Getting control of diabetes

Damien O’Brien MPSI looks at treatment considerations in different types of diabetes and the role of the pharmacist

Introduction

Diabetes is a metabolic disease characterised by elevated blood glucose levels due to insufficient insulin production, impaired insulin action, or a combination of both. Diabetes can lead to a wide range of health complications. It is classified into several types, with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) being the most prevalent. The pathogenesis of each type is different, with varying aetiology, presentation and management.

Diabetes places a major burden on the healthcare system, causing significant morbidity, mortality and reduced quality of life. It 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 treatment plans, providing patient education, and monitoring for complications.¹

Background on type 1 diabetes mellitus (T1DM)

T1DM is an autoimmune condition characterised by the destruction of pancreatic beta cells responsible for insulin production. It is commonly diagnosed in childhood or adolescence, though it can be diagnosed at any age. A combination of genetic predisposition and environmental factors, including infections or toxins, may trigger autoimmunity.

Symptoms of T1DM include polyuria, polydipsia, polyphagia, fatigue, unexplained weight loss, and blurred vision. These symptoms can often develop rapidly and lead to diabetic ketoacidosis if not treated appropriately.^1,2

Background on type 2 diabetes mellitus (T2DM)

T2DM is a chronic metabolic condition characterised by insulin resistance, where body cells become less responsive to insulin. This is initially countered by an increase in insulin production to maintain glucose homeostasis, but this compensatory mechanism declines over time, leading to T2DM. It typically occurs in adults over 45 years of age, but is increasingly observed in younger populations due to rising obesity levels, physical inactivity, and energy-dense diets.

T2DM involves a complex interplay between genetics and lifestyle factors, including poor diet, obesity, and lack of physical activity. T2DM often has a gradual onset, with many patients remaining asymptomatic for years. Symptoms may be similar to those of T1DM and may also include recurrent infections and slow-healing wounds.^1,3

Complications

There are several complications associated with diabetes. Hypoglycaemia is defined as a plasma glucose concentration below 3.9mmol/L, with symptoms including fatigue, confusion, tremors, palpitations and seizures. Hypoglycaemia can result in diabetic coma and potential death. Hypoglycaemia is much more common in T1DM than T2DM. The most common causes of hypoglycaemia include incorrect medication administration, insufficient food intake, increased physical activity, and excessive alcohol intake.^1,2

Macrovascular complications involve large blood vessels in the body and are prevalent in diabetes. These complications are associated with poor glycaemic control, insulin resistance, and excess fatty acids. Coronary artery disease, peripheral vascular disease and cerebrovascular disease are complications of diabetes that cause significant morbidity and mortality. These macrovascular complications can lead to an increased risk of myocardial infarction, stroke, poor circulation and amputation.⁴

Microvascular complications involve the small blood vessels in the body and typically include retinopathy, nephropathy and neuropathy. These complications are generally due to poor glycaemic control. Diabetic retinopathy is damage to the retina that can potentially lead to blindness. Diabetic nephropathy is the chronic loss of kidney function in patients with diabetes, which may progress to end-stage renal disease. Diabetic neuropathy is a microvascular complication associated with nerve damage, causing pain, numbness, weakness, tingling and urinary symptoms.⁵

Diagnosis

The diagnosis of diabetes is typically based on a characteristic history, supported by elevated serum glucose levels. A diagnosis of diabetes can be made if any of the following criteria are met:

• Fasting plasma glucose (FPG) level ?7.0 mmol/L after an eight-hour fast.
• Oral glucose tolerance test (OGTT): A plasma glucose level ?11.1mmol/L two hours after a 75g glucose load.
• Glycated haemoglobin (HbA1c) level ?6.5%: Glycated haemoglobin is a form of haemoglobin that is linked to a sugar molecule and is used to determine the three-month average plasma glucose level.
• Random plasma glucose level ?11.1mmol/L along with symptoms of hyperglycaemia (polyuria, polydipsia, polyphagia, weight loss).¹

Non-pharmacological treatment

The management of diabetes necessitates a multi-faceted approach for effective control. Non-pharmacological approaches are crucial in the management of diabetes. Optimal management of T1DM requires patient education on diet and lifestyle. Patients should understand the interaction between diet, insulin, physical activity and daily routine, with nutritional education on carbohydrate estimation being important in managing this condition. Consultation with a dietitian can help diabetic patients learn carbohydrate estimation to determine appropriate mealtime insulin dosing.

Physical activity is vital, as it has beneficial effects on insulin sensitivity and overall health, but it requires careful management to avoid glucose fluctuations. Smoking cessation should be promoted to reduce cardiovascular risks, while moderating alcohol intake is important as it can affect blood glucose levels.²

The cornerstone of treatment of T2DM is diet and physical activity. Reducing intake of refined carbohydrates and saturated fats, while increasing the intake of fibre and monounsaturated fats, is crucial. A minimum of 90-to-150 minutes of aerobic exercise per week should be encouraged. In obese patients, weight loss should be promoted to improve insulin sensitivity. Similarly to T1DM, smoking cessation and reducing alcohol intake should be encouraged.³

Pharmacological treatment in T1DM

The goal of pharmacological management of T1DM is the replacement of insulin. This is achieved through the administration of multiple daily insulin injections (basal-bolus), or continuous subcutaneous insulin infusion using an insulin pump.

Basal-bolus insulin treatment involves administering a long-acting basal insulin once or twice daily, and a prandial short- or rapid-acting insulin administered before meals. Long-acting insulin is often administered once daily and used for the basal dose to maintain baseline glucose levels, with examples including glargine and detemir. Intermediate-acting insulin is typically 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 aspart, lispro and glulisine.

Basal-bolus regimens typically include a daily long-acting insulin, as well as a rapid-acting insulin before meals for hyperglycaemia correction. The regimen should be titrated to achieve a blood glucose range that minimises the risk of hypoglycaemia and hyperglycaemia. Continuous subcutaneous insulin infusion administers a continuous infusion of rapid-acting insulin to meet basal requirements, with mealtime boluses administered for prandial coverage.²

Pharmacological treatment in T2DM

Patients with T2DM are more likely to develop various complications; therefore, the objective of treatment is to achieve optimal glycaemic control to reduce the risk of these complications. Pharmacological management is indicated if adequate glycaemic control cannot be achieved through diet and exercise.³

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

Metformin is considered weight-neutral, with the potential for modest weight loss. It is unlikely to cause hypoglycaemia and may have cardioprotective effects. Common adverse effects of metformin include nausea, vomiting, diarrhoea, and abdominal pain. Taking metformin with food and gradually titrating the dose upwards can help limit these adverse effects.^3,6

Sulfonylureas stimulate pancreatic beta cells to increase insulin secretion. They can be used as monotherapy or in combination with other antidiabetic drugs, except the meglitinides, as they have a similar mechanism of action. Sulfonylureas can lower HbA1c by 1% to 1.25%. Treatment should be initiated at a low dose, with a gradual increase based on glycaemic control.

Gliclazide is available as an immediate-release tablet (taken twice daily 30 minutes before food), or a modified-release tablet (taken once daily after food). Patients may need to hold or reduce their dose and ensure monitoring of blood glucose levels if fasting. Sulfonylureas are often used 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, as sulfonylureas may cause weight gain. Weight gain is a common adverse effect, and sulfonylureas should not be offered to obese patients. Hypoglycaemia is also a common adverse effect and may be severe, particularly after missing meals, exercise or with high doses. Other adverse effects may include nausea, vomiting, diarrhoea and dizziness.^3,7

Dipeptidyl peptidase-4 (DPP-4) inhibitors work 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. Linagliptin, saxagliptin and sitagliptin are examples of DPP-4 inhibitors. They are all administered orally once daily after food. They can be used as monotherapy or as an add-on treatment option with other antidiabetic medications. They also have the benefit of possessing antihypertensive, anti-inflammatory and immunomodulatory effects.

They are generally a well-tolerated class of medication, with weight-neutral effects and a low incidence of hypoglycaemia. However, the risk of hypoglycaemia increases when used in conjunction with sulfonylureas. Upper respiratory tract infections, gastrointestinal issues, headaches, and urinary tract infections are the most common adverse effects.^3,8

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors work by blocking the reabsorption of glucose in the kidneys, thereby lowering plasma glucose levels. Dapagliflozin, empagliflozin, and canagliflozin are all examples. They are administered orally, with canagliflozin taken before breakfast and the others taken with or without food.

In addition to their glucose-lowering effects, SGLT-2 inhibitors may also be used for the management of renal or cardiovascular disease. They may promote some weight loss, and the risk of hypoglycaemia increases in elderly patients. These medications may be used as add-on therapy, particularly in patients with comorbidities such as atherosclerosis, heart failure, or chronic kidney disease. The most common adverse effects include nausea, constipation, urinary tract infections, and increased urination.^3.9

Thiazolidinediones act on intracellular metabolic pathways to improve insulin action and increase insulin sensitivity. Pioglitazone is a thiazolidinedione used as monotherapy or in combination with other antidiabetic medications. It is administered orally once daily, with or without food.

Thiazolidinediones may be useful as they typically do not cause hypoglycaemia when used as monotherapy, and they are not contraindicated in patients with renal disease. However, due to their adverse effect profile, they are typically not used as first-line treatment unless other medications are contraindicated. The adverse effects of thiazolidinediones include weight gain, bone fractures, water retention, congestive heart failure, hepatotoxicity, and an increased risk of bladder cancer.¹⁰

Meglitinides bind to receptors on beta cells in the pancreas, stimulating the release of endogenous insulin. Repaglinide an example of a meglitinide used in the treatment of T2DM. Similar to other antidiabetic drugs, it can be used as monotherapy or in combination with other agents, with the exception of sulfonylureas due to their similar mechanism of action. They are administered orally before meals two or three times daily, with doses omitted if meals are skipped. Common adverse effects include hypoglycaemia, weight gain, upper respiratory tract infections, diarrhoea, and joint pain.¹¹

Glucagon-like peptide-1 (GLP-1) agonists work by activating the GLP-1 receptor, which delays gastric emptying, inhibits glucagon release, and stimulates the production of insulin. Dulaglutide, semaglutide, exenatide and liraglutide are examples of GLP-1 agonists used to treat T2DM. GLP-1 agonists can be used as monotherapy or in combination with other antidiabetic medications. They have a relatively low risk of hypoglycaemia. Additionally, they may lower the risk of cardiovascular events, prevent the progression of chronic kidney disease and promote weight loss. Therefore, they may be particularly beneficial for patients with these comorbidities.

GLP-1 agonists are typically administered via subcutaneous injection due to their poor oral bioavailability. Liraglutide is administered daily, while dulaglutide and semaglutide are administered once weekly. Exenatide can be administered either twice daily or once weekly, depending on the formulation. Nausea, vomiting and diarrhoea are the most common adverse effects of GLP-1 agonists. Other possible adverse effects include tachycardia, dizziness, infection, headache, injection site reactions, and acute kidney injury.¹²

Insulin therapy may be used in advanced stages of T2DM when non-insulin agents fail to achieve adequate glycaemic control. Insulin may also be useful in short-term cases to lower blood glucose levels after diagnosis or when a patient is ill. Insulin effectively reduces hyperglycaemia and the long-term complications associated with it. However, hypoglycaemia is more common with insulin therapy, although it is less frequently associated with other adverse effects, such as gastrointestinal issues.³

Role of the pharmacist

Pharmacists play a crucial role in the management of diabetes through medication management, patient education and patient monitoring. Pharmacists counsel patients on important aspects of medication management, including injection techniques, the importance of adherence, hypoglycaemia management, and strategies to minimise adverse effects. Additionally, pharmacists educate patients on lifestyle changes, such as dietary modifications, physical exercise, alcohol moderation and smoking cessation, which can help prevent diabetes-related complications.

Pharmacists also assist in monitoring patients and screening for complications, which may improve clinical outcomes. Finally, they collaborate with other healthcare professionals to provide a patient-centred approach to diabetes management.