Consider ASCVD, CKD and HF risk

Established atherosclerotic cardiovascular disease (ASCVD), heart failure (HF) or chronic kidney disease (CKD) are important indications for use of the newer therapies of SGLT-2i and GLP-1RA.

There is good evidence from large randomised clinical trials that people with a history of ASCVD, CKD and/or HF benefit from glucose-lowering treatment with SGLT-2i and GLP-1RA.^42,3

A recent population-wide study showed that more than 70% of people with T2DM in Scotland currently on non-pharmacological/ lifestyle management or metformin monotherapy have ASCVD, CKD or HF⁴³ (see section on NTIs). Trial evidence is readily available online and more continues to emerge.

See the summary algorithm of prescribing choices in T2DM, based on ADA and EASD³, and NICE² recommendations.

Cardiovascular disease risk is an important factor to consider for those with T2DM. Treatment selection for hyperglycaemia should consider whether a person has:

• established ASCVD (ischaemic heart disease, stroke); or
• cardiovascular risk factors of:
  • QRISK2 more than 10% in adults aged 40 and over (or other validated tool); or
  • a clinically assessed elevated lifetime risk of cardiovascular disease (defined as the presence of 1 or more of the below cardiovascular risk factors in someone under 40)
    • hypertension;
    • dyslipidaemia;
    • smoking;
    • obesity; or
    • family history (in a first-degree relative) of premature cardiovascular disease.⁴⁴

See Algorithm for management of Type 2 diabetes mellitus.

Any modifiable risk factors for ASCVD (hypertension, hyperlipidaemia, smoking, obesity) should be addressed. For useful links to lifestyle information see the list 'Lifestyle support resources' in Lifestyle interventions and remission.

Prescribing choices

1. Metformin remains first line.
2. SGLT-2i should be prescribed for individuals with established ASCVD⁴³, heart failure or chronic kidney disease. Individuals at high risk who have not yet developed these complications may also benefit.
3. A shared decision-making approach is recommended, considering:

• beneficial effects e.g. weight loss, extent of glucose-lowering efficacy;
• adverse effects e.g. in relation to the degree of hyperglycaemia, or the risk of hypoglycaemia; DKA
• preferences e.g. route of administration, oral verses injectable, frequency of administration, daily or weekly

SGLT-2i contra-indications/cautions:

• people 75 years and older are at increased risk of volume depletion
• not recommended for initiation when eGFR is <15 ml/min/1.73m²
• have less glucose-lowering efficacy with eGFR <45 ml/min/1.73m²
• should be avoided in those with:
  • factors predisposing to DKA/eDKA
    • pancreatic insufficiency
    • drug or alcohol misuse disorder
    • a low/ultra-low carbohydrate or keto diet
    • excessive alcohol consumption
  • frequent bacterial urinary tract infections or genitourinary yeast infections
  • low bone density or high risk for falls/fractures
  • current foot ulceration.

Increased incidence of euglycaemic diabetic ketoacidosis

With increasing use of SGLT-2i, there has been an increased incidence of eDKA in addition to DKA. Therefore the MHRA⁴⁵ has issued the following advice:

• use SGLT-2i with caution in those with risk factors for DKA, (including a low beta cell reserve, conditions leading to restricted food intake or severe dehydration, sudden reduction in insulin, increased insulin requirements due to acute illness, surgery or alcohol misuse), and discuss these risk factors with individuals
• test for raised ketones in individuals with signs and symptoms of DKA, even if glucose levels are near-normal
• discontinue treatment if DKA is suspected or diagnosed
• do not restart treatment with any SGLT-2i in those who experienced DKA during use, unless another cause for DKA was identified and resolved
• during and after surgery or during acute serious illness:
  • interrupt sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment in patients who are hospitalised for major surgical procedures or acute serious medical illnesses
  • monitor ketones during this period – measurement of blood ketone levels is preferred to urine
  • restart treatment with the SGLT2 inhibitor once ketone values are normal and the patient’s condition has stabilised.

Furthermore emerging advice^46,47 regarding the period of treatment interruption is:

• For three days prior to planned surgery (four days if prescribed ertugliflozin), (or immediately if unplanned surgery) and for a further three days after surgery
• During acute illness, e.g. diarrhoea, vomiting (see sick day guidance).

Individuals considering an SGLT-2i should be advised about the risks of eDKA associated with a low/ultra-low carbohydrate or keto diet.

See Case study 3.

Due to the different licenses for SGLT-2i (and GLP-1RAs), prescribers should familiarise themselves with the indications and contra-indications as well as interactions listed in the BNF and/or the Electronic Medicines Compendium before initiating therapies.

Where there is no difference between drugs within a class, the most cost-effective drug should be chosen, and NHS boards should consider their formulary choices.

The recent NICE² guideline Type 2 Diabetes in adults: management supports the introduction of SGLT-2i as first-line therapy with metformin, if the individual has chronic heart failure or established atherosclerotic cardiovascular disease. These drugs should be started sequentially, with metformin first, then once tolerability is established, the SGLT-2i can be started.

Cardiovascular disease and risk should be reviewed regularly, and may require a change/addition in therapy. See the summary algorithm for the management of type II diabetes mellitus.

T2DM is a risk factor for developing CKD and therefore monitoring for CKD should be part of the annual review. Frequency of monitoring is dependent on the classification and stage of CKD.

Classification of CKD⁴⁸ is based on a combination of glomerular filtration rate (GFR) and albumin to creatinine ratio (ACR). The risk of adverse outcomes increases as CKD category decreases (GFR) or as ACR increases. This happens independently but with greater risk if both are present (see the table below).

Prescribing choices

The table below outlines prescribing choices for people with CKD.

Offer an ARB or an ACE inhibitor if ACR is 3mg/mmol or more (titrated to the highest licensed dose that the individual can tolerate). This is a lower ACR threshold than for those without diabetes.

If the ACR is between 3-30mg/mmol, consider offering an SGLT-2i (dependent on license) in addition to the highest tolerated dose of ACEi or ARB.

If the ACR is over 30mg/mmol, offer an SGLT-2i (dependent on license) in addition to the highest tolerated dose of ACEi or ARB.

Note: Consider the appropriateness of therapy with other factors such as increasing frailty, due to risks of side-effects, e.g., hypotension and falls, against time to realise benefit of therapy.

See Case study 4.

Other medication for the treatment of T2DM in CKD

Consider dose reduction in response to reducing renal function in:

• metformin
• SGLT-2i
• GLP-1RA
• DPP-4i
• in addition to ACEi, ARBs, diuretics and NSAIDs

Note that all people treated with medication that can affect kidney function during acute illness (with or without existing renal disease) should be issued with Sick Day guidance information to prevent acute kidney injury.

Individuals with T2DM prescribed a SGLT-2i/GLP-1RA and existing therapy suggestive of atherosclerotic cardiovascular disease (ASCVD)

This indicator should have a high level of SGLT-2i and/or GLP-1RA prescribing, indicating good practice, with suitable patients receiving appropriate medication.

The most up to date national therapeutic indicator data is available here.

This indicator identifies individuals prescribed SGLT-2i and/or GLP-1RA in the same quarter as a nitrate and/or nicorandil, aspirin or clopidogrel as a proportion of people prescribed anything from BNF 060102 in the same quarter as a nitrate and/or nicorandil, aspirin or clopidogrel. This surrogate marker indicates there is a proportion of those with T2DM who may benefit from treatment with SGLT-2i or GLP-1RA, irrespective of glycaemic control.   

Although the indicator is limited to ASCVD, there will be others with chronic heart failure (cHF) and CKD, who would similarly benefit.

The Scottish Therapeutics Utility (STU) available in all GP practices enables identification of those with T2DM and ASCVD, cHF and/or CKD (see Using data to drive change).

Due to the change in prescribing guidance, clinicians should identify individuals who would benefit from prescribing of SGLT-2i or GLP-1RA. these include people

• with T2DM and existing CVD and cHF;
• at high risk of CVD; and
• with T2DM and chronic kidney disease, based on eGFR and elevated ACR values.

These identified individuals should have all prescribed medicines reviewed to ensure their doses are appropriate for the degree of renal impairment.

There will be individuals with T2DM, who are not at risk of or do not have ASCVD, cHF or CKD. For those individuals consider:

• Whether weight loss or minimising risk of hypoglycaemia is a priority for the individual.
• Where weight loss is a priority, or minimising weight gain, SGLT-2i and GLP-1RA remain appropriate therapies in line with formulary guidance.
• Where minimising the risk of hypoglycaemia is a priority, GLP-1RA, SGLT-2i and DPP-4i are suitable second line therapies.
• DPP-4i and sulfonylureas are also acceptable second line therapies either used alone or in combination, considering the following:
  • the degree of hyperglycaemia (sulfonylureas more efficacious in the short term)
  • potential adverse effects (e.g. DPP-4i's are not associated with a risk of hypoglycaemia or weight gain).
  • sulfonylureas may have particular benefit in steroid-induced diabetes and in individuals with normal or low BMI and T2DM (Type 1 diabetes must be excluded in such individuals).

Other agents (e.g. thiazolidinediones, acarbose) are now rarely used in treatment.

See Case study 2.

At each review consider:

• lifestyle and diet advice (see Lifestyle interventions and remission for resources), reinforced with an assessment of the individual’s current risk factors
• an assessment of cardiovascular risk and renal risk with
  • blood pressure
  • lipids
  • smoking status.
• glycaemic control

These should all be treated in line with respective treatment targets.

Review 3-6 months after initiating therapy or amending treatment.

A significant proportion of individuals with T2DM continue to have sub-optimal diabetes and cardiovascular management. While ensuring timely review can be challenging, it is important to guard against clinical inertia and the long-term sequelae of suboptimal management (see the summary algorithm).