CPD Module: Diabetes

Diabetes is a group of chronic endocrine diseases characterised by elevated blood glucose levels. This is due to insufficient insulin production, impaired insulin action, or a combination of both. On completion of this module, it is expected the reader will have an enhanced understanding of the different types of diabetes, diagnostic tools, comorbidities and complications. This module will also touch on disease monitoring and pharmacological and non-pharmacological management strategies.

Introduction

Diabetes can lead to a range of health complications, including disorders of the eye, kidney, nerves and heart. There are three major types of diabetes: Type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus. The pathogenesis of each subtype is different, with each subtype having a varying etiology, presentation and management.

Diabetes has a significant health burden and therefore requires a comprehensive management plan, with both pharmacological and non-pharmacological interventions necessary to achieve optimal clinical outcomes. Pharmacists play a vital role in the management of diabetes, including optimising a treatment regimen, providing patient education, and monitoring for complications.¹

Type 1 diabetes mellitus (T1DM)

T1DM is an autoimmune condition that destroys pancreatic beta cells responsible for insulin production. This destruction of beta cells occurs over months or years and leads to insufficient insulin production. A combination of genetic susceptibility and environmental factors, including infection or toxins, may trigger autoimmunity.  

T1DM often appears in childhood or early adulthood, accounting for 5-to-10 per cent of all diabetes cases. The onset of T1DM increases from birth and peaks at ages 4-to-6 years and 10-to-14 years. Symptoms of T1DM include polyuria, polydipsia, polyphagia, fatigue, weight loss and blurred vision. These symptoms can often develop rapidly and lead to diabetic ketoacidosis if not treated appropriately.

Diabetic ketoacidosis is life-threatening and occurs due to a shortage of insulin, which causes the body to break down fatty acids into ketone bodies. Symptoms of diabetic ketoacidosis include nausea, vomiting, abdominal pain and decreased level of consciousness.^1,2

Type 2 diabetes mellitus (T2DM)

T2DM is a chronic metabolic condition. It is characterised by insulin resistance, where the cells in the body become less responsive to insulin. Initially, this is countered by an increase in insulin production to maintain glucose homeostasis, but this declines over time, leading to T2DM.

T2DM involves a complex interplay between genetics and lifestyle factors. It is linked to lifestyle factors such as poor diet, obesity and lack of physical activity. T2DM accounts for approximately 90 per cent of diabetes cases worldwide. It often occurs in adults over 45 years of age, but it can also affect younger populations due to an increase in obesity levels, physical inactivity and energy-dense diets. The main symptoms of T2DM include frequent infections, slow-healing wounds, blurred vision, tingling in the hands/feet and fatigue. T2DM often has a gradual onset, with many patients remaining asymptomatic for years.³

Gestational diabetes

Gestational diabetes is a form of diabetes that develops during pregnancy, usually in the second or third trimester. It occurs when the body does not produce enough insulin to meet the increased demands during pregnancy. It has an estimated prevalence of approximately 10 per cent among pregnant women.

Gestational diabetes has a genetic component and is also linked to obesity and physical inactivity. Additionally, conditions such as hypertension, hypercholesterolemia and polycystic ovarian syndrome are associated with an increased risk of developing gestational diabetes. Gestational diabetes can increase the risk of complications for both mother and baby during the pregnancy. It also can predispose the mother to developing T2DM later in life.

Gestational diabetes is often detected during pregnancy screening, as it may present with no symptoms. Some signs of gestational diabetes can include polyuria, polydipsia, fatigue and blurred vision.⁴

Diagnosis

The diagnosis of diabetes is generally through a characteristic history and elevated serum glucose levels. There are four main diagnostic criteria, and diagnosis can be made if any of the following are met:

• Fasting plasma glucose (FPG) level ?7.0 mmol/L after an eight-hour fast.
• Oral glucose tolerance test (OGTT) – A two-hour plasma glucose level ?11.1 mmol/L following a 75g glucose load.
• Glycated haemoglobin (HbA1c) level ?6.5%. Glycated haemoglobin is a form of haemoglobin that is chemically linked to a sugar molecule. It is used to determine the three-month average plasma glucose level and is therefore useful for assessing glycaemic control.
• Random plasma glucose level ?11.1 mmol/L along with symptoms of hyperglycaemia (polyuria, polydipsia, polyphagia, weight loss).

There are several methods to distinguish T1DM from T2DM. C-Peptide levels tend to be lower in T1DM, indicating low production of insulin in the body. Furthermore, the glutamic acid decarboxylase (GAD) antibodies are indicative of T1DM. Finally, T1DM often presents at a younger age and with a more rapid onset of symptoms than T2DM, although this alone cannot give a definitive conclusion. The diagnosis of gestational diabetes is usually based on a glucose challenge test performed between 24-to-28 weeks of pregnancy. A high score on this test will lead to an OGTT to confirm diagnosis.¹

Co-morbidities and complications

There are several comorbidities associated with the subtypes of diabetes that can lead to complications and poor clinical outcomes. Patients with T1DM are at a greater risk of developing other autoimmune conditions such as Graves’ disease, Hashimoto’s thyroiditis and coeliac disease. Diabetic ketoacidosis, as described above, results from low insulin levels and is a potential life-threatening complication. Hypoglycaemia is generally defined as plasma glucose concentration below 3.9mmol/L. Hypoglycaemia is much more common in T1DM than T2DM. The most common causes of hypoglycaemia include incorrect medication use, insufficient food intake, increased physical activity and excessive alcohol intake. Signs and symptoms of hypoglycaemia include fatigue, confusion, tremors, palpitations and seizures. Hypoglycaemia can result in diabetic coma and potential death.¹

Macrovascular complications involve the large blood vessels in the body and are prevalent in all types of diabetes. Macrovascular complications are associated with poor glycaemic control, insulin resistance and excess fatty acids. The primary macrovascular complications include coronary disease, peripheral vascular disease and cerebrovascular disease.

Early macrovascular disease is linked to the accumulation of atherosclerotic plaque in the blood vessels supplying blood to the heart, brain, limbs and other organs. Atherosclerosis is a thickening and hardening of the arterial walls from plaque deposits of lipids, calcium and other substances. This condition may be associated with hypertension and dyslipidaemia.

Atherosclerosis can lead to complete obstruction of blood vessels, causing claudication, myocardial infarction and stroke. Cardiovascular disease is the primary cause of morbidity and mortality in diabetic patients.^1,5

Microvascular complications involve the small blood vessels in the body and are also prevalent in all types of diabetes. These complications are generally caused by poor glycaemic control, and they typically include retinopathy, nephropathy and neuropathy. Diabetic retinopathy is characterised by the proliferation of new retinal blood vessels, which can lead to retinal haemorrhage and swelling of the macula, ultimately resulting in blindness.

Signs of retinopathy are minimal until the disease is advanced, at which point symptoms can include loss or blurring of vision, microaneurysms, venous loops, hard exudates and soft exudates. The risk of diabetic retinopathy increases with the duration of diabetes and uncontrolled hypertension.^1,5

Diabetic nephropathy is the chronic loss of kidney function in patients with diabetes. It can occur in both T1DM and T2DM and is a leading cause of chronic kidney disease. Proteinuria is characteristic of diabetic nephropathy. Hypertension is an early sign of nephropathy, often accompanied by the development of microalbuminuria (protein in the urine). As the disease progresses, patients may develop oedema, arrhythmias and symptoms related to kidney failure.^1,5

Diabetic neuropathy is a diverse condition associated with nerve pathology and can include focal, diffuse, sensory, motor and autonomic neuropathy. The pathophysiology of neuropathy is complex and involves nerve glycation, possibly with an autoimmune component. Symptoms of neuropathy depend on the site of nerve damage and may include weakness, numbness, tingling, pain and urinary symptoms.^1,5

There is an increased risk of pregnancy complications, both maternal and foetal, associated with gestational diabetes. Maternal complications include preterm birth, pre-eclampsia and the development of T2DM. Pre-eclampsia is a multisystem disorder characterised by the onset of hypertension and proteinuria. It increases the risk of adverse events during pregnancy, including impaired liver and renal function, and can even result in death. Foetal complications can include macrosomia, hypoglycaemia, hyperbilirubinaemia and neonatal respiratory distress syndrome.⁴

Monitoring

Patients with diabetes require regular blood glucose monitoring. Glycaemic targets should be individualised based on each patient’s health and comorbidities. Monitoring blood glucose levels is vital in the management of diabetes and can be achieved through capillary blood sampling with a glucose meter or continuous glucose monitors. Patients using a glucose meter should check their blood glucose levels at least four times daily, including before meals and before sleeping.

Continuous glucose monitors have become the standard of care in recent years. These devices measure glucose levels every few minutes and transmit data to a receiver or phone application. They can raise an alarm when hypoglycaemia or hyperglycaemia thresholds are met. They also allow patients to anticipate glucose levels and adjust treatment. Optimal HbA1c levels should be attained to reduce the risk of microvascular and macrovascular complications, while also preventing hypoglycaemia. The objective for most patients is less than or equal to 7 per cent, but some patients may benefit from more relaxed targets.¹

Regular blood pressure screening is recommended for all diabetic patients, with a target of 130/85mmHg. Lipid monitoring is also crucial, with a target of less than 5mmol/L if cardiovascular disease is not present or less than 3.9mmol/L if cardiovascular disease is present. Patients with diabetes may have foot complications due to neuropathy and poor circulation. Therefore, regular foot exams may be necessary.

Retinal changes generally start after five years of disease onset in T1DM, so it is recommended to start yearly retinal exams at this time. In T2DM, patients may already have retinal changes at the time of diagnosis, so yearly retinal exams are recommended at the time of diagnosis. Finally, a random spot urine sample measuring the albumin-to-creatinine ratio is an easy method to detect microalbuminuria.¹

Non-pharmacological treatment

The management of diabetes is complex and requires a multi-faceted approach for effective control. Non-pharmacological management plays a crucial role in diabetes care, with lifestyle changes necessary to prevent complications. In T2DM, the cornerstone of treatment is diet and physical activity. A diet low in refined carbohydrates and saturated fats, while high in fibre and monounsaturated fats, is crucial. Aerobic exercise for a minimum of 90-to-150 minutes per week is highly beneficial.

In obese patients, weight loss should be promoted to improve insulin sensitivity. Smoking cessation should be encouraged in both T1DM and T2DM, as smoking exacerbates cardiovascular risks. Alcohol moderation is also important as it can affect blood glucose levels.^1,3

The optimal management of T1DM requires patient education on diet and lifestyle. Patients should understand the interaction between diet, insulin, physical activity and daily routine. Nutritional education on carbohydrate estimation is vital in the management of diabetes. Consultation with a dietitian can assist patients in learning carbohydrate estimation to determine appropriate mealtime insulin dosing. Exercise is also important for patients with T1DM. Physical activity has beneficial effects on insulin sensitivity and overall health, but it requires careful management to avoid glucose fluctuations.^1,2

In gestational diabetes, non-pharmacological treatment is the cornerstone of management. Increased physical activity, dietary modification and glucose monitoring are all recommended. Engaging in at least 30 minutes of moderate-intensity aerobic exercise at least five days per week is advised. Furthermore, postprandial exercise can be shown to control glucose levels for up to three hours after meals.⁴

Pharmacological management

The objective of pharmacological management is to maintain optimal glycaemic control to prevent complications. The treatment approaches vary between T1DM, T2DM and gestational diabetes.

T1DM pharmacological management

The goal of pharmacological management of T1DM is the physiological replacement of insulin. This can be achieved by administering either multiple daily insulin injections (basal-bolus) or continuous subcutaneous insulin infusion using an insulin pump. Basal-bolus insulin treatment involves a long-acting basal insulin administered once or twice daily and a prandial short or rapid-acting insulin administered before meals.

The choice of insulin may depend on patient preference. Long-acting insulin is used for the basal dose, is often administered once daily, and examples include glargine and detemir to maintain baseline glucose levels. Intermediate-acting insulin is often injected twice daily and includes neutral protamine Hagedorn (NPH) or neutral protamine lispro. Rapid-acting insulin is generally administered 10-to-15 minutes before meals, with examples including lispro, aspart and glulisine. Basal-bolus regimens generally include a daily long-acting insulin, as well as a rapid-acting insulin with each meal for hyperglycaemia correction. The regimen should be titrated to target a blood glucose range that minimises the risk of hypoglycaemia and hyperglycaemia.²

Continuous subcutaneous insulin infusion, also known as an insulin pump, typically administers a continuous infusion of rapid-acting insulin to meet basal requirements. Mealtime boluses are also administered for prandial coverage. The insulin pump consists of a pump, an insulin-holding reservoir, tubing and a cannula or needle inserted subcutaneously. Newer diabetic technologies feature insulin pumps that are connected to continuous glucose monitors, which allow for automated insulin delivery to achieve optimal glycaemic control.²

Identification and treatment of hypoglycaemia is critical due to the potential adverse effects, including coma or death. For patients who are conscious and able to swallow, readily absorbable sources of carbohydrates, such as fruit juice, should be administered. Severe hypoglycaemia can also be treated with intravenous dextrose followed by a glucose infusion.

Glucagon can also be administered, if the patient is unable to take oral agents, either intramuscularly or intranasally. Glucagon is a peptide hormone produced by alpha cells in the pancreas. It causes the liver to engage in glycogenolysis, converting glycogen to glucose, which is released into the bloodstream. When the patient wakes, a complex carbohydrate source should be administered to achieve sustained normal blood glucose levels. Patient education and frequent blood glucose monitoring are important in reducing the risk of hypoglycaemia.⁶

T2DM pharmacological management

Patients with T2DM are more likely to develop various other medical issues, and therefore the objective of treatment is to achieve optimal glycaemic control to reduce the risk of these complications. Pharmacological management is generally initiated if adequate glycaemic control can’t be achieved through diet and exercise. There are various classes of antidiabetic drugs, and these can be used as monotherapy or in combination with other antidiabetic medications.^3,7

Metformin is generally considered first-line treatment for T2DM management. Metformin is recommended as monotherapy if the HbA1c level is 9% or lower at diagnosis, while it may be recommended as part of combination therapy if HbA1c level is greater than 9%. Metformin is a biguanide drug and effectively lowers blood glucose levels by decreasing glucose production in the liver, reducing intestinal absorption and improving insulin sensitivity. Therefore, metformin lowers both basal and postprandial blood glucose levels.

Metformin is generally weight-neutral, with the potential for slight weight loss. Metformin has the benefit of being unlikely to cause hypoglycaemia and it may have cardioprotective effects. It is generally fairly well-tolerated, with common adverse effects including nausea, vomiting, diarrhoea and abdominal pain.

Metformin should be administered with food to reduce the risk of gastrointestinal upset. Taking metformin with food can help minimise gastrointestinal upset, and gradually increasing the dose may reduce these adverse effects. However, there is a slight risk of lactic acidosis, particularly in patients with kidney problems, heart failure or alcohol dependence.^3,7,8

Sulfonylureas are a class of antidiabetic drug that stimulate pancreatic beta cells to increase insulin secretion. Sulphonylureas are effective in treating T2DM and can lower HbA1c by 1% to 1.25%. Treatment should begin with a low dose, with gradual increases based on glycaemic control. Gliclazide is a commonly used sulfonylurea in Ireland, available as an immediate-release tablet (taken twice daily 30 minutes before meals) and a modified-release tablet (taken once daily with meals). Hypoglycaemia is the most common adverse effect and can be severe, particularly after missing meals, exercise or with high doses.

Weight gain is another common adverse effect and the patient’s weight should be considered when choosing a sulfonylurea. Other adverse effects include nausea, vomiting, diarrhoea and dizziness. Sulfonylureas can be used as monotherapy or in combination with other antidiabetic drugs, except the meglitinides, as they have a similar mechanism of action. Sulfonylureas are often used as as an add-on to metformin, as they have different mechanisms of action and improve glycaemic control. Furthermore, this combination may have a neutral impact on body weight.^7,9

Dipeptidyl peptidase-4 (DPP-4) inhibitors are also used in the treatment of T2DM. They exert their mechanism of action by acting on incretin hormones, mainly GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide), which maintain glucose homeostasis by stimulating insulin secretion and decreasing glucagon secretion. Examples of DPP-4 inhibitors include linagliptin, saxagliptin and sitagliptin, and they are all administered orally once daily, with or after food. They are generally well-tolerated, with a low incidence of hypoglycaemia and having weight-neutral effects.

The most common adverse effects are upper respiratory tract infections, gastrointestinal problems, headaches and urinary tract infections. DPP-4 inhibitors also have antihypertensive effects, anti-inflammatory effects and immunomodulatory effects on the heart, kidneys and blood vessels. They can be used as monotherapy or as add-on therapy with other antidiabetic medications.¹⁰

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors work by inhibiting the reabsorption of glucose in the kidney, thereby lowering blood glucose levels. Dapagliflozin, empagliflozin and canagliflozin are examples of SGLT-2 inhibitors that are used to treat T2DM. Their use may vary, including for renal and cardiovascular diseases, but all are used to treat T2DM. They are administered orally, with the dose varying according to the indication. Canagliflozin should be administered before breakfast, while the others can be administered with or without food.

SGLT-2 inhibitors can be used as add-on therapy and may be based on risk factors such as atherosclerosis, heart failure and chronic kidney disease. The most common adverse events include female genital infections, urinary tract infections, increased urination, nausea, and constipation. They may cause slight weight loss and may cause hypoglycaemia, particularly when co-administered with insulin or sulfonylureas.¹¹

Thiazolidinediones work by acting on intracellular metabolic pathways to enhance insulin action and increase insulin sensitivity. Thiazolidinediones are administered orally once daily, with or without food. Pioglitazone is an example of a thiazolidinedione that can be used as monotherapy or in combination with other antidiabetic medications. The benefits of thiazolidinediones are that they are less likely to cause hypoglycaemia when used as monotherapy and are not contraindicated in patients with renal disease. However, they are generally not used as first-line treatment unless other medications are contraindicated, due to their adverse effect profile. The adverse effects of thiazolidinediones include weight gain, bone fractures, water retention, heart failure and increased risk of bladder cancer.^7,12

Meglitinides work to reduce blood glucose levels by binding to receptors on beta cells in the pancreas and stimulating the release of endogenous insulin. Repaglinide is an example of a meglitinide used to treat T2DM. It can be used as monotherapy or in combination with other antidiabetic drugs, though it should not be paired with sulfonylureas. It is a potential treatment option in patients with kidney disease. It is taken orally just before meals, with doses omitted if skipping meals. Common adverse effects include hypoglycaemia, weight gain, respiratory tract infections, diarrhoea and joint pain.^7,13

Glucagon-like peptide-1 (GLP-1) agonists work by activating the GLP-1 receptor. This slows gastric emptying, inhibits glucagon release and stimulates the production of insulin, thereby reducing hyperglycaemia. Dulaglutide, semaglutide, exenatide and liraglutide are examples of GLP-1 agonists.

Although metformin is first-line treatment for T2DM, GLP-1 agonists can be used in patients with an intolerance or contraindication to metformin, those with an HbA1C more than 1.5% above the target, or patients who have not reached their target HbA1C. GLP-1 agonists can be used as monotherapy or in combination with other antidiabetic medications. Most GLP-1 agonists are administered subcutaneously due to their poor oral bioavailability.

Liraglutide follows a daily dosing schedule, dulaglutide and semaglutide are administered once-weekly, and exenatide can be taken either twice daily or once weekly, depending on the formulation. GLP-1 agonists can also reduce obesity, lower risk of cardiovascular events and decrease the progression of chronic kidney disease; therefore, they can be beneficial for patients with these comorbidities. The main adverse effects of this class of drugs are nausea, vomiting and diarrhoea, which can potentially lead to acute kidney injury. Dizziness, mild tachycardia, infection, headaches and pruritus at the site of injection are also possible adverse effects. There is a low risk of minor hypoglycaemia.¹⁴

Insulin therapy can be used if non-insulin agents do not achieve adequate glycaemic control. In some cases, insulin may be used short-term to lower blood glucose levels after diagnosis or if the patient is ill. Insulin has the benefit of reducing hyperglycaemia and the long-term complications associated with it. However, hypoglycaemia is more common with insulin than with other antidiabetic medications, though insulin is less associated with other adverse effects such as gastrointestinal issues.⁷

Gestational diabetes management

Non-pharmacological approaches are the cornerstone of gestational diabetes management. However, pharmacological treatment may be necessary if glycaemic control is inadequate, despite adherence to exercise and diet.

Insulin does not cross the placenta and is considered first-line pharmacological treatment for gestational diabetes. Insulin regimens are typically basal-bolus regimens, which can effectively control blood glucose levels. Insulin dosages should be individualised based on glucose monitoring.

Metformin is the oral antidiabetic agent of choice, though its effectiveness shows mixed results. Use of metformin in pregnancy is off-label. Metformin does cross the placenta and may have adverse effects including abdominal pain, diarrhoea and preterm birth. Furthermore, treatment with metformin often fails, leaving insulin as the gold standard in the pharmacological treatment of gestational diabetes.⁴

Role of the pharmacist

Pharmacists play an important role in managing diabetes through medication management, patient education, monitoring and lifestyle advice. Pharmacists can counsel patients on key aspects of their medication management, including injection technique, the importance of medication adherence, and hypoglycaemia management. They can provide important valuable information on lifestyle changes, including dietary modifications, physical exercise, alcohol moderation and smoking cessation, all of which can help prevent complications associated with diabetes.

Pharmacists can also assist patients in monitoring the disease and screening for complications, thereby reducing the risk of complications and improving quality of life for patients. Finally, pharmacists can collaborate with other healthcare professionals to focus on a patient-centred approach to managing diabetes and improving clinical outcomes.