Biography - Eamonn Brady MPSI is the owner of Whelehans Pharmacy in Mullingar. He graduated from the Robert Gordon University in Aberdeen in 2000 with a Masters in Pharmacy. He worked for Boots in the UK before moving back to Ireland in 2002. He bought Whelehans Pharmacy in Mullingar in 2005. He undertakes clinical training for nurses in the midlands.

CPD 17: DIABETES

Diabetes

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60 Second Summary

Diabetes is one of the fastest growing diseases in Ireland. The Diabetic Federation of Ireland estimates that there are over 200,000 diabetics in Ireland and that over half of these have no idea that they have diabetes. Some countries have a population prevalence of up to 6% for diabetes.

Diabetes mellitus is a metabolic disorder of multiple aetiology, characterised by chronic hyperglycaemia, with disturbances of carbohydrates, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.

There are two types of Diabetes, Type 1 and Type 2. In Type 1 diabetes, the pancreas does not make enough insulin. In Type 2 diabetes, the body cannot respond normally to the insulin that is made, which is often called insulin resistance.

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Diabetes is one of the fastest growing diseases in Ireland. The Diabetic Federation of Ireland estimates that there are over 200,000 diabetics in Ireland and that over half of these have no idea they have diabetes. Some countries have a population prevalence of up to 6% for diabetes.1

WHAT IS DIABETES?

The World Health Organisation (WHO) defines diabetes mellitus as “a metabolic disorder of multiple aetiology, characterised by chronic hyperglycaemia, with disturbances of carbohydrates, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both”.2 Diabetes mellitus is a condition that occurs when the body cannot use glucose normally. Glucose is the main source of energy for the body's cells. The levels of glucose in the blood are controlled by the hormone insulin, which is made by the pancreas. Insulin helps glucose enter the cells.

TYPES

Type 1 - This type of diabetes usually appears before the age of 40 and most often starts as a teenager. Type 1 diabetes is the least common of the two main types and accounts for between 5 and 15 percent of all people with diabetes.

Type 2 - In most cases this is linked with obesity. Obesity results in insulin resistance which interferes with insulin’s action on glucose uptake and its effect on fatty acids and protein metabolism.3 This type of diabetes usually appears in people over the age of 40, though in South Asian and African-Caribbean people, it often appears after the age of 25.

DIABETES SYMPTOMS

• Frequent urination

• Excessive thirst

• Extreme Hunger

• Increased fatigue

• Irritability

• Increased weight loss

• Blurred vision

• Genital itching or regular thrush

• Slow healing of wounds

CAUSES AND RISK FACTORS

Type 1 diabetes - Type 1 diabetes develops when the insulin producing cells in the pancreas have been destroyed. It is not known for sure why these cells have been damaged but the most likely cause is an abnormal reaction of the body to the cells. This may be triggered by a viral or other infection.

Type 2 diabetes - Risk factors are as follows:

Age - Risk of diabetes increases in patients over 40 or over 25 in African and Asian patients.

Family and ethnicity - Having diabetes in the family increases the risk of diabetes. The closer the relative is, the greater the risk. People of Afro-Caribbean or South Asian origin are at least five times more likely to develop diabetes.

Weight - Over 80 per cent of people diagnosed with Type 2 diabetes are overweight. The more overweight and inactive the person is, the greater is their risk of diabetes.

Waist size - Women – if the waist measures 31.5in (80cm) or more the risk of diabetes increases.

Men – if the waist is 37in (94cm) or more means increased risk of developing diabetes

Gestational Diabetes - Pregnant women can develop a temporary type of diabetes called gestational diabetes. Having this, or giving birth to a large baby, can increase the risk of a woman going on to develop diabetes in the future.

DIAGNOSIS

Guidelines exist to help diagnose diabetes. According to these guidelines, people without diabetes have fasting blood glucose no higher than 6.0 mmol/l; after a meal blood glucose does not exceed 7.8 mmol/l. If fasting blood glucose is 7.0 mmol/l or above, and /or it rises to more than 11.1 mmol/l after a meal, the diagnosis of diabetes is made. A further blood

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ESSENTIALS

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CPD 17: DIABETES

test called a HbA1c can then be used to monitor diabetes control over a three month period.

HbA1c - HbA1c level may be checked every 2-6 months. This test measures recent average blood glucose level. HbA1c occurs when haemoglobin joins with glucose in the blood. When glucose sticks to haemoglobin it forms a glycated haemoglobin molecule, also known as A1c and HbA1c. The more glucose found in the blood the more glycated haemoglobin (HbA1c) will be present.

HbA1c gives a good indication of average blood glucose over the previous 2-3 months. Studies including the UK prospective diabetes study (UKPDS)4 have shown that HbA1c levels can predict the risk of development of diabetes related complications better than other measures. In the UKPDS each 1% reduction in mean HbA1c provided a 21% risk reduction for any diabetes-related endpoint including a 21% reduction for diabetes related death; 14% reduction for myocardial infarction and 37% reduction for microvascular complications.4,5

The target level is usually somewhere between 48 and 53 HbA1c (mmol/mol) which is between 6.5% and 7.5% under the traditional percentage measuring tool. If HbA1c level is above the target level then treatment may need to be reviewed. There is no need to fast prior to HbA1c test.

New units to measure HbA1c - Glycated haemoglobin (HbA1c) has traditionally been reported as a percentage of total haemoglobin. The new International Federation of Clinical Chemistry (IFCC) reference method is more specific for HbA1c than the traditional percentage measurement of HbA1c. The change is due to the development of a new standardised reference method for measuring HbA1c and also a move to use the Standard International (SI) unit of millimoles of HbA1c per mole of HbA1c (mmol/mol). From June 2011, the measurement of HbA1c is only in mmol/mol. Comparing results from different labs throughout the world and interpreting clinical trial results will now be easier.6 See Table 1

Target HbA1c - The general target for HbA1c under the traditional percentage method was HbA1c < 7.0%. However, this could vary slightly depending on the person's risk of severe hypoglycaemia, cardiovascular status and co-morbidities.

The non-diabetic reference range for HbA1c using the IFCC reference method is now 20- 42 mmol/mol, rather than the traditional recommended HbA1c range of 4.0 – 6.0 %. When HbA1c results are expressed as % haemoglobin, the equation to convert the value to the new IFCC recommended HbA1c (mmol/mol) value is: IFCC-HbA1c (mmol/mol) = HbA1c (%) - 2.15 x 10.929

Limitations of HbA1c Measurement - HbA1c results can be misleading in certain situations. For example HbA1c can be inaccurate in a variety of haematological conditions where there is abnormal red cell turnover, where there is abnormal haemoglobin, during pregnancy and in some patients with renal or liver disease.

HbA1c testing is not recommended for diagnosis of type 1 diabetes, and should not be used to diagnose type 2 diabetes in children, or patients with end-stage kidney disease,

haemoglobinopathies or anaemia.

COMPLICATIONS

Short term complications

Hypoglycaemia - Hypoglycaemia (or a ‘hypo’) occurs when the level of glucose in the blood falls too low, usually under 4 mmol/l. A hypo may occur if the patient has taken too much diabetic drugs, delayed or missed a meal or snack, not eaten enough carbohydrate, taken more strenuous exercise than usual, and have been drinking alcohol without food. Symptoms of hypoglycaemia include feeling shaky, sweating, tingling in the lips, paleness, pounding heart, confusion and irritability. It can be easily treated by drinking glucose or sugary drink. If left untreated, hypoglycaemia can lead to unconsciousness and would need to be treated with a glucagon injection. Glucagon is a hormone excreted by the liver and causes the liver to convert glycogen to glucose thus raising blood sugar levels. Glucagon raises blood sugar quickly and the injectable form is reserved for when the patient is unconscious as the patient can no longer take glucose orally.

Diabetic Ketoacidosis - Consistent high blood glucose levels over the short term can lead to diabetic ketoacidosis. This happens because there is a lack of glucose entering the body’s cells so the body begins to use stores of fat as an alternative source of energy. This in turn produces an acidic by-product known as ketones. This leads to nausea, vomiting and dehydration. If left untreated it can lead to a coma and even death.

LONG TERM COMPLICATIONS

The long term complications of both type 1 and type 2 diabetes are similar if not treated properly. Complications include:

• angina

• heart attack

• stroke

• diabetic kidney damage

• diabetic foot ulcers or circulation problems in your legs and feet

• diabetic eye

Cardiovascular Disease - Cardiovascular disease is the leading cause of mortality in type 2 diabetes; accounting for over 70% of deaths in diabetic patients due mostly to acute MI, congestive heart failure and stroke.7 The risk of cardiovascular disease in diabetic patients without a history of cardiovascular disease is similar to the risk in non-diabetes patients who have a history of myocardial infarction.8

Hypertension - Evidence shows that 80% of patients with type 2 diabetes have hypertension (defined as blood pressure over 140/90mmHg). The UKPDS demonstrated that improved control of blood pressure in diabetic patients reduced morbidity and mortality. A blood pressure reduction of 10/5mmHg was associated with a 24% reduction in the risk of diabetic related problems.8 A blood pressure of less than 130/80mmHg is recommended for diabetic patients to maintain renal function and reduce cardiovascular problems.

ACE inhibitors or angiotensin 2 inhibitors are generally the preferred first-line options for hypertension in diabetic patients, especially in the presence of microalbuminuria, since both classes have been shown to delay deterioration in renal function.9 Renal function must be carefully monitored early in treatment due to the risk of bilateral renal artery stenosis.8 Diuretics may worsen insulin resistance particularly at

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Table 1HbA1c Conversion Table

% mmol/mol % mmol/mol % mmol/mol % mmol/mol5 31 7 53 9 75 11 97

5.1 32 7.1 54 9.1 76 11.1 985.2 33 7.2 55 9.2 77 11.2 995.3 34 7.3 56 9.3 78 11.3 1005.4 36 7.4 57 9.4 79 11.4 1015.5 37 7.5 58 9.5 80 11.5 1025.6 38 7.6 60 9.6 81 11.6 1035.7 39 7.7 61 9.7 83 11.7 1045.8 40 7.8 62 9.8 84 11.8 1055.9 41 7.9 63 9.9 85 11.9 1076 42 8 64 10 86 12 108

6.1 43 8.1 65 10.1 87 12.1 1096.2 44 8.2 66 10.2 88 12.2 1106.3 45 8.3 67 10.3 89 12.3 1116.4 46 8.4 68 10.4 90 12.4 1126.5 48 8.5 69 10.5 91 12.5 1136.6 49 8.6 70 10.6 92 12.6 1146.7 50 8.7 72 10.7 93 12.7 1156.8 51 8.8 73 10.8 95 12.8 1166.9 52 8.9 74 10.9 96 12.9 117

Glycaemic Control Index

Excellent Good Borderline

Poor Very Poor

HbA1c HbA1c HbA1c HbA1c

TABLE 1 - HbA1c Conversion Table

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CPD 17: DIABETES

higher doses but may be used effectively at low dose, especially in combination with other agents such as ACE inhibitors or angiotension inhibitors.9,8 Beta-blockers (especially non-cardio selective) can worsen glycaemic control. In type 2 diabetes, beta-blockers should only be used for blood pressure management after the other drug classes have been tried. Combination of beta blockers with thiazides in particular should be avoided.8

Cholesterol - Studies have shown a three times higher incidence of dyslipidaemia with type 2 diabetes with females showing an even higher comparative increase than males.10 Typically there is moderate hypertriglyceridaemia and low HDL with diabetes. LDL levels may be within the normal range, but are composed of small dense particles, which are associated with increased atherosclerosis. Evidence shows that statins are very beneficial in preventing atherosclerosis in diabetic patients. The European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) have recommended that statin therapy should be considered in type 2 diabetics adults without cardiovascular disease if total cholesterol is greater than 3.5mmol/L, to achieve a target reduction of 0-40% in LDL.10

DIABETIC KIDNEY DAMAGE (NEPHROPATHY)

Each kidney is made of hundreds of thousands of filtering units called nephrons. Each nephron has a cluster of tiny blood vessels called a glomerulus which remove waste from the body. Too much blood sugar can damage nephrons, causing them to thicken and become scarred. Slowly, over time, more and more blood vessels are destroyed. The kidney structures begin to leak and protein (albumin) begins to pass into the urine. High blood pressure exacerbates the problem.

Symptoms - Symptoms develop late in the disease and may include:

• Fatigue

• Foamy appearance or excessive frothing of the urine

• Frequent hiccups

• General ill feeling

The main sign of diabetic nephropathy is persistent protein in the urine. A microalbuminuria test can confirm diabetic nephropathy.

The goals of treatment are to keep the kidney disease from getting worse and prevent complications. Keeping blood pressure under control (under 120/80) is the best way to prevent diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors (eg. Lisinopril) and angiotensin 2 inhibitors (eg. Irbesartan) are used to lower blood pressure and protect kidneys from damage in diabetic nephropathy:

It is important to note that non-steroidal anti-inflammatory drugs such as ibuprofen and diclofenac should be avoided in diabetic nephropathy as they can further damage the kidneys.

DIABETIC NEUROPATHY

Diabetic neuropathy is a common complication of diabetes, in which nerves are damaged as a result of high blood sugar. Approximately 50% of people with diabetes will eventually develop nerve damage.

Symptoms

Digestive tract: Constipation, diarrhoea, nausea and vomiting and swallowing difficulty

Legs and arms:

• Deep pain, most commonly in the feet and legs

• Loss of the sense of warm or cold

• Muscle cramps

• Numbness

• Tingling or burning sensation in the extremities, particularly the feet

• Weakness

Treatment - The goals of treating diabetic neuropathy are to prevent the disease from getting worse and to reduce the symptoms of the disease. Tight control of blood sugar (glucose) is important to prevent symptoms and problems from getting worse.

Medication may be used to reduce the symptoms in the feet, legs, and arms, including:

• Antidepressant drugs, such as amitriptyline, doxepin (Sinequan®), or duloxetine (Cymbalta®)

• Anticonvulsants such as gabapentin (Neurontin®), pregabalin (Lyrica®), carbamazepine (Tegretol®), and valproate (Epilim®)

Diabetic Retinopathy - Diabetic retinopathy is caused by damage to blood vessels of the retina, the tissue at the back of the eye. Symptoms of diabetic retinopathy include:

• Blurred vision and gradual sight loss

• Shadows or missing areas of vision

• Floaters

• Difficulty seeing in darkness

Many people with early diabetic retinopathy have no symptoms before major bleeding occurs in the eye. Therefore annual dilated eye examinations are important for diabetics.

DIABETES TREATMENT

The aim of diabetes treatment is to do what the body once did automatically which is to mimic the insulin pattern before diabetes and to keep blood sugar under control.

For type 1 diabetes, insulin is always part of treatment as the body does not produce any insulin. In type 2 Diabetes, your body still produces some insulin so non-drug options or drugs may be used to help the body make better use of the insulin that it still produces.

There is no cure for type 1 diabetes but it can be kept under control. Type 1 diabetes is controlled by administering insulin. This allows glucose to be absorbed into cells and converted into energy, stopping it building up in the blood.

Many with type 2 diabetes can manage to control their condition simply by changing their lifestyle. Changes include:

Diet - A healthy diet is essential and it is important to eat regularly three times a day. Special diabetic foods are not needed for a healthy diet; eating a balanced diet that is low in saturated fat, sugar and salt and high in fibre, vegetables and fruit is sufficient. Include carbohydrates, such as pasta, potatoes or sugary foods such as fruit in each meal. There is strong evidence that progression from hyperglycaemia to type 2 diabetes can be

prevented or at least delayed by dietary effort.

Exercise - Exercise promotes a healthy circulation and maintains a healthy weight. At least half an hour of moderate activity on at least five days a week is recommended.

Smoking - It is especially important for diabetics to quit smoking. This is because a diabetic already has a five fold increased chance of developing cardiovascular disease or circulatory problems compared to non-diabetics. Smoking makes the chances of developing these diseases even greater.

Medication - If lifestyle changes alone don't reduce glucose levels, medication may be used to increase insulin production and strengthen its effect. All of the types of oral hypoglycemic drugs and insulin are safe in older patients, although each has some limitations in older people. "Start low and go slow" is a good principle to follow when starting any new medications in an older adult.

Metformin improves the effectiveness of insulin by reducing the amount of glucose released from the liver and improving the way glucose is used by muscles. It causes less weight gain than other diabetic medication. Metformin acts on the liver to lower production of glucose and reduce glycogenolysis; it has no effect on insulin release so is not associated with hypoglycaemia. Up to 3g of metformin can be administered daily.14 Metformin is an attractive agent to use in the elderly due to a low risk of hypoglycemia. However, it should be given with caution in older diabetic patients because of the risk of lactic acidosis. Older patients often have impaired renal function despite an apparently normal serum creatinine concentration.

Sulphonylureas encourage the pancreas to produce more insulin. Because they stimulate insulin secretion, they are most effective in newly or recently diagnosed patients who still have relatively active beta-cell function. Sulfonylureas are usually well tolerated in older patients; however hypoglycemia is the most common side effect and are more common with older long-acting sulfonylurea drugs. However Gliclazide MR is well tolerated in elderly patients.

Thiazolidinediones reduce the body's resistance to insulin and are generally limited to use with metformin and sulphonylureas if other standard treatments were not working or not tolerated. They are licensed as monotherapy in obese patients if metformin is ineffective or not tolerated. They work by reducing insulin resistance in adipose tissue, muscle and liver.17 They take up to 12 weeks to exert their full affect. Thiazolidinediones are useful for some older diabetic patients because they can be given to patients who have impaired renal function. Pioglitasone (Actos) is still on the Irish market but must be used in caution in those with cardiovascular problems.

Newer medicines called DPP-4 inhibitors, such as sitagliptin (Januvia®), help the body to produce more insulin in response to meals.

They work by enhancing the levels of active incretin hormones thus enhancing insulin and reducing glucagon secretions.18 DPP-4 inhibitors don't cause weight gain and only rarely cause hypos.

The combination of sitagliptin and metformin has been shown to be better tolerated (14.5%

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CPD 17: DIABETES

incidence of adverse effects) compared with a combination of sulfonylurea and metformin (30.3% incidence of adverse effects).28 Long-term safety with this class of drug in the elderly has not been established.

Acarbose (Glucobay®) lowers blood glucose by slowing the breakdown of some carbohydrates. Acarbose reduces the digestion and absorption of starch and sucrose by competitively inhibiting the intestinal enzymes involved in the degradation of disaccharides, oligosaccharides and polysaccharides. The reduction in HbA1c is modest, however it very unlikely to cause weight gain.19 Acarbose has not been widely tested in elderly diabetic patients, but is likely to be fairly safe and effective.

Meglitinides include repaglinide (Novonorm) and nateglinide (Starlix). Meglitinides act as postprandial glucose regulators. They increase insulin secretion by binding to specific sites within the ß cells in the pancreas. They have a rapid onset of action meaning they need to be administered shortly (1 – 30 minutes) before meals.21 They have a short duration of action, requiring multiple daily dosing.22 Long-term data are on treatment outcomes of meglitinides are not available.23 Meglitinides may play a useful role in patients with irregular meal times (e.g. shift workers).23 Gastrointestinal upset is generally less than with metformin however weight gain is greater than experienced with metformin and can be as much as 3kg in three months.

Exenatide is synthetic peptide drug that works by increasing the secretion of insulin and reducing secretion of glucagon in response to hyperglycaemia.24 It is administered by subcutaneous injection twice daily. The two drugs available in this class in Ireland (and allowed on the GMS) are Bydureon® taken once weekly and Byetta® taken twice daily.

Fast-acting insulin preparations include insulin aspart (NovoRapid®) and insulin lispro (Humalog®). The onset of action of insulin aspart is 10-20 minutes and the duration of action is 3-5 hours. Insulin lispro has an onset of action of approximately 15 minutes and duration of action of 2-5 hours.26

Insulin aspart is injected subcutaneously immediately before meals or, when necessary, soon after. Insulin lispro is injected subcutaneously shortly before meals or, when necessary, soon after. Insulin aspart and insulin lispro are normally used in combination with longer-acting insulin to provide a steady glucose level throughout the day. The dose of insulin aspart or lispro needs to be individualised to the patient.

The long-acting insulin glargine (Lantus®) is administered subcutaneously once daily. It can be administered at any time, but it should be given at the same time each day. The dosage and timing of administration should be individualised to the patient. It shows a constant concentration-effect versus time profile which lasts approximately 24 hours. Insulin glargine is used as an additional therapy to oral hypoglycaemic agents in type 2 diabetes where oral hypoglycaemic agents do not provide adequate glucose control on their own.27

Metformin remains the most effective monotherapy, especially in obese patients.

Sulfonylureas remain a good choice if the patient is not overweight. Repaglinide and acarbose are also authorised for monotherapy but are rarely used due to reasons described above. Thiazolidinediones may be used as monotherapy only in overweight patients if metformin is ineffective or not tolerated but should be avoided in patients with cardiovascular problems.

Step 1 if monotherapy is ineffective is dual therapy which includes metformin and/or sulfonylurea and/or thiazolidinedione. Sitagliptin (Januvia®) is a popular add on therapy to metformin due to its success and low incidence of side effects. Meglitinides, acarbose and exenatide are also authorised for combination therapy.

Step 2 is triple therapy (metformin and/ or sulfonylurea and/or thiazolidinedione and/or meglitinides and / or acarbose). Insulin therapy may be considered with dual therapy but should be initiated by a specialist.

It must be borne in mind that metformin and sulphonureas provide a greater reduction in HbA1c than any of the newer oral anti-diabetic drugs. Metformin and sulphonureas reduce HbA1c by greater than 1.5%, no other oral anti-diabetic drug reduces HbA1c by greater than 1.5%.19,23,27 Metformin and sulphonureas are central to any treatment regime of type 2 diabetes. Metformin and sulphonureas are also less expensive than other oral anti-diabetic drugs.

REFERENCES1. Stumvoll M, Goldstein BJ et al, Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365: 1333-462. World Health Organisation Expert Committee. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation, part 1: diagnosis and classification of diabetes mellitus. Geneva: World Health Organisation 19993. Nolan JJ. What is type 2 diabetes? Diabetes: Basic Facts. Medicine 2006; 34 (2): 52-564. Stratton I, Adler A et al, Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405-125. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No: CD002968. DOI: 10.1002/14651858. CD002968. Pub26. Barth JH et al. Consensus meeting on reporting glycated haemoglobin and estimated average glucose in the UK: report to the National Director for Diabetes, Department of Health. Ann Clin Biochem 2008; 45: 343–47. Fisher M. Macrovascular disease in diabetes. Complications of Diabetes. Medicine 2006; 34(3): 101-103. 20068. Hunter S, Bell P. Diabetes and hypertension. Management of Diabetes. Medicine 2006; 34 (2): 76-799. Dobesh P. Managing hypertension in patients with type 2 diabetes mellitus. American Journal Health-Syst Pharm. 2006; 63: 1140-910. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. European Heart Journal 2007; 28: 88-13611. NMIC (National Medicines Information Centre), St James Hospital Dublin. Update on Hypertension. NMIC bulletin 2004; Volume 10: 112. Anti Thrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of anti platelet therapy for prevention of death, myocardial infarction and stroke in high-risk patients. BMJ 2002; 324:71-8513. Moore H, Summerbell C, et al. Dietary advice for

Pfizer Healthcare Ireland are committed to supporting the continuous professional development of pharmacists in Ireland. We are delighted to be partnering with Irish Pharmacy News in order to succeed with this.

Throughout the year, Irish Pharmacy News will deliver 12 separate modules of continuous professional development, across a wide range of therapy areas. These topics are chosen to support the more common interactions with pharmacy patients, and to optimise the patient experience with retail pharmacy.

We began the 2011 programme with a section on the Gastrointestinal System. Other topics include Diabetes (Types I and II), the Cardiovascular System, Smoking Cessation, Infections, Parkinson’s Disease, Alzheimer’s Disease, Depression and others. We hope you will find value in all topics.

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treatment of type 2 diabetes mellitus in adults (Review). Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD004097. DOI: 10.1002/14651858. CD004097.pub314. SPC Glucophage®. Available at www.medicines.ie15. Saenz A, Fernandez-Esteban I, et al. Metformin monotherapy for type 2 diabetes mellitus (Review). Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002966. DOI: 10.1002/14651858. CD002966.pub316. Cuthbertson D, Leese G. Managing type 2 diabetes: oral anti-diabetic drugs. Prescriber 5 July 2003: 47-5217. Davies M, Srinivasan B. Glycaemic Management of type 2 diabetes. Medicine 2006; 34 (2): 69-7518. Sitagliptin in type 2 diabetes. “On the Horizon” - Post Launch Update. National Prescribing Centre and Wessex Drug and Medicines Information Centre. May 2007. Monograph Number: 119. Heine RJ, Diamant M, et al. Management of hyperglycaemia in type 2 diabetes. BMJ 2006; 333: 1200-420. SPC Glucobay® Available at www.medicines.ie 21. SPC Starlix® Available at www.medicines.ie22. Black C. Donnelly P, et al. Meglitinide analogues for type 2 diabetes mellitus (Review). Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD004654. DOI: 10.1002/14651858. CD004654. pub223. Type 2 diabetes (part 1): the management of blood glucose. MeReC Briefing, National Prescribing Centre, NHS, 2004; Issue No. 2524. Cvetkovic R, Plosker G. Exenatide. A Review of Its use in Patients with Type 2 Diabetes Mellitus (as an Adjunct to Metformin and/or a Sulfonylurea). Drugs 2007; 67 (6): 935-95425. SPC Byetta® Available at www.medicines.ie26. NMIC (National Medicines Information Centre), St James Hospital Dublin. Diabetes Mellitus- Recent therapeutic developments. Volume 9. Number 4. 200327. Nathan DM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2006; 49: 1711-172128. Update on type 2 diabetes mellitus, National Medicines Information Centre, St James Hospital Dublin. Volume 13, Number 3. July 2007