Evidence-based use of newer agents in type 2 diabetes

Recent accumulating evidence on the use of newer therapies in type 2 diabetes (T2DM) is helping to define their position in treatment. This information coupled with the increasing priority given toward individualisation of therapy can lead to more targeted use of drugs, utilising their benefits and taking account of their problems.

Overall the standpoint has shifted from a largely glucocentric approach to one considering the impact of treatments on weight, risk of hypoglycaemia, and co-morbidities (notably atherosclerotic cardiovascular disease (ASCVD), heart failure and chronic kidney disease (CKD). A truly patient-centred approach will also take account of personal circumstances and preferences (The National Institute for Health and Care Excellence (NICE), 2015; Scottish Intercollegiate Guidelines Network (SIGN), 2017; Davies et al, 2018).

This article reviews the properties of DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1 RAs) and SGLT-2 inhibitors and their pragmatic use in T2DM.

DPP-4 inhibitors (gliptins)

Mode of action

Glucagon-like peptide-1 (GLP-1) is a key hormone secreted in response to the presence of food in the gut that facilitates a reduction in glucose levels by stimulating insulin secretion and suppressing glucagon secretion (Nauck and Meier, 2016). The DPP-4 inhibitors function by inhibiting the breakdown of endogenous GLP-1 by the enzyme dipeptidyl-peptidase-4 (DPP-4) thereby prolonging the glucose-lowering activity of GLP-1.

Availability

The available DPP-4 inhibitors in the UK are sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin (Electronic Medicines Compendium (EMC), 2020a; 2021a; 2021b; 2021c). The DPP-4 inhibitors are available as combination products with metformin.

Benefits

Whilst not powerful agents (HbA1c lowering of 5-11 mmol/mol, 0.5-1%), they do carry the advantages of once daily oral administration, minimal side-effects, weight neutrality and a low tendency to cause hypoglycaemia (SIGN, 2017; Davies et al, 2018).

Cardiovascular outcome trials

Cardiovascular outcome trials (CVOTs) on the gliptins looking at the primary outcome of major adverse cardiovascular events (MACE - a triple composite end-point of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke) in individuals with T2DM at high risk of cardiovascular events have demonstrated cardiovascular safety but no benefit compared to placebo (Scirica et al, 2013; White et al, 2013; Green et al, 2015; Rosenstock et al 2019). In the saxagliptin CVOT a significantly increased risk of heart failure was evident so this agent should be avoided in the setting of heart failure (Scirica et al, 2013). There was a non-significant increase in heart failure with alogliptin versus placebo (White et al, 2013) with no signals for this in the other gliptin CVOTs.

Whilst the CVOTs on gliptins did not find a significant association between DPP-4 inhibitor use and incidence of acute pancreatitis, this association has been noted previously (Tkač and Raz, 2017), and so it is probably wise to avoid these treatments in individuals with a history of pancreatitis.

Use in renal failure

The gliptins can be used in all stages of renal failure (ie down to an eGFR of 15 mL/min/1.73m²) with dose adjustment (no dose change required for linagliptin, which is not renally excreted to any significant degree (EMC, 2019). There is some evidence to support a reduction in albuminuria (Rosenstock et al, 2019).

Case history 1

Jean is 76 years old and has had T2DM for nearly 20 years. She lives on her own but remains physically and socially active. Following an afternoon of several hours gardening Jean experienced an episode of dizziness, confusion and speech slurring. She was spotted by a neighbour who called an emergency ambulance. Jean was found to have a capillary blood glucose reading of 2.3 mmol/L and was treated for hypoglycaemia.

An appointment was made for Jean at the surgery to review her diabetes management and medication. Her current treatment for hyperglycaemia consists of metformin MR 500 mg bd (previously troublesome gastrointestinal side-effects on higher doses of metformin) and gliclazide 80 mg bd; she also takes atorvastatin 20 mg od. Recent records show: BMI 26.7 kg/m²; HbA1c 61 mmol/mol; eGFR 53 mL/min/1.73m².

Case history 1 - outcome

The priority here is to avoid future hypoglycaemia. It appears that Jean was unaware of her descent to hypoglycaemia and with reduced symptom awareness the safest course of action would be to stop the gliclazide.

Jean's general health is good and her life expectancy could easily be 10 years or more. Whilst tight glycaemic control is less critical in a person of Jean's age and duration of diabetes (Inzucchi et al, 2015), it is worth maintaining good glycaemic control if this can be done safely.

Jean is prescribed linagliptin 5 mg od to replace the gliclazide (with continuation of her metformin). The choice of a DPP-4 inhibitor is made on the grounds of safety (low risk of hypoglycaemia, safe to use in chronic kidney disease), favourable side-effect profile and ease of use.

GLP-1 receptor agonists

Mode of action The short half-life of human GLP-1 in vivo makes it untenable as a medical treatment and has led to the development of GLP-1 RAs that mimic the action of endogenous GLP-1 (by binding to and activating the GLP-1 receptor) but have resistance to breakdown by DPP-4 and thus have more prolonged activity (Meier, 2012). GLP-1 RAs lower glucose levels by stimulating insulin secretion, suppressing glucagon secretion, delaying gastric emptying and inducing satiety (Nauck and Meier, 2017)

Availability

The available injectable GLP-1 RAs and their properties are listed in Table 1 (Morris, 2020; EMC, 2020b; 2021d; 2021e; 2021f; 2021g; 2021e). They can be divided into the exendin-4 derivatives (molecules based on the peptide sequence from a salivary extract of the gila monster) and the modified human GLP-1 RAs (which have a much closer homology to the peptide sequence of endogenous GLP-1). They are administered by subcutaneous injection, usually to the abdomen, with site rotation.

Once daily injections of a combination of a GLP-1 RA and a basal insulin are now available as Xultophy (liraglutide plus insulin) and Suliqua (lixisenatide plus insulin glargine).

The GLP-1 RAs are administered by injection because if given orally they would be subject to degradation by gastric acid and proteases. However, an oral formulation of semaglutide is now licensed for use (EMC, 2021f). It is taken once daily with a small amount of water after an overnight fast following which no food or medication should be taken for 30 minutes.

Oral semaglutide is co-formulated with SNAC (sodium N-(8-(2-hydroxybenzyl) amino)-capyrate), a molecule that acts as an absorption enhancer allowing entry of semaglutide into the circulation with a bioavailability of around 1%. (Buckley et al, 2018).

Indications for use and when to avoid

GLP-1 RAs are licensed for use in T2DM in combination with other glucose-lowering medications, including insulin, when these together with diet and exercise do not provide adequate glycaemic control (SmPCs GLP-1 RAs AQ3). Liraglutide, dulaglutide and semaglutide are licensed as monotherapy in situations where metformin is poorly tolerated or contra-indicated.

Situations where GLP-1 RAs should be avoided are listed in Table 2 (Morris, 2020).

Benefits

The GLP-1 RAs are powerful glucose-lowering agents, achieving HbA1c reductions in the order of 11-16 mmol/mol (1-1.5%) compared to placebo in practice. The longer-acting GLP-1 RAs appear to be more effective than the shorter-acting agents. The evidence indicates that semaglutide is the most efficacious agent ahead of liraglutide and dulaglutide, followed by exenatide once weekly and then exenatide twice daily and lixisenatide (Htike et al, 2017; Davies et al 2018, Nauck and Meier, 2019).

The GLP-1 RAs carry a low risk of inducing hypoglycaemia because their activity is glucose-dependent (Nauck and Meier, 2016). A further important clinical benefit offered by GLP-1 RAs in T2 DM is that of weight loss associated with reduced appetite (Sun et al, 2015). This reaches a plateau after 6 months or so of treatment and whilst highly variable between individuals is typically around 1.5 kg to 6 kg (Nauck and Meier, 2019), the highest reductions being found with semaglutide.

A small reduction in systolic blood pressure (around 2-5 mmHg) is associated with GLP-1 RA treatment though this is accompanied by a small increase in pulse rate (2-5 beats/min) (Nauck et al, 2017).

The cardiovascular and renal benefits derived from GLP-1 RA use are dealt with below.

Problems and side-effects

Nausea (and vomiting) are the most troublesome features seen with use of GLP-1 RAs though commonly these settle with time (Raccah, 2017; Nauck and Meier, 2019). Diarrhoea may also be problematic.

If severe upper abdominal pain is experienced then the GLP-1 RA should be discontinued; the concern here would be acute pancreatitis. However, in the CVOTs with GLP-1 RAs (see later), the incidence of pancreatitis did not appear to be increased and recent meta-analyses did not find evidence of an increased risk of acute pancreatitis or pancreatic cancer (Monami et al, 2017; Storgaard et al, 2017) although an increased risk of gallbladder events was identified.

An association between GLP-1 RA use and medullary thyroid cancer had been suggested from animal studies. However, a meta-analysis of once-weekly GLP-1 RAs showed no increased risk in comparison with other antidiabetic drugs (Nauk and Meier, 2019).

Injection site reactions are rare with GLP-1 RAs but do appear to be significantly higher with the microsphere formulation of once-weekly exenatide (Blevins et al, 2011).

A significant deterioration in retinopathy was observed in the semaglutide CVOT, principally in subjects with pre-existing diabetic retinopathy who were using insulin (Marso et al, 2016). Accordingly, caution is advised when using semaglutide in diabetic retinopathy (EMC, 2020).

Cardiovascular outcome trials

CVOTs have been performed on all the available GLP-1 RAs except exenatide twice daily. The populations in these double-blind randomised placebo-controlled trials comprised individuals with T2 DM who had pre-existing cardiovascular disease or had cardiovascular risk factors. The primary outcome was again MACE.

CV benefits compared to placebo were demonstrated for liraglutide, semaglutide, dulaglutide and albiglutide (the latter is no longer available) (Marso et al, 2016a; Marso et al 2016b; Gerstein et al; 2019; Hernandez et al, 2018). Whilst the key finding was for secondary prevention of cardiovascular events, there was evidence of primary prevention, most notably in the dulaglutide CVOT in which nearly 70% of participants had a high risk profile (without established CVD) (Gerstein et al, 2019). Exenatide modified release showed a strong trend toward CV benefit but this just missed reaching statistical significance (Holmann et al, 2017). Cardiovascular safety but not benefit was demonstrated in the CVOT with lixisenatide (Pfeffer et al, 2015).

The CVOTs on the GLP-1 RAs do not suggest benefits in respect of heart failure.

Renal outcomes

Renal effects were studied as a secondary outcome in the CVOTs of the GLP-1 RAs. Significant reductions in the pre-specified renal composite outcome (new-onset macroalbuminuria, doubling of serum creatinine, end-stage renal disease, or death due to renal disease) compared to placebo were seen in the liraglutide (Mann et al, 2017) and semaglutide trials (Marso et al, 2016b). In both cases the most significant factor contributing to the improved renal outcome was reduced progression of albuminuria.

A similar reduction in progression to macroalbuminuria was found in the CVOTs with exenatide once-weekly (Holmann et al, 2017), lixisenatide (Pfeffer et al, 2015), albiglutide (Hernandez et al, 2018) and dulaglutide (Gerstein et al, 2019). Further reviews confirm that a beneficial effect on development of proteinuria is a consistent feature with the GLP-1 RAs although the response of eGFR and the incidence of end-stage renal failure are less clear (Kristensen et al, 2019).

SGLT-2 inhibitors

Mode of action

The SGLT-2 inhibitors prevent the resorption of glucose that has been filtered from the renal glomeruli. They achieve this by selectively inhibiting glucose transport at the SGLT-2 transporter site. As a consequence glucose is lost in the urine to the extent of 60-80 grams per day (Morris, 2019).

Licensed use and indications

The four SGLT-2 inhibitors currently available in the UK are canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. The licenses have a broad remit allowing the use of SGLT-2 inhibitors in T2DM as monotherapy or in combination with other glucose-lowering agents, including insulin, when diet and exercise (and other treatments) do not provide adequate glycaemic control (EMC, 2020c; 2020d; 2021g; 2021h). The SGLT-2 inhibitors are available as combination products with metformin and DPP-4 inhibitors.

In respect of treating hyperglycaemia in T2DM SGLT-2 inhibitors are licensed for initiation only if eGFR is 60 ml/min/1.73 m² or more, though once initiated they can be continued (at a lower dose in the case of empagliflozin, canagliflozin and ertugliflozin) down to an eGFR of 45 mL/min/1.73m². Canagliflozin has now been approved at an initial dose of 100mg od down to an eGFR of 30 mL/min in those with albuminuric CKD. Dapagliflozin has gained a license for chronic heart failure with reduced ejection fraction (with or without the presence of T2DM) and also for use at a dose of 5 mg od in TIDM as an adjunct to insulin in overweight patients (EMC, 2021g).

When to avoid SGLT-2 inhibitors

Table 3 identifies situations where SGLT-2 inhibitors should be avoided or used with caution (EMC, 2020c; 2020d; 2021g; 2021h; Wilding, 2018; Morris, 2019).

The problem of diabetic ketoacidosis

SGLT-2 inhibitors are associated with a small increased risk of diabetic ketoacidosis (DKA), and this may occur at only moderately elevated blood glucose levels (< 14 mmol/L), so called euglycaemic DKA (Fralick et al, 2017). Situations predisposing to DKA in people taking SGLT-2 inhibitors are listed in Table 4 (typically where there is a relative insulin deficiency) (Wilding et al, 2017; Morris, 2019).

If individuals develop symptoms of DKA then they should seek immediate medical advice and the key test is for blood ketones (preferable to urinary ketone testing). If DKA is suspected then the SGLT-2 inhibitor should be discontinued immediately. In the case of acute illness, dehydration or planned surgery the SGLT-2 inhibitor can be recommenced following recovery, but if there is no clear precipitating factor then it should not be restarted.

Other side-effects

The glycosuria induced by SGLT-2 inhibitors predisposes to genital fungal infection and to a lesser extent urinary tract infection (UTI). The strongest predictors of genital fungal infection are being female and having a previous history of infection (Thong et al, 2018).

The glycosuria induced by SGLT-2 inhibitors generates an osmotic diuresis that leads to more frequent voiding that can be troublesome. There may be associated volume depletion side-effects, notably postural hypotension, which could be problematic in the elderly.

An increased risk of lower limb amputation (the majority consisting of amputation at the level of the toe or metatarsal) and fracture was observed with canagliflozin in the CANVAS trial (Neal et al, 2016). The increased risk of amputation appeared to be associated with previous amputation and the presence of peripheral vascular disease. The CVOTs with dapagliflozin and empagliflozin did not show an increased risk of amputation but a warning is included in the product information for all drugs in the class (EMC, 2020c; 2020d; 2021g; 2021h).

Benefits

Table 5 summarises the benefits of SGLT-2 inhibitors (Davies et al, 2018; Morris, 2019; SIGN, 2017).

Cardiovascular outcomes

Both empagliflozin and canagliflozin demonstrated significant risk reduction in the primary outcome of MACE versus placebo in a population with T2DM and pre-existing cardiovascular disease (Zinman et al, 2015; Neal et al, 2017). The ertugliflozin CVOT showed non-inferiority to placebo (ie safe but no advantage) (Cannon et al, 2020).

The CVOT with dapagliflozin engaged a population with T2 DM predominantly without CV disease. Here, there was a trend toward improved MACE but this did not reach clinical significance (Wiviott et al, 2019). This suggested that the CV benefit from SGLT-2 inhibitors is seen primarily in those with established CV disease (ie secondary prevention).

Whilst the glucose-lowering potential of SGLT-2 inhibitors decreases with falling eGFR (hence their licensing restriction in accordance with eGFR) their capacity for CV protection appears to be maintained at lower eGFR.

The cardiovascular outcome trials (CVOT) of SGLT-2 inhibitors demonstrate that they could be useful in the prevention of heart failure. In a population with T2 DM and mostly with established cardiovascular disease (CVD) empagliflozin, canagliflozin and ertugliflozin showed a reduced risk of hospital admission for heart failure (HHF) versus placebo as a secondary outcome in these CVOT studies (Zinman et al, 2015; Neal et al, 2017, Cannon et al, 2020). In the CVOT with dapagliflozin the majority of subjects did not have pre-existing CVD but benefits in HHF were seen regardless of pre-existing atherosclerotic cardiovascular disease or heart failure or not (Wiviott et al, 2019).

In DAPA-HF, a randomised controlled trial, the benefits of dapagliflozin (versus placebo) in individuals with heart failure with reduced ejection fraction were demonstrated both in those with and without T2 DM (McMurray et al, 2019). Importantly, benefits in the primary outcome were seen in subjects whether or not baseline eGFR was greater or less than 60ml/min/1.73m2. It was also noteworthy that this group already had largely optimised medication for heart failure (ACE-inhibitors or angiotensin receptor blockers, beta blockers, aldosterone antagonists and diuretics). Similarly, the EMPEROR-Reduced study showed reduced hospitalisation for heart failure or cardiovascular death in people with heart failure with reduced ejection fraction (Packer M et al, 2020)

Renal outcomes

In all of the CVOTs with empagliflozin, empagliflozin and dapagliflozin the secondary composite renal outcomes showed significant benefit compared to placebo (Wanner et al, 2016; Neal et al, 2017; Wiviott et al, 2019). The renal outcome in the ertugliflozin CVOT just fell short of significant improvement over placebo (Cannon et al, 2020).

CREDENCE, a dedicated renal outcome trial comparing canagliflozin versus placebo in people with T2DM and albuminuric diabetic kidney disease and a range of eGFR of 30-90 ml/min/1.73m2, showed significant reduction in the composite primary outcome of end-stage renal disease, doubling of serum creatinine and death from renal or cardiovascular cause (Perkovic et al, 2019). The DAPA-CKD trial demonstrated improved renal outcomes versus placebo in albuminuric individuals with a range of renal function (down to eGFR of 25 mL/min/1.73m²) whether or not they had T2DM (Heerspink et al, 2020).

It should be noted that whilst the HbA1C lowering potential of SGLT-2 inhibitors falls in parallel with reducing eGFR their renoprotective properties are retained.

Guidelines and use in practice

Both NICE and ADA/EASD guidelines stress the importance of assessment of individual factors and an individual's preference in deciding the choice of therapy to improve glycaemic control (NICE, 2015; Davies et al, 2018). The ADA/EASD guidelines offer specific advice on second line therapy after metformin and triple therapy depending on circumstances (notably co-morbidities such as atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, obesity).

The DPP-4 inhibitors, SGLT-2 inhibitors and GLP-1 RA all have the advantage (over sulphonylureas, meglitinides or insulin) of carrying a low risk of hypoglycaemia and represent good choices where it is important to avoid this. In the frail elderly person with T2DM where tight glucose control is not the priority but avoiding hypoglycaemia is, then a DPP-4 inhibitor is a safe option, particularly so in the presence of chronic kidney disease.

An important consideration in lowering HbA1c in the obese individual with T2DM would be using an agent which can facilitate weight loss (SGLT-2 inhibitors or GLP-1 RAs), or at least weight neutrality (DPP-4 inhibitors), whereas pioglitazone, sulphonylureas, meglitinides and insulin are likely to induce weight gain.

The ADA/EASD guideline recommends GLP-1 RAs as second-line to metformin in those with pre-existing CVD (ischaemic heart disease, stroke/TIA, peripheral vascular disease) and also those with risk factors (age < 55 years with left ventricular hypertrophy, chronic kidney disease or > 50% stenosis of coronary, carotid or peripheral arteries). SGLT-2 inhibitors are also recommended for secondary prevention of cardiovascular events if GLP-1 RAs are unsuitable. DPP-4 inhibitors can be safely used in those with cardiovascular disease but do not provide additional cardiovascular protection (Davies et al, 2018; Buse et al 2020).

In the situation of heart failure SGLT-2 inhibitors are the clear choice of treatment add-on to metformin. If they are not tolerated or contraindicated then GLP-1 RAs are recommended. Saxagliptin should be avoided in heart failure (although other DPP-4 inhibitors may be used).

SGLT-2 inhibitors are also the first-line add on to metformin to improve glycaemic control in CKD because of their renoprotective properties (attenuating the progression of albuminuria and fall in eGFR). Again, if they cannot be used then the GLP-1 RAs are considered to be the next option because they have evidence of renoprotection (principally reducing new-onset albuminuria) and importantly can be used in some cases down to end-stage renal failure (Davies et al, 2018; Buse et al, 2020). DPP-4 inhibitors are a safe option in renal failure (again down to end-stage renal failure).

In considering injectable treatments, GLP-1 RAs hold an advantage over basal insulin for T2DM in that HbA1c lowering can be at least as effective whilst they induce weight loss rather than weight gain and do not carry the risk of hypoglycaemia associated with insulin (Davies et al, 2018; Buse et al, 2020). For similar reasons addition of a GLP-1 RA in those established on a basal insulin may be preferable to adding in a prandial insulin or switching to a premixed biphasic insulin.

Oral semaglutide offers an alternative means of administering a GLP-1 RA that may be more convenient, particularly for individuals with a fear of injection, and may facilitate improved adherence. Dosing instructions will be key to effectiveness. Oral semaglutide may prove to be an attractive choice in primary care.

SGLT-2 inhibitors are a little more expensive than DPP-4 inhibitors with GLP-1 RAs being approximately twice as expensive again.

Case history 2

Andrew is a 56 year old HGV driver diagnosed with T2DM 7 years ago. His current medication consists of metformin 500 mg bd, gliclazide 160 mg bd, sitagliptin 100 mg od, atorvastatin 20 mg od, ramipril 10 mg od and amlodipine 5 mg od. Recent results include: HbA1c 71 mmol/mol; eGFR 85 mL/min/1.73m²; cholesterol 4.3 mmol/L, non-HDL cholesterol 2.8 mmol/L; BMI 34.3 kg/m²; BP 138/87. Andrew has not suffered from any recent hypoglycaemia. He is known to have background diabetic retinopathy.

Case history 2 - outcome

HbA1c is well above target despite triple oral therapy. Andrew was encouraged to focus attention on lifestyle measures and given supportive literature and signposted to useful websites. Strategically, given his work as an HGV driver, gliclazide is better avoided because of the risk of hypoglycaemia. Useful options for Andrew would be an SGLT-2 inhibitor or a GLP-1 RA. These treatments offer the possibility of substantial improvements in HbA1c, with a secondary benefit of weight loss, but carry a low risk of hypoglycaemia.

After discussion with Andrew dapagliflozin 10 mg od was added to his regime and the dose of gliclazide cut to 80 mg bd. Subsequently once weekly semaglutide injections were started (noting Andrew does not have advanced retinopathy) with discontinuation of the gliclazide and sitagliptin.

A year later with the semaglutide dose titrated up to 1 mg once weekly by subcutaneous injection Andrew's HbA1c had fallen to 56 mmol/mol and he had lost around 6 kg in weight.

Conclusions

The DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors are agents for glycaemic control in type 2 diabetes that can offer additional health benefits. It is important that healthcare professionals with responsibility in diabetes familiarise themselves with these treatments in order to know when and how to safely and effectively deploy them. The selection of newer agents should be based on careful assessment of individual circumstances.

Key Points

• DPP-4 inhibitors offer a moderate reduction in HbA1c levels. GLP-1 RAs and SGLT-2 inhibitors are more powerful glucose-lowering treatments. They all carry a low risk of hypoglycaemia
• DPP-4 inhibitors are well tolerated, weight neutral agents that may be used down to end-stage renal failure. Cardiovascular safety but not benefit has been demonstrated
• GLP-1 RAs and SGLT-2 inhibitors can facilitate weight loss
• GLP-1 RAs and SGLT-2 inhibitors are effective in secondary prevention of cardiovascular events in type 2 diabetes. GLP-1 RAs can also offer primary prevention in those at high risk of cardiovascular disease
• SGLT-2 inhibitors are the agents of choice to add to metformin for glycaemic control in chronic kidney disease and heart failure. GLP-1 RAs can be considered if SGLT-2 inhibitors are poorly tolerated or contraindicated
• Gastrointestinal side-effects can be problematic with GLP-1 RAs though commonly they settle with time
• The most common side-effect with SGLT-2 inhibitors is genital thrush. Euglycaemic diabetic ketoa cidosis is a rare but serious side-effect. In situations of significant acute illness and hypovolaemia SGLT-2 inhibitors should be temporarily stopped to reduce the risk of acute renal failure and DKA.