Type 2 diabetes is characterised by hyperglycaemia, insulin resistance, and impairment in insulin secretion. Diagnosis is made based on measures that show evidence of elevated glycaemia due to both issues with insulin secretion (beta-cell dysfunction) and insulin action, or resistance. Resistance to insulin may contribute to further physiological abnormalities in type 2 diabetes such as inflammation, lipoprotein abnormalities, hypertension, and further metabolic issues. Metabolic syndrome refers to type 2 diabetes when accompanied by additional clinical conditions like hypertension, dyslipidaemia, and central obesity; issues that may be caused at least in part due to insulin resistance.

Pathophysiology of type 2 diabetes

The cause of insulin resistance is commonly attributed to environmental factors related to increased food intake and a sedentary lifestyle, which causes overweight and obesity. Genetics and ageing also contribute. Issues with insulin secretion result from genetics and how pancreatic beta-cells are made and programmed in utero. The presence of hyperglycaemia can itself also impair beta-cell function, further exacerbating the problem.

Studies have shown that defects in beta-cell function can occur early in disease pathogenesis, even before the development of obesity and insulin resistance. Substances released by adipocytes [adipokines, eg, leptin, adiponectin, tumour necrosis factor (TNF) alpha, resistin] may, at least in part, cause insulin resistance. Insulin release involves the cleavage of proinsulin to insulin. In type 2 diabetes, there is an increase in proinsulin secretion, suggesting that this processing is somehow impaired in the beta-cells in type 2 diabetes. Insulin resistance becomes more pronounced with increasing age and weight, revealing any underlying defect in beta-cell function in affected individuals. The mechanism through which obesity causes insulin resistance, however, is poorly understood. Some studies have investigated the role of inflammation in the development of type 2 diabetes (and also atherosclerosis), the incidence of which is correlated with increased levels of inflammatory markers such as C-reactive protein, interleukin (IL)-6, TNF alpha, chemokines, and adipokines. These inflammatory markers can be reduced by intensive lifestyle interventions. Interestingly, the anti-inflammatory effects of medications, like statins, may provide a greater therapeutic benefit beyond their intended effect. Use of anti inflammatory medications even in other diseases such as rheumatoid arthritis and psoriasis is linked with a lower incidence of type 2 diabetes.

Drug-induced hyperglycaemia

Certain drugs impair glucose tolerance through reducing insulin secretion, increasing hepatic glucose production, or causing insulin resistance (Table 1). Where appropriate, patients should be informed about these risks (especially with prolonged steroid use), as with all clinically-relevant side-effects.

Table 1: Examples of drugs that may impair glucose tolerance

Treatment

Lifestyle interventions are a mainstay of weight management, but used alone are associated only with moderate weight loss. Maintenance of weight loss is intrinsically difficult due to counter-regulatory neuroendocrine pathways that increase hunger and reduce satiety, promoting weight gain, and possibly reducing energy expenditure.

Metformin, the most common antidiabetic drug, decreases hepatic glucose production and intestinal glucose absorption, and increases peripheral glucose uptake. It does not affect insulin secretion.

Dipeptidyl peptidase (DPP) 4 Inhibitors (eg, sitagliptin, saxagliptin, linagliptin) inhibit DPP-4, which deactivates glucagon-like peptide (GLP)-1 and also the glucose-dependent insulinotropic polypeptide (GIP). These are oral GLP-1 based therapies that increase levels of GLP-1, but are not as effective as GLP-1 agonists at glucose or weight reduction.

Thiazolidinediones (eg, pioglitazone) increase insulin sensitivity by acting on adipose tissue and muscle to increase glucose use. They also reduce glucose production by the liver. Their mechanism of action is not fully understood, although they bind to and activate peroxisome proliferator-activated receptors (PPARs), mostly PPAR-gamma, which alters the transcription of multiple genes involved in glucose and lipid metabolism. Use of thiazolidinediones has decreased in recent years because of concerns about safety and side-effects such as heart failure and increased risk of fractures.

Sulfonylureas (eg, gliclazide) only benefit patients with some residual beta cell function. These drugs bind to specific receptors, with the ultimate effect of insulin release and stimulation of new insulin granules.

Sodium glucose co-transporter (SGLT) 2 inhibitors inhibit SGLT2 receptors in the kidneys’ proximal convoluted tubule, resulting in the prevention of glucose reabsorption. Glucose is then excreted in the urine, helping with weight loss, but also increasing UTI risk.

GLP 1 agonists (eg, exenatide, liraglutide, dulaglutide, semaglutide) are injectable medications that enhance the effect of GLP-1. GLP-1 is a gastrointestinal peptide contributing to the regulation of glucose levels when released after food consumption, when it stimulates insulin formation and release. It also slows gastric emptying and inhibits excess postprandial glucagon release. These drugs promote weight loss by reducing energy intake, increasing satiety, reducing hunger, and improving glycaemic control. Semaglutide is a long-acting GLP-1 analogue.

Type 2 diabetes is associated with an increased risk of cardiovascular and kidney disease and corresponding impaired quality-of-life and increased mortality. In recent years, it has been suggested that cardiovascular and kidney disease markers in type 2 diabetes are at least, if not more, clinically important for long-term outcomes than measures of glycaemia. Two classes of antidiabetic drugs in particular have been shown to help mitigate these risks: SGLT-2 inhibitors and GLP-1 receptor agonists.

Future care

Two new drugs are now available to treat type 2 diabetes: Finerenone (a non-steroidal mineralocorticoid receptor antagonist), and tirzepatide (a dual GIP/GLP-1 receptor agonist). The National Centre for Pharmacoeconomics (NCPE) in Ireland recently recommended that the HSE should consider funding finerenone if its cost-effectiveness can be improved relative to existing treatments, while a full health technology assessment was recommended by the NCPE for tirzepatide to assess its clinical and cost effectiveness compared with the current standard of care.

In trials investigating finerenone, findings suggested cardiovascular and kidney benefits in both patients with type 2 diabetes and those with chronic kidney disease.

Tirzepatide is also beneficial in terms of effects on weight loss and quality-of-life.

GLP-1 inhibitors are also successful in reducing body weight, with semaglutide the most effective in this class. A recent network meta-analysis investigating the benefits and harms of available drug treatments for type 2 diabetes found that SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone showed the most benefits in terms of, eg, overall mortality reduction, fewer hospital admissions, and reducing end-stage kidney disease. Predictably, the absolute benefits of these drugs are dependent on individual baseline risk levels. The authors recommend a risk-stratified approach for future treatment recommendations, tailored depending on each patient’s risk profile.

Pre-diabetes

In pre-diabetes, glycaemic values are in between normal and those that define diabetes. Like type 2 diabetes, it is characterised by decreased insulin sensitivity and impaired insulin secretion. Measures of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) based on World Health Organisation criteria can be used to diagnose the condition, although there are alternative diagnostic definitions depending on the guidelines used.

Pre-diabetes identifies people at risk of progression to diabetes, but the estimated risks vary depending on the definition used (isolated IFG, or isolated IGT, a combined measure of these, or HbA1c).

Intensive lifestyle intervention (ie, dietary modification and increased physical activity) and pharmacological intervention (ie, metformin) can reduce progression to diabetes. In the Diabetes Prevention Programme (a large trial in the US that compared metformin, placebo, and lifestyle interventions), intensive lifestyle intervention was found to be more effective than metformin.

Multiple clinical guidelines, including those from the National Institute for Health and Care Excellence, stress lifestyle intervention as the preferred initial step to reduce risk of diabetes, with metformin recommended for use in certain circumstances, eg, if the individual’s participation in intensive lifestyle change programmes has not worked, or they are unable to participate. Unfortunately, not all individuals have access to the type of lifestyle intervention programme that proved so effective in improving glycaemic values in research studies. Orlistat may also be offered to help with obesity management where appropriate in order to improve glycaemic parameters.

References on request

Type 2 diabetes is a complex chronic disease, which requires a multifactorial behavioural and pharmacological approach to treatment in order to prevent or delay complications and maintain quality-of-life. This includes management of blood glucose levels, weight, cardiovascular risk factors, comorbidities, and complications. A holistic, person-centred approach is essential to enhance engagement, and careful consideration of social determinants of health and preference of the person living with diabetes must guide individualisation of treatment goals and strategies.¹ This module will summarise the latest guidelines on the management of type 2 diabetes in non-pregnant adults.

Principles of glycaemic control

Achieving recommended glycaemic targets has been shown to substantially reduce the onset and progression of microvascular complications in patients with type 2 diabetes. Target HbA1c for adults with a life expectancy of >10 years is approximately 53mmol/mol. Aiming for a lower HbA1c level than this may be associated with significant hypoglycaemia and other adverse treatment effects. Higher HbA1c targets are appropriate in cases of limited life expectancy, advanced complications, or if factors such as frailty are present.¹ Monitoring of blood pressure, lipids, and other risk factors such as smoking and alcohol intake is extremely important in people with type 2 diabetes; however, detailed discussion of these is beyond the scope of this module.

DESMOND

Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) is a free HSE course available to people with type 2 diabetes. Patients are provided with up-to-date information and practical skills to manage their diabetes, including diet and exercise, blood glucose monitoring, smoking cessation, eye care, and foot care.²

Weight loss of 5-to-15 per cent should be a primary target of management for many people living with type 2 diabetes. Weight loss of 5-to-10 per cent confers metabolic improvement, and weight loss of 5-to-15 per cent or more can have a disease-modifying effect and lead to remission of diabetes.¹

Physical activity significantly impacts cardiovascular health in type 2 diabetes. Individuals living with type 2 diabetes are advised to undertake 30 minutes of moderate exercise at least five times per week.¹

Oral medications for lowering glucose

Metformin

Metformin has traditionally been recommended as first-line therapy for the management of type 2 diabetes due to its high efficacy in lowering HbA1c, minimal hypoglycaemia risk, weight neutrality, good safety profile, and low cost. Metformin should not be used in people with an estimated glomerular filtration rate (eGFR) <30ml/min per 1.73m,² and dose reduction should be considered when the eGFR is <45ml/min per 1.73m.² Metformin use may lower serum vitamin B12; therefore, periodic monitoring and supplementation are recommended.¹

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors reduce plasma glucose by enhancing urinary excretion of glucose. They have intermediate-to-high glycaemic efficacy, with lower glycaemic efficacy at lower eGFR. Cardiorenal outcome trials have demonstrated their efficacy in reducing the risk of major adverse cardiovascular events, cardiovascular death, myocardial infarction (MI), hospitalisation for heart failure, and improving renal outcomes in individuals with type 2 diabetes.

In patients with established cardiovascular disease, heart failure, or chronic kidney disease, early combination therapy with metformin should be considered at treatment initiation provided the eGFR is above the threshold for metformin initiation. Their use should also be considered in those who are considered high risk for cardiovascular disease.¹

SGLT2 inhibitors are associated with increased risk of urinary tract infections. They are also associated with a low but serious risk of euglycaemic diabetic ketoacidosis (DKA).¹ Patients should be advised to hold the medication if they are unwell or fasting for a procedure, otherwise known as sick-day rules. Many centres provide patients with written information leaflets or alert cards, and the risk of euglycaemic DKA should be reiterated at each visit.

Glucagon-like peptide-1 (GLP-1) receptor agonists

GLP-1 receptor agonists increase glucose-dependent insulin secretion and glucagon suppression, slow gastric emptying, curb post-meal glycaemic increments, and reduce appetite, energy intake, and body weight. The most common side-effects of GLP-1 receptor agonists are nausea, vomiting, and diarrhoea, which tend to occur during initiation and dose escalation, and diminish over time. Gradual up-titration is recommended to mitigate gastrointestinal side-effects. Patients should be encouraged to eat slowly, stop eating when full, and not to eat when not hungry.

Studies have shown average weight loss of 5.5kg with semaglutide 1mg weekly; however, on stopping the drug people regain approximately one-third of the weight lost. GLP-1 receptor agonists are an appropriate second-line agent in patients whose primary target is weight loss and who do not have cardiovascular disease, heart failure, or chronic kidney disease.¹ GLP-1 receptor agonists are contraindicated in people at risk for medullary thyroid cancer.

In patients with pre-existing diabetic retinopathy and high glycaemic levels, their use can lead to increased retinopathy complications due to the magnitude and rapidity of HbA1c reduction. They are also associated with an increased risk of gallbladder and biliary diseases.¹

Dipeptidyl peptidase 4 (DPP-4) inhibitors

DPP-4 inhibitors inhibit the enzymatic inactivation of endogenous incretin hormones, resulting in glucose-dependent insulin release and a decrease in glucagon secretion. They have a more modest glucose-lowering effect and are weight neutral with minimal risk of hypoglycaemia.¹

Sulfonylurea

Sulfonylureas have high glucose-lowering efficacy; however, due to their glucose-independent stimulation of insulin secretion, they are associated with an increased risk of hypoglycaemia. They are also associated with weight gain. Use of sulfonylureas for early intensive blood glucose control has been shown to significantly reduce the risk of microvascular complications; however, some observational studies raised concerns about adverse cardiovascular outcomes with their use.¹

Thiazolidinediones (TZDs)

TZDs increase insulin sensitivity and have high glucose-lowering efficacy. In the PROactive trial,³ TZDs were shown to reduce secondary cardiovascular endpoints in adults with type 2 diabetes and macrovascular disease. The IRIS study demonstrated that in adults without diabetes, but with insulin resistance and a recent history of stroke or transient ischaemic attack (TIA), there was a lower risk of stroke or MI with pioglitazone.⁴ These benefits must be balanced with the possible side-effects of fluid retention and congestive heart failure, weight gain, and bone fracture. These side-effects can be mitigated by using lower doses and combining TZDs with other medications that promote weight loss and sodium excretion, such as SGLT2 inhibitors and GLP-1 receptor agonists.¹

Combination therapy

Early use of combination therapy allows tighter glycaemic control than monotherapy, and therefore, is indicated in those with a HbA1c >1.5 per cent above their target at diagnosis. Immediate and sustained glycaemic control should be particularly pursued in young adults with type 2 diabetes, aiming for HbA1c <53mmol/mol; therefore, combination therapy should be considered in this group at diagnosis. This allows the best opportunity to avoid complications of diabetes across their lifespan.¹

Insulin

Insulin therapy lowers glucose in a dose-dependent manner; however, its efficacy and safety are largely dependent on the education and support provided to facilitate self-management. Challenges of insulin therapy include weight gain, risk of hypoglycaemia, the need for regular glucose monitoring, and cost.

Comprehensive education on self-monitoring of blood glucose, diet, injection technique, self-titration of insulin, and prevention and treatment of hypoglycaemia are essential when initiating insulin therapy.¹

Starting doses of basal insulin are estimated based on body weight (0.1-0.2 units/kg per day) and the degree of hyperglycaemia. Short- and rapid-acting insulin can be added to basal insulin to intensify treatment and optimise prandial blood glucose levels. Premixed insulins combine basal insulin with mealtime insulin in the same pen. This offers convenience for some but reduces treatment flexibility.¹

Patients should continue metformin, SGLT2 inhibitors, and GLP-1 receptor agonists to avoid weight gain and limit insulin dose and hypoglycaemia risk. Sulfonylureas should be discontinued due to the increased risk of hypoglycaemia.¹

Combination GLP-1-insulin therapy

A fixed-ratio combination of a GLP-1 receptor agonist (liraglutide) with a basal insulin analog (insulin degludec) is available as Xultophy. This combination results in greater glycaemic lowering efficacy than its individual components, with less weight gain and lower rates of hypoglycaemia than with intensive insulin regimes, as well as better gastrointestinal tolerability than with a GLP-1 receptor agonist alone.¹

Screening and monitoring

In primary care, under the Diabetes Cycle of Care, now part of the chronic disease management (CDM) programme, GMS patients with type 2 diabetes are entitled to two visits a year.

Blood glucose monitoring

Regular capillary blood glucose monitoring helps with self-management and medication adjustment, particularly in those using insulin. In those not using insulin, regular glucose monitoring is of limited benefit while adding burden and cost.¹

RetinaScreen

Anyone with diabetes can develop diabetic retinopathy, which can lead to significant vision loss if untreated. The longer someone has diabetes, the more likely they are to develop the condition. Poor glycaemic control in diabetes can make diabetic retinopathy worse and can increase the risk of developing sight problems.

Risk factors for diabetic retinopathy

• Poor blood glucose control;
• High blood pressure;
• Raised triglycerides;
• Pregnancy (not gestational diabetes).
  During pregnancy, diabetes can worsen diabetic retinopathy. Common signs and symptoms include:
• Blurred or distorted vision (linked to blood glucose levels);
• Floaters (small black spots) and flashing lights;
• Trouble reading or seeing faraway objects;
• Loss of central vision;
• Sudden loss of vision (blindness);
• New colour blindness or seeing colours as faded;
• Poor night vision.

Diabetic retinopathy eye screening is a key part of diabetes care. The National Diabetic Retinal Screening Programme, Diabetic RetinaScreen, offers free, regular diabetic retinopathy screening to all people with diabetes aged 12 and older. See www.diabeticretinascreen.ie for further information.

Foot care

Patients with diabetes are at a 15-to-40-fold higher risk of a lower limb amputation than a non-diabetic patient. Early recognition and management of independent risk factors for ulcers and amputations can prevent or delay the onset of adverse outcomes.

All individuals with diabetes should receive an annual foot examination to identify their risk stratification and appropriate referral to specialists if required. In addition, all patients should be educated regarding foot care and the importance of their annual foot screen along with the management they may require. In 2021, the HSE National Clinical Programme for Diabetes published the Diabetic Foot Model of Care, which outlines the care diabetes patients should receive in relation to monitoring and treating diabetic foot issues.⁵

Driving guidelines

People with diabetes who are treated with insulin or sulfonylureas must check their blood glucose level before driving and every two hours while driving. If blood glucose is <5.0mmol/l, they should not drive. If a person develops hypoglycaemia while driving, they should stop the car, switch off the engine, take the keys out of the ignition, and move from the driver’s seat. They should take appropriate action to treat their hypoglycaemia and they should not drive again until 45 minutes after their blood glucose level has returned to normal.

People with type 2 diabetes must inform the National Driver Licence Service (NDLS) if they are treated with insulin or tablets which carry a risk of inducing hypoglycaemia, eg, sulfonylureas.⁶

Continuous glucose monitoring (CGM)

CGM devices provide interstitial glucose readings from sites in the abdomen or arm and make use of alarms and alerts to improve glycaemic control and reduce frequency of hypoglycaemia. ‘Time in range’ is defined as the percentage of time that CGM readings are in the range of 3.9-10.0mmol/L. Time in range is associated with the risk of microvascular complications and can be used for assessment of glycaemic management.

A HbA1c <53mmol/mol is equivalent to a time in range of >70 per cent, with additional recommendations to aim for time below range of less than 4 per cent. Like HbA1c targets, a lower percentage time in range is appropriate in cases of limited life expectancy, advanced complications, or if factors such as frailty are present. In the Republic of Ireland, CGM devices are not automatically funded for people with type 2 diabetes. Individual applications can be made for reasons such as hypo unawareness or severe needle phobia.

Support

Diabetes Ireland is the national charity dedicated to helping people with diabetes. It achieves this by providing support and education (including free online educational courses and support groups) to everyone affected by diabetes. It also raises public awareness of diabetes and its symptoms, and actively funds research into finding a cure for diabetes. See www.diabetes.ie.

Resources

Irish College of General Practitioners (ICGP). A practical guide to integrated type 2 diabetes care. 2016.⁷

HSE National Clinical Programme for Diabetes.Available at www.hse.ie/eng/about/who/cspd/ncps/diabetes.