Prevention of complications of diabetes Oral therapies for T2D

Practice nurses are at the forefront of diabetes care in many practices and it is essential that they keep abreast of new developments. In this article we look at the oral therapies. In part two, next month, we will look at issues surrounding the initiation of insulin.

With so much attention focused on achieving blood glucose control targets in diabetes, it is perhaps easy to overlook the real goal of management, which is to prevent - or reduce the risk of - the development of complications, including blindness, kidney failure, amputation and premature cardiovascular death.

It is more than 30 years since these treatment goals were enshrined in the St Vincent Declaration1 - an agreement ratified by governments and healthcare professionals, to:

• Reduce the incidence of blindness by one third
• Reduce the incidence of end stage renal failure by one third
• Reduce amputations by one half
• Reduce cardiovascular morbidity and mortality
• Achieve pregnancy outcomes in women with diabetes that approximate those in women without diabetes.

T2D is a metabolic disorder in which there is both a relative insulin deficiency and a relative resistance to insulin in peripheral tissues, which may then lead to hyperinsulinaemia. It differs from type 1 diabetes, where islet cells, which produce insulin, are destroyed, leading to an absolute lack of insulin. Type 2 typically affects overweight adults over 40 years, although increasingly it is developing in younger patients due to overconsumption of a Western diet and rising obesity.

If we could tackle obesity in society, we could reduce the incidence of type 2 diabetes massively. In recent years, considerable progress has been made towards those goals. Our understanding of the mechanisms which cause damage to small blood vessels, ultimately leading to the late complications of micro and macrovascular disease, have increased, and we can target our treatments and lifestyle interventions far more effectively to prevent them. Progression towards renal and eye problems, and increasing disability is no longer as likely as it was. Control of blood glucose, blood pressure and blood lipids, and management of lifestyle issues - particularly weight control and stopping smoking - have potential to reduce morbidity and save lives.

Nonetheless, by the time they are diagnosed, half of the people with T2D show signs of complications.²

Improved blood pressure and glucose control reduces the risk of the complications that cause both morbidity and premature mortality.³ But according to results of the most National Diabetes Audit (2009-2010), the NICE recommended target HbA1c of <=7.5% (59mmol/mol) was achieved by only 66.5% of people with T2D, and overall, 37% of people with diabetes (types 1 and 2) are at high risk of future complications. 4

Even if ideal blood glucose levels cannot be reached, any improvement will help to reduce risks.⁵

MICROVASCULAR COMPLICATIONS

Kidney damage

Kidney disease in T2D is an increasing health burden, reflecting the increasing prevalence of diabetes, better cardiovascular survival as a result of current management of CVD and better management of the progression of kidney damage itself. Primary prevention of kidney failure due to diabetes centres around the prevention of microvascular damage (classical diabetic nephropathy) and arterial (renovascular) damage. Fundamental to this aim is the need to control both blood glucose and blood pressure.⁶

Eye damage

Diabetic eye damage is the single largest cause of blindness before old age, with a progressively increasing incidence in people with T2D. Retinopathy screening programmes, and the success of laser therapy in the treatment of sight-threatening retinopathy, have improved the management of diabetic eye damage, but good blood glucose, blood pressure and lipid control are essential to reduce the risk of developing this complication.⁶

Foot damage

Foot ulceration, foot and limb amputation and some forms of deformity such as Charcot arthropathy (Charcot foot) are major forms of disability arising from diabetes; factors contributing to the development of foot complications in T2D include old age, duration of diabetes, neuropathy, peripheral vascular disease, renal disease, poor vision, poor footwear, smoking and social deprivation. The risk of ulceration and amputation increases if supervision of care in elderly patients is inadequate.⁷

Nerve damage

Neuropathic pain is one symptom of nerve damage resulting from chronic exposure to poor blood glucose control, that cannot be managed acutely by restoration of blood glucose control. Another common manifestation of nerve damage is loss of foot sensation. Erectile dysfunction is also common in men with T2D, the result of a combination of nerve damage and peripheral vascular disease.⁶

ESTABLISHED TREATMENT

Diet

Initial management of T2D, particularly in asymptomatic patients, may be by diet alone.⁶ This may be tried for 3 months or more, depending on the patient's co-operation, BMI and current diet.

Ideally Caucasians should have a BMI <= 25 and Asians a BMI <= 23.

In some patients modification of diet, particularly if coupled with weight loss and an increase in exercise levels, will be enough to push their blood glucose back into the normal range for some months or years, if not indefinitely. However, in symptomatic patients - those losing weight or suffering recurrent infections - it is generally best toproceed straight to oral therapy.

Early insulin use

Some patients with T2D present in ketoacidotic states - usually due to intercurrent illness - and are admitted to hospital and started on insulin. It's not unusual for those patients to come back to the practice nurse still on insulin, with no really clear plan to come off it. Once the acute episode is over they can usually be switched to oral therapies, and this should always be considered.

Although lifestyle interventions (diet and physical activity) are the first-line treatments for the management of T2D, most people subsequently need sequential addition of oral glucose-lowering drugs.⁶

ORAL THERAPIES

Drug treatments for type 2 diabetes are based on a mixture of principles including:

• Stimulating the pancreas to release more insulin (secretagogues)
• Increasing the body's sensitivity to insulin (sensitisers)
• Insulin itself
• Reducing the availability of glucose by reducing absorption or renal re-absorption

Metformin

Metformin is the recommended first line drug for patients with normal renal function, especially those who are overweight and those in whom hypos would be a particular concern. It should be stopped in patients whose estimated glomerular filtration rate (eGFR ) falls below 30.

Metformin takes 3-4 weeks to take effect, and works by suppressing glucose production by the liver (which is increased in people with diabetes) and increasing both sensitivity to insulin and uptake of glucose in tissues. It doesn't usually cause hypos but has to be increased slowly as it can cause gastrointestinal side effects. For example, start on 500mg once daily, then twice daily, and review the HbA1C in 3 months before up-titrating the dose further. It may be better tolerated in the slow release form, but this is more expensive so the standard form should be tried first.

Sulphonylureas

Sulphonylureas are the NICE recommended next choice (or first choice for patients with normal or low BMI or who need a more rapid reduction in blood sugar). They are cheap and we have many years experience in their use, but there are arguments for moving away from them to DPP4 inhibitors, which tend to aid weight loss, improve control and don't 'kick the pancreas when it's down'.

However, they have a tendency to cause weight gain and hypos.

Sulphonylureas mainly act by increasing production of insulin by the pancreas. Because insulin promotes hunger, weight gain and deposition of fat, they tend to produce weight gain. Sulphonylureas also work irrespective of the actual plasma glucose level and can cause hypos if patients don't eat enough. For these reasons, they are becoming a less preferred option.

Some experts feel that sulphonylureas speed up disease progression by accelerating loss of functioning beta cells in the pancreas. It is important to note that the ADVANCE trial 8 found no benefit from tight control with gliclazide for the outcomes of heart attack, cardiovascular death, or all-cause death.

However, they work fairly swiftly and are first line therapy in patients with lower BMI or when rapid reduction of blood sugar levels is desirable i.e. symptomatic individuals with recurrent infections or marked thirst and/or polyuria. The most commonly used sulphonylureas are glipizide and gliclazide. The dose is slowly increased according to the HbA1C.

Meglitinides

Meglitinides, e.g. repaglinide, work in a similar way to sulphonylureas, but are slightly less prone to cause hypos as they are very short acting and are only taken with meals. They are recommended in the current NICE guideline6 for people with erratic lifestyles as they offer flexibility; you only take them if you eat and, if you don't eat, you don't take them.

Thiazolidinediones (glitazones)

These drugs, introduced in the late 1990s, increase insulin sensitivity, and improve lipid profiles by decreasing triglycerides and increasing HDL (although they also slightly increase LDL). Rosiglitazone was withdrawn due to concerns about increased stroke risk, leaving only pioglitazone in this group of drugs. Glitazones are usually used with either a sulphonylurea or metformin - triple therapy including these agents is discouraged due to the risk of hypos - but some specialists now use them with one or other of these drugs plus a gliptin (discussed later).

The MHRA has issued a warning of a slight increase in the risk of bladder cancer associated with pioglitazone, although the benefits of treatment with this agent continue to outweigh the risks. Patients with active bladder cancer, a history of bladder cancer or uninvestigated haematuria, should not be treated with pioglitazone. Before starting treatment, patients should be assessed for their risk of bladder cancer, and pioglitazone should be avoided in elderly patients because the risk increases with age.⁹

Acarbose

Acarbose inhibits absorption of sugars from the gut, thus inhibiting conversion of complex carbohydrates to glucose. Its effectiveness depends on diet and it tends to cause flatulence. It is not recommended by NICE,6 except for people unable to use other oral glucose-lowering medications, since it is no more effective and its gastrointestinal side effects common.

Gliptins (dipeptidyl peptidase (DPP4) inhibitors)

GLP-1 and GIP are naturally produced peptides which increase insulin production and secretion, delay gastric emptying so that patients feel fuller for longer, and decrease glucagon secretion thus reducing glucose output from the liver. Dipeptidyl peptidase is an enzyme that degrades GLP-1 (glucagon-like peptide) and GIP (glucose dependent insulinotropic polypeptide). Gliptins work by inhibiting this enzyme, thus increasing natural GLP-1 and GIP levels.

DPP4 inhibitors:

• Act in a glucose-dependent manner, stimulating insulin secretion only when blood glucose levels are high , therefore carrying negligible risk of hypos
• Suppress pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing glucose
• Slow down gastric emptying decreasing the rate at which meal-derived glucose appears in the bloodstream
• Reduce appetite and promote satiety via central brain mechanisms
• Reduce liver fat content and lower triglyceride levels.

DDP4 inhibitors are once, or twice daily oral drugs. The reductions in HbA1C and weight that they promote tend to be comparatively small but seem to be sufficient. Saxagliptin, sitagliptin, vildagliptin and the latest addition, linagliptin, are currently available and licensed for use as dual therapy. Many specialists, however, already use them as a part of triple therapy or, indeed, monotherapy. They can cause headaches and nausea but are generally well tolerated.

NICE10 recommends substituting a DPP4 inhibitor or thiazolidinedione for sulphonylurea if:

• There is a significant risk of hypoglycaemia (or concerns about its consequences), or
• A sulphonylurea is contraindicated or not tolerated

POOR CONTROL

Patients on dual therapy whose control is poor - particularly those who are markedly hyperglycaemic and symptomatic - should be considered for insulin therapy. However, commencing insulin is a big step for many patients. It has significant implications for those who drive for a living and many patients will initially reject the idea out of hand.

Alternative options at this stage are glitazones (although these should be avoided in patients with heart failure or at high risk of heart failure), DPP4 inhibitors and the injectable GLP-1 agonists.

GLP-1 agonists improve glycaemic control, do not mean loss of HGV or PSV drivers' licenses and promote weight loss in most individuals. Exenatide is injected twice daily and liraglutide once daily.

Exenatide may be an option if:

• BMI >= 35 kg/m2 with problems associated with obesity, or
• BMI < 35 kg/m2 and insulin is unacceptable or if weight loss would benefit other comorbidities.¹⁰

NICE10 states that all third stage oral therapies should only be continued if they achieve acceptable results over 6 months, i.e.:

• A reduction in HbA1c of at least 0.5% in 6 months for the oral therapies, or
• A reduction in HbA1c of >= 1.0% and >= 3% of initial body weight in 6 months for the injectables.

COLLABORATIVE CARE

The 2010 NICE guidance on the use of newer agents therapies10 emphasizes the importance of structured education and dietary advice, and agreeing a target HbA1C that may be above that of 48 mmol/mol (6.5%) set for diabetes in general with the individual patient.

Methods of behavioural change and motivational interviewing techniques to empower patients, aid their understanding and improve concordance with advice and therapy should be utilised. Above all, care should be collaborative. This is the patient's disease and he or she needs to be fully involved in its management, with your support and advice, including taking responsibility for lifestyle issues such as smoking.

CONCLUSION

With such a wide choice of therapies now available, the interested practitioner can offer an informed choice to patients and help them follow the right treatment path for them.

NICE, while making recommendations and offering guidance, essentially gives us permission to use the therapy that is best for the patient, taking into account their whole health and their preferences. This means we have a huge opportunity to share the management of their condition with every patient, helping them to avoid the risk of disabling complications.

REFERENCES

1. WHO/IDF Saint Vincent Declaration Working Group. Diabetes Mellitus in Europe: a problem at all ages in all countries. A model for prevention and self care. Acta Diabetol 1990; 27:181-3.

2. Diabetes UK. Diabetes in the UK 2010: Key statistics on Diabetes. Available at: http://www.diabetes.org.uk/Documents/Reports/Diabetes_in_the_UK_2010.pdf

3. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998;352:837-53.

4. NHS Information Centre 2011. National Diabetes Audit Executive Summary 2009-2010. http://www.ic.nhs.uk/webfiles/Services/NCASP/Diabetes/200910%20annual%20report%20documents/National_Diabetes_Audit_Executive_Summary_2009_2010.pdf

5. Diabetes UK. UKPDS - Implications for the care of people with Type 2 diabetes (Jan 1999). Available at: http://www.diabetes.org.uk/ukpds

6. National Institute for Health and Clinical Excellence, 2008. type 2 diabetes: the managements of type 2 diabetes. Clinical Guideline 66. http://www.nice.org.uk/nicemedia/pdf/CG66NICEGuideline.pdf

7. NICE. Type 1 diabetes in adults: full guideline part 2. CG15, July 2004. Available at: www.nice.org.uk/CG15

8. Chalmers J, et al. ADVANCE (Action in Diabetes and Vascular Disease), Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72

9. Medicines and Healthcare Regulatory Authority, 2011. Pioglitazone: risk of bladder cancer. Drug Safety Update 2011;5(1). Available at: www.mhra.gov.uk

9. NICE. Type 2 diabetes: newer agents. CG87. May 2009 (Updated September 2010). Available at: http://guidance.nice.org.uk/CG87/NICEGuidance/pdf/English Accessed December 2011