Key Learning Points: Managing Type 2 Diabetes in Adults

Dr Pam Brown and Dr Colin Kenny Provide Seven Key Learning Points from the Updated NICE Guideline on the Management of Type 2 Diabetes

Nearly 5 million people in the UK live with diabetes, 90% of whom have type 2 diabetes. Around 850,000 people with diabetes remain undiagnosed.¹  

During the past 2 years, people with diabetes have experienced direct detrimental effects from COVID-19, including increased disease severity, an elevated likelihood of hospitalisation and admission to intensive care, and raised mortality. Indirect effects of the pandemic on diabetes care are ongoing, and include reduced access to routine diabetes reviews, delayed diagnosis of type 2 diabetes and, for many people, deterioration in glycaemic control. Many practices are now coping with a backlog of diabetes reviews, and are working hard to prioritise the care of people most at risk.²

Against this backdrop, the long-awaited update to NICE Guideline (NG) 28, Type 2 diabetes in adults: management,³ was published on 15 February 2022. NICE Technology Appraisal (TA) Guidance 775, Dapagliflozin for treating chronic kidney disease,⁴ was published on 9 March and referenced in the updated NG28, and guidance on continuous glucose monitoring (CGM) was added to NG28 on 31 March.

Few significant changes were made as a result of feedback on the draft NG28 update, despite interested parties—including the Primary Care Diabetes Society—providing evidence-based comments. The final scope of the update was limited, and the guideline committee did not look at the clinical and cost effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for glucose lowering. Therefore, they were unable to significantly alter the 2015 GLP-1 RA recommendations in the 2022 update.³ However, in view of the anticipated increased use of sodium–glucose co-transporter-2 inhibitors (SGLT-2is) with metformin as combination first-line therapy, the need to include a sulfonylurea in the triple therapy regimen when starting a GLP-1 RA was removed.³

Navigating the Updated Guideline

The updated NG28 can be viewed on the NICE website,³ and features links to Type 2 diabetes in adults: choosing medicines resources, which include prescribing guidance (see Box 1), advice on how to choose first-line medicines (see Figure 1), and guidance on how to choose further medicines (see Figure 2), along with summaries of the medicines recommended.⁵ A link to a new patient decision aid on agreeing a target glycated haemoglobin (HbA_1c) level is also included (see Figure 3).

Viewed on the NICE website, the guideline also contains links to other NICE diabetes guidance referred to in the update, which is listed in Box 2.^3,7–22 It refers clinicians to the content relevant to type 2 diabetes in these guidelines, rather than summarising their recommendations in the update. The Rationale and impact section includes the background to the recent recommendations, and sections of that are summarised in this article to explain and support the recommendations where appropriate.

Need for the Updated Guidance

NG28 was first published in 2015. Since then, there have been considerable advances in understanding the cardiometabolic and renal benefits of glucose-lowering drugs, with the publication of cardiovascular and renal outcome studies involving both older and newer glucose-lowering drugs. The guideline has, therefore, been out of date for several years, prompting clinicians in the UK to follow the American Diabetes Association/European Association for the Study of Diabetes consensus reports on the management of hyperglycaemia published in 2018²³ and 2019²⁴ to ensure that practice is evidence based and up to date.

Other diabetes guidance aimed at clinicians in primary care includes the 2022 update to the position statement by Primary Care Diabetes Europe on the pharmacological management of type 2 diabetes in primary care.²⁵

Some of the updates in NG28 affect only the language used—for example, throughout the guideline ‘individually agreed threshold for intensification’  has been replaced with ‘individually agreed threshold for further intervention’.³‘Initial drug treatment with metformin’ has been changed to ‘monotherapy’ because some people may now receive monotherapy with an SGLT-2i if they are unable to be treated with metformin.³ These changes will not be discussed further.

Repaglinide, rarely used in the UK, has been removed from the guideline.³

This article summarises the clinically important changes to recommendations in the updated NG28, and the areas in which no significant changes have taken place.

1. Alert Patients to the New Decision Aid on Glycaemic Targets

A new patient decision aid (see Figure 3) has been added to NG28’s resources to help people with diabetes prepare for their diabetes review and to discuss glycaemic targets with their healthcare professional.⁶ However, the decision aid links tighter glycaemic control to an increased risk of side effects and hypoglycaemia,⁶ risks that some people understandably do not find acceptable and that can make the subsequent discussion about glycaemic targets challenging. Appropriate use of newer medications should make glycaemic control easier without increasing these risks and, in the author’s view, modification may be needed before people with diabetes can use the decision aid to prepare for consultations.

As in the previous guideline and in current practice, NG28 recommends individualised glycaemic targets, with higher targets agreed when longer-term risk reduction is unlikely, when tight glycaemic control may cause hypoglycaemia and increase risk, or in some cases when people drive or operate machinery or have significant comorbidities.³

2. Harness the Benefits of Continuous Glucose Monitoring

The section on self-monitoring of capillary blood glucose remains unchanged in NG28, but a new section explains how CGM technologies can be used in people with type 2 diabetes.³ These recommendations are summarised in Box 3.

NICE recommends that commissioners, providers, and healthcare professionals should address inequalities in CGM access and uptake in their practice in line with this guidance.³

NICE identified that, although more people with type 2 diabetes are likely to be offered CGM following these recommendations, there should be fewer hypoglycaemic events to manage, which will reduce the anticipated increase in costs.³ Interestingly, the Guideline Development Committee did not expect these changes to have a significant resource impact related to education and monitoring;³ however, in my opinion, the more prevalent belief is that more people using CGM will result in additional workload both for education and monitoring.

3. Be Aware of New Recommendations on Dual First-line Therapy

The most significant change to the guideline relates to first-line therapy, for which clinicians are now encouraged to assess HbA_1c, cardiovascular risk, and kidney function.^3,5

Dual therapy with metformin and an SGLT-2i with proven cardiovascular benefit should be offered to people with type 2 diabetes and chronic heart failure (HF) or established atherosclerotic cardiovascular disease (ASCVD).³  For definitions of some of the terms used in the guideline, see Box 4.

Dual therapy should be considered for adults with type 2 diabetes who are at high risk of developing cardiovascular disease (CVD) and have:

• a QRISK2 score of 10% or higher in those aged 40 years and over, or
• an elevated lifetime risk of developing CVD if aged less than 40 years (defined as one or more of the following risk factors: hypertension, dyslipidaemia, smoking, obesity, or a first-degree relative with premature CVD).³

This advice is summarised in Figure 1.

When initial dual therapy is recommended, metformin should be started first, building up from 500 mg once daily to 1 g twice daily in 500 mg per day increments at weekly intervals, if tolerated. If estimated glomerular filtration rate (eGFR) is persistently less than 45 ml/min/1.73 m², the dosage should only be titrated to 1 g daily. If eGFR drops to less than 30 ml/min/1.73 m², the drug should not be initiated, and ongoing therapy with the drug should be stopped because of the very small increased risk of lactic acidosis.²⁶ Slower titration is sometimes necessary if gastrointestinal (GI) symptoms occur; for those in whom GI disturbance persists, a trial of modified-release metformin should be considered.³ Once the full metformin dose appropriate to the eGFR is achieved, an SGLT-2i with proven cardiovascular benefit (canagliflozin, dapagliflozin, or empagliflozin) should be added without waiting to repeat HbA_1c testing.

NICE recognises that some people who would benefit from dual first-line therapy will be unable to take or tolerate metformin. In this situation, an SGLT-2i with proven cardiovascular benefit can be used as monotherapy for first-line therapy.³ For people who are unable to take an SGLT-2i, NICE recommends metformin alone as first-line therapy; this is because NICE found that GLP-1 RAs were not cost effective for cardiovascular risk reduction.³

One area in which the guideline is not clear is in relation to people who have ASCVD or have a high risk of developing CVD who are not able to take an SGLT-2i or metformin. For this group, the guideline recommends they should take ‘the next most effective and cost-effective treatment’, but it stops short of specifically recommending any drug class, preferring to leave it to prescribers to use their clinical judgement to choose an appropriate treatment ‘based on the individual clinical circumstances and needs of the person with type 2 diabetes’.³ In practice, the only available choice would be a GLP-1 RA with proven cardiovascular benefit, such as liraglutide, dulaglutide, or semaglutide, despite NICE stating that GLP-1 RAs are not a cost-effective option in this situation.³

An SGLT-2i with proven cardiovascular benefit should also be added at any time if people have or develop heart failure or established ASCVD during diabetes treatment, and should be considered if they develop a high risk of CVD.³ This advice is summarised in Figure 2.⁵ In these scenarios, discussion is recommended as to whether an SGLT-2i is added or an existing medication is replaced with an SGLT-2i, depending on the individual’s current therapies, preferences, and HbA_1c level.^3,5

4. Understand the Licensed Uses of SGLT-2is

Because the recommendations of the updated guideline are expected to increase the use of SGLT-2is, it is important for primary care teams to have a clear understanding of when and how to use these drugs safely, and how to counsel people on initiating and continuing therapy with an SGLT-2i.³ In particular, NG28 highlights the risks of potentially avoidable diabetic ketoacidosis (DKA), and the importance of identifying risk factors for DKA (including the use of very low-carbohydrate or ketogenic diets), and modifying risk factors when possible before starting an SGLT-2i.³

NICE’s recommendations for the use of SGLT-2is as dual first-line therapy in people with chronic HF or established ASCVD and in those at high risk of developing CVD, are based on findings from cardiovascular outcome trials (CVOTs) and network meta-analyses.³ Differences were identified between the drugs in this class depending on the end point explored in the studies. Therefore, NICE recommends that SGLT-2is with proven cardiovascular benefit should be chosen for these patients.³

5. Appreciate the Renal Benefits of SGLT-2is

NICE published its guideline on CKD in August 2021, and updated it in November 2021.²² Information relevant to type 2 diabetes was used to update the CKD section in NG28, and this remains unchanged in the February 2022 update.³ Under this guidance, some people with CKD qualify for SGLT-2i use to slow the progression of CKD.

If a patient’s albumin–creatinine ratio (ACR) is 3 mg/mmol or higher, offer an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and titrate to the highest licensed dose that is tolerated, as recommended in the NICE CKD guideline.²²

For those with CKD taking the maximum tolerated dose of an ACEI or ARB, offer an SGLT-2i if their ACR is greater than 30 mg/mmol and they meet the licence criteria for the SGLT-2i.³ If their ACR is between 3 and 30 mg/mmol, consider an SGLT-2i if they meet the licence criteria.³ Note that not all SGLT-2is were licensed for CKD or diabetic kidney disease (DKD) at the time of this recommendation, and that there have historically been different eGFR thresholds for initiating and stopping SGLT-2is in people with CKD, so consult the British National Formulary (BNF) or individual Summary of Product Characteristics (SPC) to choose appropriately.^27–30

The recommendations of TA775⁴ were referenced in NG28 as follows. Dapagliflozin is recommended as an option for treating CKD in adults only when:⁴

• it is an add-on to optimised standard care including the highest tolerated licensed dose of ACEIs or ARBs, unless these are contraindicated, and
• eGFR is 25–75 ml/min/1.73 m² at the start of treatment and the person has
  • type 2 diabetes, or
  • a urine ACR of 22.6 mg/mmol or higher.

6. Recognise the Recommendations that Are Unchanged

Recommendations in the updated NG28 that remain unchanged are listed in Box 5.³ The focus on individualised care is retained, and clinicians are encouraged to consider comorbidities, the likelihood of benefit from long-term interventions, the risks from polypharmacy, and the multimorbidity that is increasingly prevalent in people with type 2 diabetes.³

The recommended HbA_1c level remains at 48 mmol/mol for those managing type 2 diabetes by diet alone or by diet and one drug that does not cause hypoglycaemia, and the recommended HbA_1c level of 53 mmol/mol is unchanged for those taking a drug that can cause hypoglycaemia.³ If a patient’s HbA_1c level rises to 58 mmol/mol, clinicians are reminded to reinforce advice about diet, lifestyle, and adherence with medication, and consider intensifying drug treatment to aim for an HbA_1c level of 53 mmol/mol.³

Prescribing guidance, which is packaged with advice on choosing first-line and further medicines, reiterates previous guidance on factors to consider when choosing, reviewing, and changing medicines.⁵ When a treatment change or review is planned, clinicians should think about and discuss the following with the person with diabetes:³

• how to optimise their current therapy and lifestyle
• stopping any medicines that have not been effective in reducing glucose levels or weight, unless they are being used for additional benefits, such as cardiovascular or renal protection
• whether switching rather than adding drugs may be effective.

In these discussions and decisions, the prescribing guidance outlined in Box 1 should be taken into account.⁵

For people who are not at high risk of developing CVD and who do not qualify for SGLT-2i use for CKD, first-line therapy remains metformin alone.³ When metformin is contraindicated or not tolerated, a dipeptidyl peptidase-4 inhibitor (DPP-4i), pioglitazone, a sulfonylurea, or an SGLT-2i as outlined in the relevant TA guidance—TA390³¹ or TA572³² —may be used as monotherapy.³ The TA guidance recommends SGLT-2is as monotherapies in a specific scenario: when metformin is unsuitable and diet and exercise alone do not provide adequate glycaemic control, and a DPP-4i would otherwise be prescribed and a sulfonylurea or pioglitazone is not appropriate.^31,32

As in previous guidelines, rescue therapy with insulin or a sulfonylurea should be considered in people who have symptoms of hyperglycaemia.³ Use of these rescue therapies can be reviewed once glycaemic control is achieved.³ In my clinical experience, people with type 2 diabetes may be more likely to accept either drug or the glucose self-monitoring required in the short term if they understand that their need for these treatments will be reconsidered when glycaemic control is achieved, and that if they are able to alter their diet or lose weight, it may help them to achieve glycaemic control earlier.

At any point, when HbA_1c is not controlled below the individually agreed target, the updated guideline recommends switching or adding a DPP-4i, pioglitazone, or a sulfonylurea as it did previously.³ SGLT-2is remain an option for dual or triple therapy at this stage,³ as recommended in the following TA guidance:

• dual therapy—TA288³³, TA315³⁴, and TA336³⁵
• triple therapy—TA315³⁴, TA336³⁵, and TA418³⁶.

This section of NG28 was updated to include ertugliflozin as monotherapy, as part of dual therapy with metformin (TA572), or as part of triple therapy with metformin and a DPP-4i (TA583).^3,32,37 This advice is summarised in Figure 2.⁵

The positioning of insulin remains unchanged: consideration as an alternative to a third oral therapy when dual therapy has failed to control HbA_1c levels to the agreed target, including when metformin is contraindicated or not tolerated.³ When using long-acting insulin analogues, consider initiating or switching to biosimilars for cost savings when appropriate.³

7. Note that GLP-1 RAs Are Not Recommended as a First-line Therapy

GLP-1 RAs were not recommended by NICE for use for cardiovascular benefit at any stage because:

• in the NICE modelling, they were not cost effective as a class for people with established ASCVD or at high risk of developing CVD,³ presumably because not all drugs showed cardiovascular benefit in their respective CVOTs (only dulaglutide, liraglutide, and semaglutide have demonstrated cardiovascular benefits)
• although the incremental cost-effectiveness ratios for injectable semaglutide were similar to those for individual SGLT-2is in several of the modelling scenarios, NICE stated there was more certainty that SGLT-2is as a class were cost effective compared with GLP-1 RAs³
• differences in clinical effectiveness, particularly for all-cause mortality between oral and injectable semaglutide in relatively small trials with low event rates, were also cited as contributing to the uncertainty.³

This means that GLP-1 RAs are positioned very differently in NG28 for people with established ASCVD or at high risk of developing CVD than they are in other guidelines in current use, in which they are a joint first-line therapy for these groups and a second-line therapy for those with CKD, as well as being recommended as an option after metformin when hypoglycaemia needs to be avoided or weight loss is a priority.²³

GLP-1 RAs retain their unchanged position for consideration when triple therapy with metformin and two other drugs (or dual therapy in those unsuitable for metformin) is not effective, not tolerated, or contraindicated.³ Switching one drug for a GLP-1 RA can be considered in people with:³

• a body mass index (BMI) of 35 kg/m² or more (adjusted for those from Black, Asian, and other minority ethnic groups) and specific psychological or other medical problems associated with obesity, or
• a BMI less than 35 kg/m² and for whom insulin would have significant occupational implications, or for whom weight loss would benefit other significant obesity-related comorbidities.

Previous recommendations on stopping therapy have been retained, meaning that people initiated on a GLP-1 RA need to show a reduction of 11 mmol/mol (1%) in HbA_1c and a weight loss of at least 3% of their initial body weight in 6 months.³ For those who tolerate once-weekly dulaglutide or semaglutide, it is likely that many will achieve the HbA_1c reduction depending on their baseline HbA_1c, although weight reduction is known to be slower in people with diabetes compared to those without the disease.³⁸

GLP-1 RAs can still be used in combination with insulin, but this needs to be initiated by a consultant-led specialist diabetes service, which can be based in primary, secondary, or intermediate care settings.³

Action Plan for Implementing the Changes

Using SGLT-2is as dual first-line therapy with metformin:

• discuss with those who meet the criteria at the time of a new diagnosis; starting two medications may be overwhelming for some people, especially if they are already on medications for other conditions. A 4-week telephone review, to check tolerance of metformin and to counsel about the benefits of adding an SGLT-2i, is likely to be useful. Discussing lifestyle changes and remission at each opportunity may also motivate people to make changes at these teachable moments
• every practice will have many people with ASCVD, at a high risk of developing ASCVD, or with chronic HF who retrospectively now qualify for dual first-line therapy. Practice searches can identify these people, and a discussion with them about the addition of an SGLT-2i can be had either face to face or virtually. This is best practice. However, given clinicians’ excessive workloads, the backlog of diabetes reviews, and that for SGLT-2is to be initiated safely these consultations will take time, practices may choose to wait until the next planned diabetes review, prioritising this group so that it occurs as soon as possible. When dual therapy is not initiated immediately, it can be useful to flag it up for consideration as an alert on the electronic record.

Because of their mode of action, all SGLT-2is have decreased or absent glucose lowering at a sustained eGFR of less than 45 ml/min/1.73 m², and therefore additional glucose-lowering medications should be considered if the agreed, individualised glycaemic target is not met.

NG28 does not differentiate between different types of chronic HF. At the time of writing, only dapagliflozin and empagliflozin are licensed for use in heart failure with reduced ejection fraction;^28,29 therefore, some SGLT-2i use may be off-label, and this should be discussed with the patient. Currently, not all SGLT-2is are licensed specifically for CVD, even though they have demonstrated benefits in CVOTs. Ertugliflozin is only licensed for uncontrolled type 2 diabetes,³⁰ so its use to reduce cardiovascular risk when blood glucose is controlled would be off-label. In the UK, only dapagliflozin has licensed indications for CKD in those with or without type diabetes mellitus,²⁸ and canagliflozin is licensed for use in those with DKD.²⁷ Licences are changing rapidly, so check the latest SPCs or consult the links to the electronic BNF in the guideline visual aids before prescribing to ensure that the product is licensed for the indication and that the eGFR is within the range in which the drug can be initiated.

Practices will have patients who are either already taking GLP-1 RAs or it is being considered as the next step in therapy, so it is useful to highlight how this update to NG28 could change practice:

• for those already on GLP-1 RAs who meet the current criteria for initiation, treatment can continue
• for those already on GLP-1 RAs who do not meet the current initiation criteria, medications prescribed before guideline publication can be continued, provided that the clinican feels it is appropriate
• for those being considered for GLP-1 RAs with cardiovascular benefits who have established ASCVD or are at a high risk of developing ASCVD and for whom SGLT-2is are unsuitable or not tolerated, initiation is supported by other contemporary guidelines, so clinicians will need to make an informed decision based on the cardiovascular trials for the specific drug they plan to prescribe. As discussed earlier, choosing not to initiate a GLP-1 RA that has proven cardiovascular benefits in this scenario may be difficult to justify
• when considering the use of a GLP-1 RA for glycaemic control, the majority of patients will already be receiving three oral drugs and will meet the new criteria for use, as inclusion of a sulfonylurea in triple therapy is no longer required.

Summary

As with all NICE guidelines, the decision about how to implement this update to NG28 lies with the clinician. All GPs support people with type 2 diabetes whose management is suboptimal. It is hoped that, by working to implement this update to NG28 despite its perceived limitations, we will re-energise efforts to improve care and optimise treatment, particularly in relation to dual first-line therapy and CGM.

Dr Pam Brown

Joint Editor-in Chief, Diabetes and Primary Care and Diabetes Distilled; GPwSI diabetes, obesity, and lifestyle medicine; Tutor, University of Warwick/iHeed Global Diabetes Diploma; member of the  Guidelines in Practice Editorial Advisory Board

Dr Colin Kenny

Diploma in Diabetes Course Leader, University of Warwick/iHeed Global Diabetes MSc