The updated NICE guideline on Type 2 diabetes in adults: Management (NG28), was published in February 2022. It recommends offering sequential initiation of dual first-line therapy with metformin and an SGLT2 inhibitor with proven cardiovascular (CV) benefit to those with chronic heart failure (HF) or established atherosclerotic CV disease (coronary heart disease, acute coronary syndrome, previous MI, stable angina, prior coronary or other revascularisation, cerebrovascular disease [ischaemic stroke and TIA] and peripheral arterial disease). Dual first-line therapy should also be considered in those at high risk of CV disease (defined by NICE as people with type 2 diabetes over the age of 40 with a QRISK2 score of >10%, or people with an elevated lifetime risk of CV disease [one or more CV risk factor in someone aged <40 years]). The metformin should be initiated and titrated first and, once tolerability is confirmed, the SGLT2 inhibitor should be added immediately rather than waiting for another HbA1c measurement first. In recommending that SGLT2 inhibitors are offered to all people with type 2 diabetes and chronic HF, the guideline does not differentiate between different types or stability of chronic HF, and this could lead to potentially unsafe prescribing of SGLT2 inhibitors outside of their licence. These new recommendations mean that more of our population with type 2 diabetes will need the addition of an SGLT2 inhibitor, even if their glucose is well-controlled. Since at present SGLT2 inhibitors are not licensed in the UK for reduction in CV risk when glucose is controlled, people will also need to be counselled about off-licence use.
NICE recommends that people with or at high risk of CV disease who are not able to take an SGLT2 inhibitor should receive only metformin as first-line therapy, despite the proven CV benefits of some injectable GLP-1 mimetics and their recommendation for use in these high-risk groups in other guidelines. This is because NICE argues that GLP-1 mimetics as a class are not cost-effective at any stage of treatment for CV benefits, despite injectable semaglutide demonstrating cost-effectiveness in some scenarios.
The guideline reminds us of the importance of reinforcing diet and lifestyle advice, reviewing adherence, optimising existing therapy use and considering stopping therapy when additional treatment is considered, and it provides checklists to prompt these discussions. An SGLT2 inhibitor should be initiated at any time if CV disease or high risk of CV disease is diagnosed, even if not commenced as first-line therapy. Otherwise, the glycaemic targets and addition of further glucose-lowering medication remain unchanged from the previous 2015 version of the guideline.
Since the recommendations are likely to greatly increase prescribing of SGLT2 inhibitors, NICE highlighted potential safety concerns, but focused only on the risk of diabetic ketoacidosis (DKA) and the need for appropriate counselling, including avoidance of a very-low carbohydrate or ketogenic diet (20–50 g carbohydrate per day or <10% of calories as carbohydrate) while taking these drugs. Prescribers should ensure they are aware of other potential adverse effects and counsel about these too.
Two visual summaries guide drug treatment choice – “Choosing medicines for first-line treatment” and “Choosing medicines for further treatment” – and these include checklists for optimising all aspects of glycaemic management, including lifestyle. For guidance on hypertension, lipids and CV Risk, and chronic kidney disease (CKD) management in people with type 2 diabetes, NICE refers to their other guidelines. There was no major change to the section on glycaemic targets, but a patient decision aid was added. However, this assumes that tighter control will be associated with hypoglycaemia and other side effects, so may have limited usefulness.
Rationale for the recommendations
NICE chose not to review the clinical and cost-effectiveness evidence relating to GLP-1 mimetic use for glucose-lowering, so updating the positioning of these drugs and their “stopping rules” from the 2015 update of the guideline were “out of scope” for this update. Thus, GLP-1 mimetics remain for use in triple therapy, after triple oral therapy has failed to provide glycaemic control. However, NICE realised that since many people would now have combination first-line therapy with an SGLT2 inhibitor and metformin, it would be inappropriate for people to switch to a sulfonylurea (SU) to meet the criteria for previous GLP-1 mimetic initiation. The need for an SU was, therefore, removed. When using the newer, potent GLP-1 mimetics, it is more likely that people will achieve the 11 mmol/mol reduction in HbA1c and 3% weight reduction required to continue therapy, but, if not, the guidance is that the drug must be stopped. NICE highlights that, “These recommendations set tight limits on who should be offered a GLP-1 mimetic…”.
Prescribers are referred to NICE’s guideline on Cardiovascular disease: risk assessment and reduction, including lipid modification (CG181) for advice on using risk scores and QRISK2 to identify those at high risk of CV disease.
CV outcome studies and other large clinical trials have identified benefits of the individual SGLT2 inhibitors when used in the specific trial populations. NICE relied on network meta-analyses as well as original trial data to try to differentiate between SGLT2 inhibitors, and concluded that the class as a whole should be recommended.
From a cost-effectiveness perspective, although dapagliflozin was consistently cost-effective at a threshold of £20,000 per QALY across many different scenarios, the cost-effectiveness of the other drugs varied. NICE recommends the class as a whole, due to uncertainty of the clinical data and economic modelling. They recognised the findings in the VERTIS CV trial (Cannon et al, 2020) and chose to qualify their recommendation to “SGLT2 inhibitors with cardiovascular benefit”, allowing prescribers to individualise drug choice and to recognise that future drugs with CV benefits may be added to the class.
If further medications are required to help people reach their individual, agreed, glycaemic target with dual or triple therapy and they do not have and are not at high risk of developing CV disease, SGLT2 inhibitors can only be initiated in people who meet the criteria in technology appraisals 315, 572, 288 and 336; that is, only if a DPP-4 inhibitor would otherwise be prescribed and an SU or pioglitazone is not appropriate. Otherwise, the choice is between the older drugs, DPP-4 inhibitors, pioglitazone or an SU and, for triple therapy, insulin as an option. Insulin or an SU are also recommended for rescue therapy in symptomatic hyperglycaemia at any stage, with review once glycaemia is controlled.
The section of the guideline covering management of CKD was last updated in 2021. This recommends SGLT2 inhibitors for those with CKD who are already treated with maximal tolerated dose of an ACE inhibitor or ARB, and who have an ACR of 30 mg/mmol and meet the licensed criteria for use in the UK. SGLT2 inhibitors can also be considered in those with an ACR of 3–30 mg/mmol. However, people with CKD who do not qualify for an SGLT2 inhibitor through this route will also meet the criteria of being at high risk of CV disease, so can still be offered an SLGT2 inhibitor.
The updated NICE guideline and resources can be accessed here.