Diagnosis and management of type 2 diabetes mellitus
Patient education and self management are central to treating type 2 diabetes mellitus and preventing its associated complications.
There are 4.7 million people in the UK living with diabetes mellitus — more than 3.2 million of whom are in England, equivalent to a prevalence of around 6.8% in England. The NHS spends at least £10bn on diabetes each year, with nearly 80% of this being spent on treating diabetic complications. Around one in three of these people will already have microvascular complications on diagnosis of type 2 diabetes mellitus (T2DM) and 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). Another complication, diabetic retinopathy, is a leading cause of preventable sight loss among working-age people wth T2DM in the UK.
More than a third of people who require kidney dialysis or a kidney transplant have diabetes. 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).
Diabetes mellitus is a long-term condition characterised by hyperglycaemia as a result of insulin deficiency, insulin resistance, or both. Type 1 diabetes mellitus (T1DM) and T2DM are the two most common types of diabetes globally, with around 90% of people having T2DM.
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.
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. 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.
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. 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,. 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.
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.
Some people may have body adiposity genes and beta-cell dysfunction genes that predispose them to T2DM. 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. 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 phosphoinositol 3-kinase (PI-3 kinase) proteins, have been linked with impaired glucose uptake and use in the body, which consequently leads to insulin resistance. Beta-cell function related to insulin sensitivity and secretion is heritable, as demonstrated in studies with families that have a high risk of T2DM,. Collectively, these polymorphisms may contribute to the genetic predisposition of some individuals to developing T2DM.
An alternative hypothesis has been proposed that liver and pancreatic fat deposition, owing to long-term caloric excess, is linked with beta-cell dysfunction. 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 reintroduction 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).
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.
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. 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. This results in persistent hyperglycaemia and glucose intolerance. 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,.
Obesity is a major risk factor of T2DM. 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. An elevated plasma-free fatty acid concentration in overweight/obese individuals is strongly associated with the development of insulin resistance and impaired glucose tolerance. 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,.
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, and thus T2DM.
Other risk factors include first-degree relatives of patients with diabetes, women with gestational diabetes or polycystic ovary syndrome (which increases the risk of impaired glucose regulation). 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.
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,. 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 it is in their country of origin.
Systemic inflammation also contributes to insulin resistance as an improvement in inflammatory markers, such as C-reactive protein and interleukin-6, are linked to an improvement in beta-cell function.
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. Diabetic ketoacidosis is less common in those with T2DM because the majority of people are insulin resistant rather than insulin deficient.
This 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. The OGTT has largely been replaced by the HbA1c test and is now mainly used in the diagnosis of gestational diabetes.
An 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. If only one measurement is in diabetic range, a second abnormal result using the same test is required to confirm the diagnosis.
Box 1: The International Diabetes Federation and World Health Organization diagnostic criteria for type 2 diabetes mellitus
Presence of diabetes symptoms (e.g. frequent urination, thirst, unexplained weight loss) and one of the following abnormal test results:
- A fasting plasma glucose concentration of ≥7.0mmol/L;
- A random venous plasma glucose concentration of ≥11.1mmol/L;
- A plasma glucose concentration of ≥11.1mmol/L two hours after 75g anhydrous glucose in an oral glucose tolerance test;
- An HbA1c level of ≥48mmol/mol (6.5%).
In the absence of diabetes symptoms, two abnormal test results are required for confirmation (preferably the same test).
Source: International Diabetes Federation
However, there are patient groups in whom HbA1c is inappropriate for diagnosis, including:
- 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).
Urinary glucose should not be used as a diagnostic test owing to its low sensitivity. 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, which is characterised by impaired insulin secretion with minimal or no defects in insulin action resulting from genetic defects in beta-cell function.
Diabetes care should encompass patient education, dietary and lifestyle advice, management of cardiovascular risk, as well as detection and management of long-term complications. For example, patients should be encouraged to eat high‑fibre, low‑glycaemic‑index sources of carbohydrate (e.g. fruit, vegetables, wholegrains and pulses), as well as low‑fat dairy products and oily fish.
Since 2015, NICE has been advocating a patient-centred approach to glycaemic control and provides best practice advice on setting glycaemic targets and selecting hypoglycaemic agents for treatment intensification after metformin (first-line treatment for T2DM) in those with inadequate diabetes control. One of the main recommendations in the NICE guideline is the broadening of the choices of second-line hypoglycaemic agents, either as an adjunct to metformin or as first-line therapy if metformin is not tolerated or is contraindicated. These agents are a dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea, pioglitazone and a sodium–glucose cotransporter 2 (SGLT-2) inhibitor. GLP-1 receptor agonists and insulin therapy (with the exception of insulin being used as rescue therapy in those with symptomatic hyperglycaemia) are generally recommended as third-line agents (see Figure).
Figure: Overview of type 2 diabetes mellitus blood glucose management
The second recommendation from NICE describes setting an individualised HbA1c target, which aims to intensify treatment when HbA1c rises to ≥58mmol/mol (7.5%). Advice on diet, lifestyle and medicines adherence should be reinforced to support the patient to aim for an 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 DPP-4 inhibitor, should aim for a tighter HbA1c target of 48mmol/mol (6.5%). Patients who are taking a single drug that is associated with hypoglycaemia, for example a sulfonylurea, an HbA1c target of 53mmol/mol (7.0%) should be set. A higher HbA1c target should be set for those in whom a target of 53mmol/mol would impair their quality of life; for example, if it would cause them to have hypoglycaemic episodes. In the presence of frailty or for those with a limited life expectancy, a relaxed glycaemic target should be considered based on the level of frailty, where an HbA1c of up to 70mmol/mol (8.5%) may be considered appropriate.
Recent evidence from cardiovascular outcomes clinical trials demonstrating cardiovascular benefits of some agents within the class of SGLT-2 inhibitors and GLP-1 receptor agonists has prompted a review of pharmacological treatments to improve cardiovascular risk beyond glucose control. Both the updated Scottish Intercollegiate Guidelines Network guideline and the American Diabetes Association’s and the European Association for the Study of Diabetes’s 2018 Consensus Report recommend a comprehensive, patient-centred and cardiovascular risk-focused approach in managing T2DM in patients with a high cardiovascular risk, through the use of evidence-based therapy with proven cardiovascular benefit.
Similarly, the updated Diabetes Canada Clinical Practice Guidelines 2018 also recommend that a hypoglycaemic agent with evidence of a cardiovascular outcome benefit should be considered for patients with T2DM and high cardiovascular risk.
The Table shows the side effects and safety profile of the commonly prescribed hypoglycaemic agents for the treatment of T2DM in adults in the UK. Pharmacists should note that the only UK-licensed medicines for T2DM 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.
|Drug class||Advantages/benefits||Disadvantages/risks||Renal impairment||Hepatic impairment||Recommendations/main counselling points|
|Postprandial regulators (meglitinides)|
|Dipeptidyl peptidase-4 inhibitors|
|Sodium–glucose cotransporter 2 inhibitors|
|Glucagon-like peptide-1 receptor agonists|
Note: Additional references that are not found in the BNF are included for information.
Sources: National Institute for Health and Care Excellence; British National Formulary; The Lancet; US Food and Drug Administration; European Medicines Agency; eMC; Am J Kidney Dis; Diabetes Care; eMC; eMC; eMC; Medicines and Healthcare products Regulatory Agency; Medicines and Healthcare products Regulatory Agency; eMC; eMC; eMC; European Medicines Agency; Br J Clin Pharmacol; eMC; eMC.
Blood pressure and lipids
All patients aged 12 years and over with diabetes should receive the following nine healthcare checks at least once per year to reduce the risk of long-term complications:
- HbA1c level;
- Blood pressure;
- Retinal screening;
- Foot examination;
- Kidney function;
- Urinary albumin;
- Body mass index;
- Smoking status.
Reducing glucose levels lowers the risk of all long-term complications of diabetes, while reducing cholesterol levels lowers the risk of heart attacks and strokes.
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 (see Box 2). In relation to cholesterol targets, prescribing data have been added to the 2017 to 2018 NDA audit to capture the proportion of patients aged 35–80 years prescribed a statin for primary and secondary prevention. Guidance on primary prevention of cardiovascular disease (CVD) in people with T2DM was updated in 2014, which lowered the ten-year risk of CVD threshold for statin initiation. Atorvastatin 20mg daily is recommended for primary prevention in those who have a ‘QRISK2’ score of 10% or greater.
Box 2: National Institute for Health and Care Excellence-recommended treatment targets for people with type 2 diabetes mellitus
- HbA1c ≤58.0mmol/mol (7.5%);
- Blood pressure <140/80mmHg;
- Total cholesterol <5mmol/L and <4mmol/L.
Source: National Institute for Health and Care Excellence
In severely obese patients with T2DM, bariatric surgery has resulted in better glucose control than medical therapy. 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 at 15 years,. 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. One study found that, at 15 years’ follow up, diabetes remission rates were significantly lowered in patients who had had bariatric surgery and the incidence of microvascular complications was half of that in control patients. 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.
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.
Box 3: Access to bariatric surgery for people with type 2 diabetes mellitus
In people who have recent-onset type 2 diabetes mellitus and are also receiving or will receive assessment in a tier 3 service (or equivalent):
- Offer an expedited assessment for bariatric surgery to those with a body mass index (BMI) of ≥35;
- Consider an assessment for bariatric surgery for people with a BMI of 30.0–34.9;
- Consider an assessment for bariatric surgery for people of Asian family origin at a lower BMI than other populations (a lower BMI cut-off of 27.5kg/m2 is considered as obese for this population).
NICE recommends that all patients with T2DM should be referred to a diabetes structured education programme at or around the time of diagnosis. 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, CVD should also be targeted.
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. 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. 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.
Box 4: Case study
A 48-year-old Caucasian female diagnosed with type 2 diabetes mellitus (T2DM) four years ago was reviewed in a pharmacist-led diabetes clinic. She lives with her husband and two young children, and works as an office secretary.
Past medical history: T2DM and hypertension.
Family history: her mother had T2DM; both parents had hypertension.
Social history: she does not smoke and only drinks alcohol occasionally at social events.
- Overweight with a body mass index of 29.7kg/m2;
- HbA1c is 65mmol/mol (four weeks ago);
- Blood pressure is 137/84mmHg;
- Total cholesterol is 4.6mmol/L;
- Non-high-density lipoprotein (HDL) cholesterol is 3.6mmol/L;
- Estimated glomerular filtration rate is 88mL/min;
- Liver function tests (LFTs) are normal.
- Metformin 1g twice daily;
- Pioglitazone 45mg once daily;
- Ramipril 5mg once daily.
During the 20-minute consultation, the pharmacist checked medicines adherence and gathered information about diet and lifestyle. The patient is struggling to lose weight as it has been difficult to find time for exercise around looking after her children. Her work involves sitting down and does not permit much activity throughout the day. She also snacks on a lot on biscuits and nuts. A QRISK2 score has not been documented on her patient record, but it was calculated to be 18%.
Outcome of consultation:
The patient was given an explanation about the need to improve her diabetes treatment regimen owing to her inadequate glucose control on the maximum doses of her current diabetes medicines. This is to help achieve her HbA1c target of 53mmol/mol (7.0%) and reduce the risk of complications. Since pioglitazone causes weight gain and fluid retention, she was given the option to switch pioglitazone to a sodium–glucose cotransporter 2 (SGLT-2) inhibitor. The advantages and disadvantages of this class of medicine were discussed. A SGLT-2 inhibitor is considered appropriate for her as it can help with weight loss. Trial evidence has also shown that SGLT-2 inhibitors can cause a small reduction in blood pressure†. The patient was informed of possible side effects, such as an increased risk of genitourinary infections and diabetic ketoacidosis, as well as discussing the need to keep hydrated and the sick day rules (i.e. consider temporary cessation of certain medicines during peroids of acute illness). The QRISK2 score and its implications were also discussed; the patient was reluctant initially, but was subsequently willing to try a low-dose statin (i.e. atorvastatin 20mg).
The patient took the advice and, as a result, empagliflozin 10mg daily was initiated. The pharmacist reinforced the importance of lifestyle changes and explored the activity options that would best suit the patient. It was agreed that she would try brisk walking for 30 minutes two to three times per week initially, to fit into her routine. The patient was aware that frequent snacking can lead to calorie excess; however, it would be challenging for her to stop snacking altogether. Hence, advice was given to replace high-fat/sugary snacks with healthier options and the patient was reminded of the importance of portion control.
The patient had attended a DESMOND programme soon after diagnosis, and felt that she just needed motivation to get herself back on track and make positive changes that fit into her busy life. As such, she was referred to a diabetes specialist dietitian for further dietary advice.
The pharmacist checked tolerance to empagliflozin after two weeks and atorvastatin 20mg daily was started.
The patient was referred to a community pharmacy three months later for initiation on the new medicines service, and was to be followed up for LFT monitoring and a diabetes review.
Source: †N Engl J Med
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2019.20206770
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