd to be titrated up to 10 micrograms bd after one month. Exenatide modified-release  is given 2mg once weekly. Liraglutide is started at 0.6mg od, to be titrated up to 1.2mg after at least one week and thence 1.8mg od, although the 1.8 mg dose is not recommended by NICE in the UK. Lixisenatide is started at 10 micrograms od, and titrated to 20 micrograms od after two weeks. 

Nausea is a common and transient side effect that patients should be warned of but advised to persevere if they experience it.

Xultophy has become the first fixed-ratio combination basal insulin and GLP-1 receptor agonist preparation to be licensed. It combines insulin degludec with liraglutide, for use in type 2 diabetes mellitus. It is initiated at 10 “dose-steps” od (one dose step = insulin degludec 1 unit/liraglutide 36 micrograms) if initiating insulin, or 16 dose-steps if transferring from a basal insulin, to a maximum of 50-dose steps.  

Insulin therapy

Insulin Initiation in T2DM

Insulin initiation in T2DM is usually necessary after approximately 10 years of oral hypoglycaemic therapy although this can be much earlier in some people.

Once the patient is on maximal tolerated OHAs and has an HbA1c higher than 7.5% (58 mmol/mol) insulin initiation should be considered.

If the patient is on metformin and a sulphonylurea then the commonest way to start insulin is as a once daily, bed-time injection of long acting insulin to be given in addition to the OHAs. Typically an isophane human sequence insulin such as Humulin I (TM) is used. Alternatively, if there have been significant problems with hypoglycaemia on the isophane insulin, an analogue such as insulin glargine (Lantus, TM), or insulin detemir (Levemir, TM) may be used.

Usual starting doses of insulin will be in the range of 10-20 units per day depending on the patient's likely degree of insulin resistance (i.e. BMI). However, these are only starting points from which to titrate up the dose to achieve the desired HbA1c. Since HbA1c should not be repeated more frequently than three times a month, in the interim pre-prandial blood sugars of less than 10 mmo/L (or less than 8 mmol/L for really 'tight'glycaemic control) are a good target.

If the patient is already on metformin plus sulphonylurea plus thiazoledinedione then it is possible to start insulin as an add-on but is more conventional to stop one of the oral hypoglycaemic agents at this point, usually the thiazoledinedione or the sulphonylurea.

Insulin intensification

For the first year or two after addition of a long acting insulin to the OHAs it is usually possible to titrate up the dose of insulin to achieve adequate HbA1c without causing excessive hypoglycaemia. Eventually, however, as beta cell failure progresses the intensification of insulin therapy will become necessary.

This can be achieved in a number of ways:

1. Stopping the sulphonylurea, continuing the metformin and swapping the once daily long acting insulin for a twice daily biphasic insulin. Twice daily biphasic insulin regimens (with insulins such as biphasic insulin aspart (Novomix 30 TM), biphasic human sequence insulin (eg Humulin M3 TM) or biphasic insulin lispro (Humalog Mix 25 or Mix 50 TM) have the advantage of fewer injections (two per day as compared to four a day for a basal bolus regimen) and may therefore be preferred in the elderly and in those who are very reluctant to inject insulin at all.

The major draw back of twice daily mixed insulin regimens is that the longer acting component tends to 'peak' five to six hours after injection. This mandates eating a midday meal within a relatively narrow time window and at night leads to increased risk of nocturnal hypoglycaemia and often mandates a pre-bed time snack to reduce this risk.

2. Progressively changing the patient to a basal bolus regimen by stepwise addition of rapid acting insulin with meals and simultaneously withdrawal of the sulphonylurea until the patient is eventually on a full basal bolus regimen consisting of once daily long acting insulin alongside three injections of prandial insulin plus metformin.

3. Other approaches to this situation are to switch the patient to a tds biphasic insulin regimen alongside metformin, or, in the advanced elderly, a single once daily injection of long acting insulin with or without accompanying OHAs may be adequate to achieve compromise HbA1c (i.e. one which is higher than 7.5% (58 mmol/mol)but still deemed to be acceptable to keep the patient free from osmotic symptoms and immediate hyperglycaemic complications).

What are the advantages of a basal bolus regimen?

In younger patients with T2DM with very active lifestyles who require insulin therapy starting a QDS or 'basal bolus' insulin regimen as their first insulin therapy may be appropriate.

In such circumstances, metformin is often continued, other OHAs are discontinued and the basal bolus regimen is started directly. This will consist of a once daily long acting insulin (normally an analogue such as insulin glargine or insulin detemir) and three injections of prandial insulin such as soluble human sequence insulin (eg Humulin S TM) or a rapid acting analogue such as insulin lispro (Humalog TM) or insulin glulisine (Apidra TM).

New insulins

Recently we have seen the addition of two new insulin glargine products to the market which may cause confusion. Abasaglar is a bio-similar version (100 units/ml), which has an identical license to the original product, Lantus. Toujeo, however, is a more concentrated product (300 units/ml) allowing smaller volume injections and it is promoted as a longer-acting product.

Any switch from Lantus to Toujeo will therefore require dose adjustment and glucose monitoring. Dose adjustment may also be required from Lantus to Abasaglar and glucose monitoring will certainly still be required. Switching, therefore, should only be performed by specialists.

There have also been updates to the short-acting market, with a recent launch of Humalog (insulin lispro) in a more concentrated form (200 units/ml). No dose conversion is required, as the Kwik pens dial in the same one unit increment, but a smaller volume is delivered.

When is continuous subcutaneous insulin infusion (CSII) therapy indicated?

CSII is not usually indicated in the treatment of T2DM.

Patient education

Who should be taught the self-monitoring of glucose levels?

There is a general opinion that self-monitoring of blood glucose levels is not mandatory for patients with T2DM who are only taking OHAs. This opinion is reasonable and many such patients can be managed exclusively on the basis of their HbA1c.

However, patients who strongly wish to monitor their blood sugars should be allowed to do so. Preventing them from doing so might disengage them from managing their own long-term condition.

In addition, the risks of hypoglycaemia should not be underestimated on sulphonylureas and if there is any suspicion that the patient may be suffering from hypoglycaemia then self-monitoring of blood sugars when hypoglycaemic symptoms are experienced is a very important part of their overall management.

What topics should be covered in general diabetes education at presentation?

This is a large and important subject and it is important that diabetes specialist nurses spend considerable time with newly diagnosed T2DM patients covering several important topics. These include hypoglycaemia recognition and self-management, sick day rules, driving and diet.

Educational topics for those requiring insulin therapy include adjusting insulin doses, use of insulin injection devices including storage of insulin, changing cartridges, changing needles and recognising potential injection device failure.

Furthermore, increasing numbers of women of child bearing age are being diagnosed with T2DM and for these patients, contraception and pre-pregnancy planning should also be covered.

What are sick day rules? 

Sick day rules are guidelines for patients with diabetes providing advice on how to manage blood sugars and insulin/tablets during times of illness, especially illnesses that lead to reduced food intake and/or vomiting.

During these times, the cardinal advice is that patients should NEVER STOP THEIR INSULIN.

Insulin requirements often actually rise during inter-current illness, even if food intake has significantly fallen. Thus, patients are advised to regularly check BMs (two to four hourly), continue their regular doses of insulin, counter any falling blood sugars with frequent small sips of sugary drinks and maintain a high fluid intake (ideally 3 litres per day).

Read more on sick day rules and T2DM.

What are the recommended precautions around driving and T2DM?

The mainstay of safe driving in people with diabetes is the avoidance, recognition and appropriate management of hypoglycaemia.

Thus, patients who are on insulin or sulphonylureas are advised to check their BM before getting in the car and to not set off if it is low until this has been rectified, to stop and check BM periodically during long journeys and to keep a source of rapidly absorbable carbohydrate such as dextrose tablets in the car.

If the patient does feel hypoglycaemia coming on they should pull over at the side of the road as soon as it is safe to do so, check their BM, ingest rapidly absorbed carbohydrate followed by a source of longer-acting carbohydrate and not proceed until their BM is back to a safe level and they feel well enough to continue.

The DVLA regularly re-assess the driving-safety of insulin-treated patients with diabetes by questionnaire to the patient and their doctor. The medical questionnaire includes an assessment of the patients knowledge of the above guidance. Patients with significant hypoglycaemia un-awareness may have their licence suspended by the DVLA for a period until some awareness has been restored.

Read more on driving. 

What should pre-pregnancy counselling cover?

The most important message for pre-pregnancy counselling in diabetes is that un-planned pregnancies should be avoided as far as possible.

While the foetal and maternal risks of pregnancy in diabetes are elevated in comparison with the background population risks, these can be significantly reduced by scrupulous glycaemic control, especially around the time of conception and thus unplanned conception should be avoided.

It is therefore essential that women with type 2 diabetes have these considerations explained to them and that they are encouraged to use effective contraception until such time as they are ready to conceive. 

Prior to attempting to conceive they need to stop taking all oral hypoglycaemic agents except metformin and also to stop GLP1 agonist therapy if this is being used, to lower the HbA1c to around 7% and aim to achieve fasting blood sugars in the region of six or less and post prandial blood sugars around 8 mmol/L or less. These are targets that should be maintained throughout pregnancy but are now thought to be most important of all around the time of conception.

Other factors to consider are the cessation of smoking, avoidance of alcohol and use of folic acid at neural-tube defect prevention doses (i.e. 5 mg/day).

Read more on pregnancy. 

What structured education systems are available for people with T2DM?

The X-PERT programme is a six week group education programme for people with diabetes helping them to learn to self-manage their condition. This philosophy accords with the diabetes NSF standard on education and makes sense from the patient's point of view since treatment of diabetes affects many basic aspects of every day life such as what food to eat, what physical activity to do and so on.

 

DESMOND (Diabetes Education and Self Management for Ongoing and Newly Diagnosed) has now become a brand in the world of diabetes education covering a wide range of patient education activity. However, the basic concept is that DESMOND providers run courses around the country for people with T2DM to educate them about T2DM and treatment thereof so that they become empowered. Education is provided in group sessions and mainly based in primary care.

Annual review

What should be covered in the consultation?

The aim of the annual review is to screen the patient for the presence of established complications and assess their risk factors for future complications.

Areas covered in the consultation depend on the patient’s history but should normally include:

1. Review of the diary and/or glucometer.

2. Assessment of the frequency of hypoglycaemia; whether the patient has adequate warning symptoms; and, does the patient know how to treat their hypos and are there any obvious precipitating factors?

3. What insulins and OHAs and what doses are being taken.

4. What other medicines are being taken, especially focussing on primary and secondary cardiovascular prevention (statins, aspirin, ACE inhibitors).

5. Is the patient a smoker?

6. Is their weight changing? Are they overweight?

7. How is their general health?

8. For all women of child bearing age, advice on pre-pregnancy measures and a discussion of effective contraception and avoidance of unplanned pregnancy.

9. An opportunity for the patient to discuss specific problems and concerns.

10. With male patients, erectile dysfunction should be discussed. 

What physical examination should be performed?

As a minimum this should always include physical examination of feet (foot pulses, two-modality sensory screening including 10g monofilament and vibration sensation), blood pressure, injection sites and retinal screening (ideally by digital retinal photography scored by an ophthalmologist or accredited retinal grader).

What biochemical investigations should be performed?

Biochemical assessment of HbA1c, ACR, renal function and fasting lipids including cholesterol and triglycerides should be undertaken.

What else? 

Patients should also be offered a review by a diabetes nurse specialist and dietician. 

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