Diagnosis and management of type 2 diabetes mellitus

There are an estimated 4.9 million people in the UK living with diabetes mellitus, with 850,000 living with diabetes but yet to be diagnosed​[1,2]​. The NHS spends at least £10bn on diabetes each year, with nearly 80% of this being spent on treating diabetic complications​[3]​. The risk of developing cardiovascular complications (e.g. heart failure, heart attack or stroke) is 2.0–2.5 times greater in people with T2DM compared with people who have never appeared in the National Diabetes Audit (NDA)​[4]​. Another complication, diabetic retinopathy, is a leading cause of preventable sight loss among working-age people with T2DM in the UK​[5]​.

More than a third of people who require kidney dialysis or a kidney transplant have diabetes​[6]​. Patients who effectively control their blood glucose levels and blood pressure are less likely to experience complications of diabetes; however, more than 40% of people with T2DM are not receiving the eight annual health checks recommended by the National Institute for Health and Care Excellence (NICE) and 60% of people with T2DM are not meeting all three of the NICE-recommended treatment targets (i.e. HbA1c≤58mmol/mol, blood pressure <140/80mmHg and cholesterol <5mmol/L)​[7]​.

Diabetes mellitus is a long-term condition characterised by hyperglycaemia as a result of insulin deficiency, insulin resistance, or both​[8]​. Type 1 diabetes mellitus (T1DM) and T2DM are the two most common types of diabetes globally, with around 90% of people with diabetes having T2DM​[9]​.

This article will discuss the causes and diagnosis of T2DM, as well as management options and how pharmacists can support patients through locally-commissioned services.

Causes

T1DM is caused by a person’s pancreas being unable to produce insulin, leading to absolute insulin deficiency, whereas T2DM is primarily caused by a combination of the body’s resistance to the action of insulin and impaired insulin secretion​[8]​. There is a multifactorial contribution to beta-cell mass reduction, and beta-cell and alpha-cell dysfunction, partly owing to glucolipotoxicity causing beta-cell apoptosis through oxidative stress​[10]​.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are both hormones released in the small intestine in response to the presence of food, and act on beta-cells to enhance glucose-dependent insulin secretion. However, GLP-1 also acts on alpha-cells to suppress glucagon secretion​[11]​. GLP-1 plasma levels generally do not differ in people with T2DM compared with people without T2DM; however, it has been shown that the beta-cell response to GLP-1 after a meal is impaired in those with T2DM, leading to impaired glucose-dependent insulin secretion​[12,13]​. It has been found that while the plasma level of glucagon may or may not be raised, the presence of hyperglycaemia fails to suppress the release of glucagon by alpha-cells in people with T2DM, which further contributes to the worsening of hyperglycaemia​[14]​.

The intestinal microbiome has also been linked with the development of obesity and insulin resistance, from evidence of the gut microbiota altering the host metabolic phenotype​[15]​.

Some people may have body adiposity genes and beta-cell dysfunction genes that predispose them to T2DM​[10]​. Genome-wide association studies conducted in several countries and across multiple ethnic groups have identified around 75 susceptibility loci on the same or different chromosomes related to T2DM​[16]​. Genetic mutations of the insulin receptor have been associated with reduced insulin sensitivity. Genetic polymorphisms of the genes coding the proteins involved in the insulin signalling pathway, such as the insulin receptor substrate (IRS) and phosphoinositide 3-kinase (PI-3 kinase) proteins, have been linked with impaired glucose uptake and use in the body, which consequently leads to insulin resistance​[17]​. Beta-cell function related to insulin sensitivity and secretion is heritable, as demonstrated in studies with families that have a high risk of T2DM​[18,19]​. Collectively, these polymorphisms may contribute to the genetic predisposition of some individuals to developing T2DM​[17]​.

An alternative hypothesis has been proposed that liver and pancreatic fat deposition, owing to long-term caloric excess, is linked with beta-cell dysfunction​[20]​. The DiRECT (diabetes remission clinical trial) study demonstrated that the use of a primary care-based structured weight management programme — which consisted of a low-calorie (around 800 calories/day) total diet replacement, stepped food re-introduction and structured support for weight-loss maintenance — can lead to diabetes remission in people with T2DM within six years of diagnosis (defined as HbA1c <48mmol/mol after withdrawal of antidiabetic medicines at baseline)​[21]​.

At 24 months, 36% of participants in the intervention group reverted to a non-diabetic state, compared with 3% in the control group. Sustained weight loss was shown to be the main factor in determining diabetes remission​[21]​.

Pathophysiology 

In the presence of insulin deficiency or insulin resistance, glucose cannot be taken into the muscle cells efficiently, leading to hyperglycaemia. The initial response to the rise in blood glucose levels stimulates the pancreatic beta-cells to increase insulin production to lower blood glucose back to the normal level​[20]​. For this reason, people with T2DM may have very high insulin levels owing to severe insulin resistance. Over time, this response becomes inadequate to maintain normoglycaemia owing to the gradual reduction in insulin secretion from the over-stimulated beta-cells​[22]​. This results in persistent hyperglycaemia and glucose intolerance​[10]​. The progressive decline of beta-cell function and the associated insulin deficiency also causes impaired metabolism of carbohydrate, protein and fat. Beta-cell failure with hyperglycaemia marks the development of T2DM​[10,22]​.

Risk factors

Lifestyle 

Obesity is a major risk factor of T2DM​[16]​. It is associated with defects in intracellular insulin signalling in both skeletal muscle and fat tissues, demonstrated by the reduced phosphorylation of IRS and PI-3 kinase, resulting in reduced insulin-regulated glucose transporter (Glut-4)-mediated uptake of glucose into skeletal muscle cells​[17]​. An elevated plasma-free fatty acid concentration in overweight/obese individuals is strongly associated with the development of insulin resistance and impaired glucose tolerance​[23]​. Studies have shown that the increase in the concentration of circulating fatty acid is not proportionate to the increase in fat mass. As fatty acid mobilisation from adipose tissue is usually suppressed by insulin, its increase has been suggested to be a contributing factor to the elevation of the free fatty acid concentration in obesity, thereby forming a cycle in worsening insulin resistance​[17,23]​.

Smoking, high alcohol consumption and reduced physical activity also contribute to obesity and insulin resistance​[16,17,24]​.

Age

Although T2DM can occur at any age, older age has been found to be associated with the progressive reduction in glucose tolerance, partly owing to the gradual decrease in responsiveness of beta-cells to carbohydrate​[25]​.

Genetics

Other risk factors include first-degree relatives of patients with diabetes, and women with gestational diabetes or polycystic ovary syndrome (which increases the risk of impaired glucose regulation)​[10]​. The risk of first-degree relatives of patients with T2DM developing the condition is 40% compared with just 6% for the rest of the general population​[16]​.

It has been highlighted that T2DM is two- to four-times more likely in people of south-Asian, Afro-Caribbean or black-African family origin than people of white-European origin​[9,19]​. Migration of various ethnic subgroups has led to a change in dietary habits, with a higher consumption of calories and fat than in their countries of origin; hence the prevalence of diabetes is often higher in immigrant communities than in their country of origin​[17]​. 

Inflammation

Systemic inflammation also contributes to insulin resistance, as an improvement in inflammatory markers, such as C-reactive protein and interleukin-6, is linked to an improvement in beta-cell function​[10]​.

Symptoms

Signs of T2DM primarily originate from the persistent hyperglycaemia and the impaired ability to use glucose as fuel, and include polyuria, nocturia, polydipsia (excessive thirst), fatigue and weight loss. A person with diabetes may also experience other symptoms, such as blurred vision, reduced sensations or pain in the hands and feet, along with recurrent genitourinary infections.

Owing to insulin deficiency and, consequently, altered energy metabolism, diabetes increases the risk of developing hyperosmolar hyperglycaemic states and ketoacidosis, both of which are life-threatening emergencies that require prompt hospital treatment​[8]​. Diabetic ketoacidosis (DKA) is less common in those with T2DM because the majority of people are insulin-resistant rather than insulin-deficient​[8]​.

Diagnosis

A diagnosis can be made when fasting plasma glucose is ≥7.0mmol/L or random plasma glucose is ≥11.1mmol/L in the presence of symptoms such as frequent urination, thirst and unexplained weight loss (see Box 1).

The oral glucose tolerance test (OGTT) can also be used as a diagnostic tool, where a diagnosis is made if a plasma glucose level of ≥11.1mmol/L is measured two hours after the ingestion of a 75g glucose solution​[26]​. The OGTT has largely been replaced by the HbA1c test and the OGTT is now mainly used in the diagnosis of gestational diabetes.

A HbA1c result of 48mmol/mol (6.5%) is recommended as the threshold for diagnosing diabetes.

In an asymptomatic person, diagnosis should be confirmed with a repeat HbA1c or plasma glucose test, preferably using the same test. However, if both HbA1c or plasma glucose measurements are in diabetic range, a diagnosis can be made​[27]​. If only one measurement is in diabetic range, a second abnormal result using the same test is required to confirm the diagnosis​[27]​.

However, there are patient groups in whom HbA1c is inappropriate for diagnosis, including:

• Children;
• Pregnant women;
• People who are taking medicines that can cause an acute glucose rise (e.g. steroids or antipsychotics);
• People with acute pancreatic damage;
• People with haematological conditions that may influence HbA1c and its measurement (e.g. haemoglobinopathies, decreased erythropoiesis/administration of erythropoietin, erythrocyte destruction, alcoholism, chronic kidney disease and chronic opioid use)​[27,28]​.

Urinary glucose should not be used as a diagnostic test owing to its low sensitivity​[29]​. Diagnosis should be further investigated in people diagnosed with T2DM who failed to respond to oral antihypoglycaemic agents. Additional diagnostic tests are often required, such as ‘GAD’ autoantibody tests or C-peptide tests, to distinguish between T1DM and T2DM.

Other types of diabetes mellitus must also be excluded, such as maturity-onset diabetes of the young (MODY), which is characterised by impaired insulin secretion with minimal or no defects in insulin action resulting from genetic defects in beta-cell function​[9]​.

Regular blood glucose testing and effective glucose management can reduce the risk of complications associated with diabetes.

Management

Lifestyle

Diabetes care should encompass patient education, dietary and lifestyle advice, and management of cardiovascular risk, as well as detection and management of long-term complications. For example, patients should be encouraged to eat fibre, low-glycaemic index sources of carbohydrate (e.g. fruit, vegetables, wholegrains and pulses), as well as low fat dairy products and oily fish​[30]​.

Blood glucose

Evidence from cardiovascular outcomes clinical trials demonstrating cardiovascular benefits of some agents within the class of SGLT2 inhibitors and GLP-1 receptor agonists has prompted a review of pharmacological treatments to improve cardiovascular risk beyond glucose control. Both the updated SIGN 154 guideline, and the American Diabetes Association and European Association for the Study of Diabetes 2019 updated consensus report recommend a comprehensive, patient-centred and cardiovascular risk-focused approach in managing those with T2DM and high cardiovascular risk, through the use of evidence-based therapy with proven cardiovascular benefit​[31,32]​.

The availability of new evidence in managing blood glucose has prompted an update of the NICE guidance on the management of T2DM in 2022. Since 2015, NICE has advocated for a patient-centred approach in glycaemic control and provided best practice advice on setting glycaemic targets and selecting hypoglycaemic agents for treatment intensification after metformin in those with inadequate diabetes control​[30]​. In the 2022 guideline update, linking with individualising therapy, additional emphasis has been placed on collaboration with the person when setting an individual HbA1c target and supporting them to achieve and maintain it. The updated guideline has included a patient decision aid to support these discussions.

Setting glycaemic targets

NICE describes setting an individualised HbA1c target, with the intention to intensify treatment when HbA1c rises to 58mmol/mol (7.5%) or higher​[30]​. Clinicians should continue to reinforce advice about diet, lifestyle and medicines adherence to support individuals aiming for a HbA1c target of 53mmol/mol (7.0%). Patients who are taking a single drug that is not associated with hypoglycaemia; for example, metformin or a dipeptidyl peptidase-4 (DPP-4) inhibitor, should aim for a tighter HbA1c target of 48 mmol/mol (6.5%). In those who are taking a single drug that is associated with hypoglycaemia; for example, a sulfonylurea, an HbA1c of 53mmol/mol (7.0%) should be the target. A higher HbA1c target should be set for those in whom a target of 53mmol/mol would impair their quality of life; for example, cause them to have hypoglycaemic episodes​[30]​.

When setting an agreed HbA1c target, in addition to supporting people who will benefit with an improvement in glycaemic control, it is equally important to work with those who will benefit from less intense glycaemic control. For example, those who are at risk of adverse effects from tight glycaemic control. The guideline recommends relaxing the HbA1c target in people who are older or frail; at risk of developing hypoglycaemia from tight blood glucose control; have significant comorbidities that intensive control would not be appropriate; or have a reduced life expectancy​[30]​. In the presence of frailty, a relaxed glycaemic target should be considered based on the frailty status, where in the case of very severe frailty, an HbA^_1c target of up to 70mmol/mol (8.5%) is considered appropriate​[33]​.

Pharmacological treatments

Since 2015, NICE has broadened the choices of second-line hypoglycaemic agents as first-line therapy if metformin is not tolerated or contraindicated. The 2022 guideline update places more emphasis on accounting for an individual’s comorbidities, contraindications, weight and risks from polypharmacy, with the aim to improve long-term health outcomes​[30]​. If the person has chronic heart failure or established atherosclerotic cardiovascular disease, NICE recommends offering a sodium glucose co-transporter-2 inhibitor (SGLT2i) with proven cardiovascular benefit (e.g. empagliflozin, canagliflozin and dapagliflozin). If the person is at high risk of developing cardiovascular disease, consider an SGLT2i with proven cardiovascular benefit​[30]​. In the absence of chronic heart failure or high cardiovascular risk, one of the following medicines should be considered: a DPP-4 inhibitor, sulfonylurea, pioglitazone, or SGLT2i​[30]​. Care must be taken to assess and address risks for DKA before initiating treatment with an SGLT2i, such as previous history of DKA or those who are following a very low carb diet. An informed discussion should take place with the individual regarding potential side effects and ensuring their understanding on the ‘sick day’ guidance with the use of this class of agents. 

When choosing a second-line hypoglycaemic agent as an adjunct to metformin, the discussion with the person with T2DM should include the long-term benefits in reducing or preventing any cardiovascular or kidney complications with the use of the best suitable drug treatment for the individual (see Table).

NICE recommends using QRISK2 risk scores to assess an individual’s cardiovascular status and risk to determine whether they have the following:

• Chronic heart failure;
• Established atherosclerotic cardiovascular disease; or
• Are at high risk of developing cardiovascular disease​[30]​.

Based on the cardiovascular risk assessment, if the person has chronic heart failure or established atherosclerotic cardiovascular disease, they should be offered an SGLT2i with proven cardiovascular benefit in addition to metformin. If the person is at high risk of developing cardiovascular disease (QRISK2 score of 10% or higher, or elevated lifetime risk), an SGLT2 inhibitor with proven cardiovascular benefit should be considered in addition to metformin​[30]​.

GLP-1 receptor agonists (GLP-1RA) and insulin therapy (in the exception of insulin being used as rescue therapy in those with symptomatic hyperglycaemia) are generally recommended as third-line agents​[30]​. A GLP-1RA would be indicated if triple therapy with metformin and two other oral agents is ineffective, not tolerated, or contraindicated. Consider switching one of the three agents for a GLP-1RA for those who satisfy the weight criteria for GLP-1 initiation​[34–39]​. NICE has prepared a visual summary outlining the factors to consider when choosing, reviewing and changing medicines for T2DM​[31]​.

Advances in pharmacological treatments for diabetes have encouraged clinicians to have a clear understanding of the benefits and risks of each class of diabetes medicines. The table shows the side-effect and safety profile of the commonly prescribed hypoglycaemic agents for the treatment of type 2 diabetes in adults in the UK​[30,34–58]​. Please note that the only licensed drug treatments for type 2 diabetes in pregnancy are metformin and insulin. Sulfonylureas should generally be avoided in pregnancy owing to the risk of neonatal hypoglycaemia; however, glibenclamide (unlicensed) can be used in the second and third trimesters of pregnancy in women with gestational diabetes​[40,59]​.

Chronic kidney disease

For those with T2DM and chronic kidney disease who are taking an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi), titrated to the highest licensed dose that they can tolerate, they should be offered an SGLT2i licensed for this indication (in addition to the ARB or ACEi) if the albumin creatinine ratio (ACR) is more than 30mg/mmol and they meet the licensing criteria, including estimated glomerular filtration rate (eGFR) thresholds (as indicated in the marketing authorisation)​[30]​ . An SGLT2i licensed for this indication (in addition to the ARB or ACEi) should be considered if ACR is between 3 and 30mg/mmol and they meet the licensing criteria, including eGFR thresholds​[30]​.

Blood glucose monitoring

NICE has provided clarity on their recommendations on routine self-monitoring of blood glucose. It is recommended that people with T2DM should not be offered self-monitoring of blood glucose unless they are:

• Taking insulin therapy;
• Experiencing hypoglycaemic episodes;
• Taking oral medication (e.g. a sulfonylurea) that may increase their hypoglycaemia risk when driving or operating machinery​[30]​.

There are other groups of people for whom self-monitoring of blood glucose is also recommended:

• Pregnant women; those who are planning to become pregnant can be considered for short-term monitoring;
• Individuals who have been started on oral or intravenous steroid treatment;
• Short-term blood glucose monitoring can be considered if the person is reporting hypoglycaemic symptoms, to confirm suspected hypoglycaemia​[30]​.

Clinicians should conduct a structured assessment at least annually with the person self-monitoring their blood glucose to ensure that this is still appropriate, and they continue to have the skills and knowledge to self-monitor and interpret and act on their results​[30]​.

In regards to continuous glucose monitoring (CGM), NICE recommends that clinicians should offer intermittently-scanned CGM, commonly referred to as ‘Flash’ glucose monitoring. Flash glucose monitoring differs from traditional monitoring in that it uses a sensor worn on the body, which allows the patient to check blood sugar levels without having to prick their fingers. CGM is recommended by NICE for people with T2DM who:

• Have recurrent or severe hypoglycaemia;
• Have impaired hypoglycaemia awareness;
• Cannot self-monitor their blood glucose by the usual finger prick testing (e.g. those who have a learning disability, cognitive impairment, or dexterity problems, but could use the intermittently scanned CGM, or someone could scan for them);
• Would otherwise need to self-monitor at least eight times per day using the finger prick blood glucose monitoring device[29].

Real-time CGM could be considered for those who are insulin-treated if it is available at the same or lower cost. And it should be provided by specialist team who has expertise in working with CGM​[30]​.

Blood pressure and lipid management

All adults aged 12 years and above with diabetes should receive the following nine healthcare checks at least once per year to reduce the risk of long-term complications: HbA1c, blood pressure, cholesterol, retinal screening, foot examination, kidney function, urinary albumin, body mass index and smoking status​[59]​. Information is gathered from GP practices and hospital diabetes clinics in the annual NDA for England and Wales on the eight care processes (excluding retinal screening) and the three NICE-recommended treatment targets (as shown in Box 2). Since 2018, new indicators were added to the NICE General Practice Quality Outcomes Framework, to support an individualised management approach that adjusts care according to an individual’s frailty status​[60]​. In relation to cholesterol targets, prescribing data have been added since the 2017/2018 NDA audit to capture the proportion of patients aged 35–80 years prescribed a statin for primary and secondary prevention​[59]​. Guidance on primary prevention of cardiovascular disease in people with T2DM was updated in 2014, which lowered the ten-year risk of cardiovascular disease threshold for statin initiation. Atorvastatin 20 mg daily is recommended for primary prevention in those who have a QRISK2 score of 10% or greater​[61]​.

Surgery

In severely obese patients with T2DM, bariatric surgery has resulted in better glucose control than medical therapy​[62]​. Diabetes remission rates have been found to be significantly higher in patients who have undergone gastric bypass compared with those who have been receiving medical therapy at 2 years and 15 years​[62,63]​. Bariatric surgery has also improved lipid profiles, with triglyceride levels normalised in more than 85% of patients who had undergone surgery compared with no improvements in patients who had just had medical therapy​[62]​. One study found that, at 15 years’ follow up, diabetes remission rates were significantly lowered in patients who had bariatric surgery and the incidence of microvascular complications was half of that in control patients​[63]​. The observed increase in concentrations of GLP-1 after bariatric surgery has been suggested to be one of the mechanisms leading to improved blood glucose levels​[10]​.

NICE guidelines on obesity recommend that assessment for bariatric surgery should be provided by the NHS if the patient meets the criteria (see Box 3); however, local referral criteria may vary.

Pharmacy interventions

NICE recommends that all patients with T2DM should be referred to a diabetes structured education programme at or around the time of diagnosis​[30]​. DESMOND (Diabetes Education and Self Management for Ongoing and Newly Diagnosed) and X-PERT are the two nationally commissioned programmes available, and versions of these have been developed to tailor education to local needs. It is crucial that pharmacists in all settings make use of all opportunities to reinforce diet and lifestyle advice, as well as the importance of medicines adherence, to ensure patients receive consistent messages about their diabetes care. The most important advice for patients should include maintaining a balanced diet, staying active, moderating alcohol intake and stopping smoking — all of which are available on the Diabetes UK website.

Community pharmacists can offer patient support concerning their medicines and the management of their long-term conditions through locally commissioned services, such as weight management programmes and blood pressure monitoring. Medicines use reviews and the new medicine service in England are advanced services that patients can use in order to maximise the benefit of their prescribed medicines. In addition to the existing three target groups, patients at risk of, or diagnosed with, cardiovascular disease (CVD) should also be targeted​[66]​.

The ‘NHS long-term plan’ sets out several actions to prevent diabetes, improve stroke services and improve detection and care for people with CVD and respiratory disease​[41]​. Workforce planning is building on the ‘General practice forward view’ to increase primary care staffing and pharmacists will play a major role in GP surgeries​[41]​. As such, there will be vast opportunities for GP pharmacist-led interventions to improve diabetes care.

Improving diabetes care by GP pharmacists can be achieved by ensuring that patients with T2DM are receiving the eight NICE-recommended care processes and meeting the three treatment targets, through tackling poor medicines adherence and encouraging lifestyle modification, alongside the use of evidence-based pharmacological therapies.

Hospital specialist pharmacists should conduct medicines reviews for patients with poor diabetes control to ensure the best treatment outcomes and prevent adverse effects before discharge.

Care home pharmacists can provide input into pharmacological management and self-care advice to residents and/or care staff during caseload review, with a focus on individualised glycaemic goals and avoidance of hypoglycaemia.

An example of how to support a patient with T2DM is described in Box 4.