Type 2 diabetes: summary of updated NICE guidance
BMJ 2022; 377 doi: https://doi.org/10.1136/bmj.o775 (Published 18 May 2022) Cite this as: BMJ 2022;377:o775
- Gregory M Moran, medicines analyst1,
- Chirag Bakhai, general practitioner2,
- Soon H Song, consultant diabetologist3,
- Juliana Chizo Agwu, committee chair and consultant paediatrician in diabetes and endocrinology4
- on behalf of the Guideline Committee
- 1National Institute for Health and Care Excellence (NICE), City Tower, Piccadilly Plaza, Manchester M1 4BT, UK
- 2Bedfordshire, Luton and Milton Keynes Clinical Commissioning Group, Capability House, Bedford MK45 4HR, UK
- 3Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield S5 7AU, UK
- 4Sandwell and West Birmingham NHS Trust, Sandwell General Hospital, West Bromwich B71 4HJ, UK
- Correspondence to: G M Moran Gregory.moran{at}nice.org.uk
What you need to know
When assessing or reviewing adults with type 2 diabetes, include an assessment of the person’s cardiovascular status and cardiovascular risk
Assess the lifetime risk of cardiovascular disease in people with type 2 diabetes aged <40 years, instead of 10-year cardiovascular risk
Offer adults with type 2 diabetes who have chronic heart failure or atherosclerotic cardiovascular disease a sodium-glucose transport protein 2 (SGLT2) inhibitor with proven cardiovascular benefit
Consider an SGLT2 inhibitor in adults with type 2 diabetes who have do not have chronic heart failure or atherosclerotic cardiovascular disease but who have an increased cardiovascular risk
If an SGLT2 inhibitor is indicated and no glucose lowering drugs are already being taken, it should be prescribed in combination with metformin as soon as metformin tolerability is confirmed
Check and address modifiable risks for diabetic ketoacidosis before starting treatment with an SGLT2 inhibitor
The National Institute for Health and Care Excellence (NICE) last updated the drug treatment section of the type 2 diabetes guideline in 2015. Since then, further evidence on drug treatment from randomised trials investigating the effects of glucose lowering drugs on cardiovascular outcomes has emerged, prompting a further update. This article summarises the most recent recommendations on drug treatment of type 2 diabetes from the NICE guideline.1 This rapid update focuses on evidence of cardiovascular outcomes, with a full update of the section now under way. Key changes to current practice include new recommendations for the use of sodium glucose co-transporter 2 (SGLT2) inhibitors in adults with type 2 diabetes who have chronic heart failure or established atherosclerotic cardiovascular disease or who are at high risk of developing cardiovascular disease. New recommendations for adults with type 2 diabetes and chronic kidney disease were added to the guideline in 2021 but are not covered in this article.
Recommendations
NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Committee’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italics in square brackets.
Choosing drug treatment
The 2015 guideline recommendation listed several factors to consider when choosing drug treatment, including the effectiveness of drug treatments in terms of metabolic response. The updated recommendation has expanded this point to include cardiovascular and renal protection based on evidence from randomised trials showing that SGLT2 inhibitors have both cardiovascular and renal benefits. The Guideline Committee has also emphasised shared decision making in relation to choosing drug treatments, considering the person’s preferences, needs, and individual clinical circumstances (such as contraindications or concerns about weight).
Assessing cardiovascular risk
Although all people with type 2 diabetes are considered at increased risk of cardiovascular disease, the recently published randomised controlled trials focused on two groups at higher cardiovascular risk: people with established atherosclerotic cardiovascular disease and those at greater risk of developing cardiovascular disease (termed “higher cardiovascular risk” below). The cardiovascular risk score QRISK2 is recommended in current NICE guidance2 for assessing cardiovascular risk in people with type 2 diabetes and is used widely in practice. However, QRISK2 does not reflect lifetime cardiovascular risk; therefore, additional risk factors should be considered for people aged under 40 years with type 2 diabetes, who may have increased risk for cardiovascular disease and mortality3 (see box 1 for details).
Assess the person’s cardiovascular status and risk to determine whether they have chronic heart failure or established atherosclerotic cardiovascular disease or are at high risk of developing cardiovascular disease. [Based on the experience and opinion of the Guideline Committee (GC)]
Definitions for atherosclerotic cardiovascular disease and high risk of developing cardiovascular disease
Atherosclerotic cardiovascular disease
Includes coronary heart disease, acute coronary syndrome, previous myocardial infarction, stable angina, previous coronary or other revascularisation, cerebrovascular disease (ischaemic stroke and transient ischaemic attack), and peripheral arterial disease
High risk of developing cardiovascular disease
Defined as adults with type 2 diabetes who have:
QRISK2 cardiovascular risk score >10% in adults aged ≥40 years or
Elevated lifetime risk of cardiovascular disease (defined as the presence of ≥1 cardiovascular risk factor* in someone aged <40 years)
* Cardiovascular disease risk factors: hypertension, dyslipidaemia, smoking, obesity, family history (in a first degree relative) of premature cardiovascular disease
First line drug treatment
In line with the 2015 guideline, the updated guideline recommends metformin as first line drug treatment for all adults with type 2 diabetes. It makes new recommendations to offer an SGLT2 inhibitor with proven cardiovascular benefit (box 2) in addition to metformin to those with chronic heart failure or established atherosclerotic cardiovascular disease, and to consider this treatment for those at high risk of developing cardiovascular disease. The Guideline Committee noted that, although all SGLT2 inhibitors were effective and cost effective, there was greater certainty associated with the cardiovascular benefits of empagliflozin, canagliflozin, and dapagliflozin at the time of publication. The guideline uses the term “SGLT2 inhibitor with proven cardiovascular benefit” to enable prescribers to choose an appropriate SGLT2 inhibitor for each person, while allowing the recommendation to remain current even if additional evidence or new SGLT2 inhibitor become available.
Evidence of cardiovascular benefit for SGLT2 inhibitors
Evidence from randomised trials4567 was included in the NICE analysis for canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. For the main composite outcome (3-point major cardiovascular events (MACE), which comprised cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke), only canagliflozin and empagliflozin showed a statistically significant reduction compared with placebo. In analyses none of the SGLT2 inhibitors could be differentiated from each other for this outcome.
Empagliflozin showed a clinically meaningful reduction compared with placebo and the other SGLT2 inhibitors for cardiovascular mortality, but the remaining SGLT2 inhibitors could not be differentiated from each other or placebo in the network meta-analysis. For non-fatal myocardial infarction and non-fatal stroke, the analyses could not differentiate between empagliflozin, canagliflozin, ertugliflozin, and placebo. The data for dapagliflozin were reported differently and could not be included in the analysis, but dapagliflozin could not be differentiated from placebo for non-fatal myocardial infarction and was not meaningfully different from placebo for stroke.
Empagliflozin, canagliflozin, and dapagliflozin showed a clinically meaningful reduction in the analysis for hospitalisation for heart failure compared with placebo. However, in sensitivity analyses, using a fixed effect model, ertugliflozin also showed a clinically meaningful reduction for this outcome compared with placebo. The SGLT2 inhibitors could not differentiated from each other for this outcome in both analyses. Dapagliflozin showed a clinically meaningful reduction in severe hypoglycaemia compared with placebo, but the remaining SGLT2 inhibitors could not be differentiated from each other and placebo in the network meta-analysis.
The SGLT2 inhibitor should be started as soon as metformin tolerability is confirmed to reduce clinical inertia and optimise cardiovascular benefit. For those at higher cardiovascular risk who cannot take metformin, the recommended first line treatment is monotherapy with an SGLT2 inhibitor. These recommendations are summarised in the infographic, which highlights changes to the guideline alongside those recommendations that remain unchanged. Risk of diabetic ketoacidosis should be considered before prescribing an SGLT2 inhibitor, as outlined in box 3.
Based on the cardiovascular risk assessment for the person with type 2 diabetes:
If they have chronic heart failure or established atherosclerotic cardiovascular disease, offer an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin
If they are at high risk of developing cardiovascular disease, consider an SGLT2 inhibitor with proven cardiovascular benefit in addition to metformin.
[Based on moderate to high quality evidence from randomised controlled trials and health economic modelling]
Checking for risk of diabetic ketoacidosis when prescribing SGLT2 inhibitors
Diabetic ketoacidosis (DKA) is a rare but potentially serious or fatal complication of type 2 diabetes. All known risk factors for DKA should be considered before starting SGLT2 inhibitor treatment. Some risk factors for DKA are non-modifiable (such as a person having had a previous episode of DKA)
Any modifiable risk for DKA should addressed before starting treatment with an SGLT2 inhibitor, for example:
Alcohol intake above recommended UK threshold
Use of illegal drugs
Use of other medicines
Concurrent illness, injury, or planned surgery
Very low carbohydrate or ketogenic diet
So, for example, before starting treatment with an SGLT2 inhibitor, adults with type 2 diabetes should be advised to discuss with a healthcare professional if they are on, or plan to start, a very low carbohydrate or ketogenic diet. It may be necessary to delay or suspend treatment until the diet has been changed or completed
The committee considered whether glucagon-like peptide-1 (GLP-1) receptor agonists such as exenatide, dulaglutide, liraglutide, lixisenatide, and semaglutide might also have a role as a first line treatment for adults at higher cardiovascular risk. However, health economic analyses found GLP-1 receptor agonists were not cost-effective options for cardiovascular risk reduction in people at higher cardiovascular risk, including if an SGLT2 inhibitor or metformin is contraindicated.
For those people who have type 2 diabetes but who do not have chronic heart failure or established cardiovascular disease, or who are not assessed as being at high risk of developing cardiovascular disease, then the existing recommendations remain unchanged from the previous guideline.
Reviewing drug treatment
The 2015 guideline recommended reassessing a person’s needs and circumstances at each review and to think about whether to stop any medicines that are not effective. The update has added a separate recommendation to emphasise important aspects of medicines optimisation during a review including considering adverse effects, adherence with treatment, and checking that doses and formulations are appropriate, as well as revisiting diet and lifestyle advice. In addition, the Guideline Committee agreed that it is important to think about stopping medicines that do not have useful clinical impact unless there is likely cardiovascular and renal benefit from continued treatment (this may involve consideration of off label prescribing as glucose-lowering drugs may not have an indication for cardiovascular or renal benefit alone), and whether switching rather than adding drugs could be effective to prevent people taking multiple drugs unnecessarily.
Adding an SGLT2 inhibitor at any stage after first line treatment has been started
The update recommends that people who are at higher cardiovascular risk or whose cardiovascular risk increases over time and who are already taking glucose lowering drugs should have the same access to the cardiovascular benefit of SGLT2 inhibitor as those starting first line treatment. A shared decision about switching treatments or adding an SGLT2 inhibitor should be made at the review.
Treatment options if further interventions are needed
The existing recommendations about what further glucose lowering drugs may be added or switched to as dual or triple therapy remain unchanged from the 2015 guideline (a DPP-4 inhibitor, pioglitazone, or sulfonylurea) and apply to people at all levels of cardiovascular risk. In addition, for people at lower cardiovascular risk an SGLT2 inhibitor could be added at this stage (if they meet the access criteria set out in the existing relevant NICE technology appraisals for the SGLT2 inhibitor). Insulin remains an option in the pathway when people have reached the point of requiring triple therapy.
The 2015 version of the guideline stated that if triple therapy with metformin and two other drugs was not effective, not tolerated, or contraindicated, then a GLP-1 receptor agonist could be considered in combination with metformin and a sulfonylurea, providing body mass index and other clinical criteria were met. However, the committee agreed that this specific combination may not always be clinically appropriate and therefore amended the recommendation to expand the triple therapy treatment combinations possible by allowing switching of one drug for a GLP-1 receptor agonist.
Future updates to the guideline
NICE have taken stakeholder comments into account and concluded that a fuller update of the drug treatment section of the guideline is still warranted. There will be opportunities for stakeholder input during the scoping stage.
Implementation
The 2022 recommendations for adults with type 2 diabetes at higher cardiovascular risk will likely have a large resource impact from increased prescribing of SGLT2 inhibitors. However, the Guideline Committee agreed that, since these drugs are clinically and cost effective for this population, it is correct to recommend them. NICE has undertaken a resource impact assessment taking into account the sizes of the populations covered by the updated recommendations at higher cardiovascular risk to help overcome implementation challenges at a local and national level. NICE has developed two visual summaries of the guidance and a patient decision aid that could be used to help clinicians support discussions with patients and carers about individual treatment targets (https://www.nice.org.uk/guidance/ng28/resources).
Guidelines into practice
How will you work with your organisation to ensure that clinical practice is in line with the new recommendations for SGLT2 inhibitors in adults with type 2 diabetes and heart failure, atherosclerotic cardiovascular disease, or higher cardiovascular risk?
When prescribing an SGLT2 inhibitor, what measures do you take to ensure it is prescribed safely and that the person is aware of the risk of diabetic ketoacidosis?
How patients were involved in the creation of this article
Committee members involved in this guideline update included lay members who contributed to the formulation of the recommendations summarised here.
Further information on the guidance
This guidance was developed by NICE’s Guideline Development Team (GDT) in accordance with NICE guideline development methods (https://www.nice.org.uk/media/default/about/what-we-do/our-programmes/developing-niceguidelines-the-manual.pdf).
A Guideline Committee (GC) was established by the GDT, which incorporated healthcare and allied healthcare professionals (a consultant paediatrician in diabetes and endocrinology, a general practitioner, four consultant diabetologists, a mental health professional (consultant clinical health psychologist) with a special interest in diabetes, a renal physician, two senior pharmacists, a diabetes nurse consultant, a consultant cardiologist) and two lay members.
The GC was involved in developing and agreeing the protocol for the 2022 update. The GC reviewed the clinical evidence that had been identified and analysed by the GDT using standard systematic review methodology. The clinical evidence was assessed for quality using GRADE methodology (www.gradeworkinggroup.org/) or modified GRADE methodology in the case of the network meta-analyses. The GC also examined the cost effectiveness of interventions, including the use of a de novo economic model that was generated for the 2022 guideline update incorporating the new cardiovascular trial evidence.
The original scope of the update was amended after development began, but the committee members agreed that the initial focus should be on reviewing the evidence from trials looking at cardiovascular outcomes.
The draft of the guideline went through a rigorous reviewing process, in which stakeholder organisations were invited to comment; the GC took all comments into consideration when producing the final version of the guideline.
The evidence reviewed in the 2022 update is available as a separate review document, while the evidence for the sections of the guideline that were not updated is contained in the 2015 full guideline document. The guideline itself contains the recommendations with a new section on the rationale for the 2022 recommendations. The documents are all available at https://www.nice.org.uk/guidance/ng28/evidence.
Acknowledgments
The members of the Guideline Committee were (shown alphabetically): Juliana Chizo Agwu (committee chair), Sarah Ali, Chirag Bakhai, Neel Basudev, Augustin Brooks, Tembi Chinaire (from August 2021), Anne Dornhurst, Dorothy Frizelle, Hugh Gallagher, Natasha Jacques, Sallianne Kavanagh, Sharon McCarthy, Soon H Song, Annette Swinkels, Malgorzata Wamil, Corrine Wykes, Ibrahim Abubakar (until June 2021), Nicola Milne (until June 2021).
The technical members of the Guideline Development Team were Omnia Abdulrazeg (until February 2021), Lucy Beggs (until October 2021), Lindsay Claxton (from November 2021), Gareth Franklin (until April 2021), Marie C Harrisingh, James Jagroo (from January to March 2021), Thomas Jones (until May 2021), Kusal Lokuge (from March 2021), Yolanda V Martinez (from June 2021 to July 2021), Gregory Moran, and Sarah Wood (from April 2021).
Footnotes
Contributors: All authors contributed to the development of the guideline and to the planning, drafting, and revision of this summary, approved the final version, and take responsibility for its accuracy. GMM acts as guarantor. The corresponding authors attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: GMM is an employee of NICE. Other authors received no specific funding to write this summary.
Competing interests: We declared the following interests based on NICE’s policy on conflicts of interests (https://www.nice.org.uk/Media/Default/About/Who-we-are/Policies-and-procedures/declaration-of-interests-policy.pdf) The guideline authors’ full declaration of interests can be viewed at https://www.nice.org.uk/guidance/ng28/history
The guideline referred to in this article was produced by the Guideline Development Team at the National Institute for Health and Care Excellence (NICE). The views expressed in this article are those of the authors and not necessarily those of NICE.