Sodium–glucose cotransporter-2 Inhibitors: Where and when?

Abstract

Tweetable abstract

Sodium–glucose cotransporter-2 inhibitors not only improve glycemic control in Type 2 diabetes mellitus but convincingly improve outcome for everyone with HFrEF and albuminuric kidney disease. Trials then license – now all we need is implementation

Keywords:

• cardiovascular disease
• chronic kidney disease
• diabetes mellitus
• guidelines
• heart failure
• implementation
• outcome trials
• SGLT2 inhibitors

Sodium–glucose cotransporter (SGLT)-2 inhibitors are rapidly becoming the new ‘wonder’ drugs for cardiovascular and renal risk reduction in a wide spectrum of patients – not only in those with a diagnosis of Type 2 diabetes mellitus (T2DM).

This class of drugs was initially developed to improve glycemic control in T2DM by increasing glycosuria by blocking the SGLT2 transporter in the proximal renal convoluted tubule. In placebo-controlled trials they improved HbA1c from -0.6 to -1.0%, with smaller differences when compared against other hypoglycemic agents [1]. They also helped patients lose a modest amount of weight (typically 2 kg of fat mass, due to calorie loss from glycosuria), and improved blood pressure by approximately 4 mmHg systolic and 2 mmHg diastolic. The blood pressure effect is likely due to initial reduction in extracellular fluid volume, followed by reduction in body mass due to loss of visceral and subcutaneous adipose tissue, modulation of the renin–angiotensin–aldosterone system and reduced plasma uric acid levels.

Large cardiovascular outcome trials for new antidiabetic drugs were mandated by the US FDA in 2008, and by the EMA in 2012, to confirm cardiovascular safety. For SGLT2 inhibitors, trial after trial has now confirmed such safety and established substantial cardiovascular and renal benefits in a broad spectrum of patients with T2DM and with (or at high risk of) atherosclerotic cardiovascular disease. This evidence has led to SGLT2 inhibitors being recommended by recent clinical guidelines as a key component of a drug strategy to control glycemia and reduce the risk of cardiovascular events, irrespective of the current (or target) HbA1c [2,3].

SGLT2 inhibitors have a wide range of physiological effects [1], beyond glycemic control and this encouraged the pursuit of evidence for benefit in patients who did not have T2DM.

Evidence in patients with heart failure, with or without T2DM

The first major trial that enrolled both patients with and without T2DM was DAPA-HF, which compared dapagliflozin 10 mg once daily with placebo (in addition to optimal medical therapy) in patients with heart failure and reduced ejection fraction (HFrEF) [4]. This trial reported a clinically important, and highly significant, reduction in the primary end point of worsening heart failure or cardiovascular (CV) death (relative risk reduction 26% (95% CI: 15–35%; p < 0.001), with nominal significance also for cardiovascular and all-cause, mortality. The effect was similar in those with or without diabetes, and the drug was well tolerated in both groups.

As a result of this trial, the FDA awarded a license to dapagliflozin ‘for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure’. A similar marketing authorization was issued by the EMA in November 2020.

As yet, few guideline writers have opined on the place of this licensed therapy in the treatment algorithm for HFrEF, although there is a strong argument that as the drug appears to improve outcome irrespective of background therapy, and is well tolerated, then it should be introduced early rather than forcing the patient to wait until all other therapies (such as RAAS inhibitors and beta-blockers) are optimized – a process that is far from optimal in many healthcare settings globally [5].

EMPEROR-Reduced, with empagliflozin 10 mg once daily in a similar (or perhaps slightly higher risk) population of patients with HFrEF confirmed similar effects on the primary end point of CV mortality and HF hospitalization risk as shown in DAPA-HF [4]. It failed to achieve nominal significance for either CV or all-cause mortality, either due to lack of power (shorter follow-up and fewer patients than in DAPA-HF) or due to differences between the molecules [6]. Meta-analysis suggests no evidence of statistical heterogeneity between the trials [7].

These two large randomized trials confirming meaningful clinical benefit in hard end points such as CV mortality and HF hospitalization would suggest that SGLT2 inhibition (at least with dapagliflozin or empagliflozin) should gain a Class I Level A rating in evidence-based guidelines for HFrEF. Such support should be followed by rapid implementation in the clinical community, provided reimbursement decisions are also positive. Economic modeling by the trialists suggests that dapagliflozin in HFrEF is not only clinically effective, but also cost-effective under currently accepted thresholds [8,9].

Evidence in chronic kidney disease, with or without T2DM

SGLT2 inhibitors have also been shown to have an important beneficial effect on kidney function in patients with T2DM and chronic albuminuric kidney disease (CREDENCE with canagliflozin 100 mg daily or placebo) [10] and in those with albuminuric kidney disease with or without concomitant T2DM (DAPA-CKD with dapagliflozin 10 mg once daily or placebo) [11]. Both trials were stopped early because of efficacy on the recommendations of the data safety and monitoring boards. The primary end point of decline in estimated GFR of 50% or more, end-stage kidney disease or death from renal or cardiovascular cause were reduced by 30% (95% CI: 18–41% ; p < 0.00001] in CREDENCE, and by 39% (95% CI 28–49%; p < 0.001) in DAPA-CKD. In the former, all-cause mortality was numerically lower (17%, but with 95% CI that spanned unity), and in the latter the all-cause mortality was reduced by 31% (95% CI: 12–47%; p = 0.004). It is important to note that patients were also on a renin–angiotensin–aldosterone inhibitor at randomization (unless this had been tried and not tolerated previously). In DAPA-CKD around a third of patients were not diabetic, but the effect size estimates for the end points were the same in those with or without T2DM.

A renoprotective effect was also reported in the two major HFrEF trials, DAPA-HF and EMPEROR-Reduced, with a slowing of deterioration in eGFR compared with placebo [4,6].

Are there safety or operational issues?

SGLT2 inhibitors share similar pharmacokinetic characteristics: rapid oral absorption, a long elimination half-life supporting once daily administration, extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, low renal elimination of the parent drug and the absence of clinically relevant drug–drug interactions. It is likely that current license restrictions on use in patients with impaired renal function will be lifted, as the recent randomized trials have recruited patients with estimated glomerular filatration rates (GFR) down to 25 ml/min/1.73 m² for dapagliflozin [4,11] and 20 ml/min/1.73 m² for empagliflozin [6].

Safety issues or challenging uptitration schedules (with the need for repeated checks of vital signs and laboratory tests) are often used as explanations that other therapies with well-demonstrated clinical benefits are not introduced even in serious conditions such as heart failure. The safety profile of SGLT2 inhibitors appears good and dosing is simple, with little if any meaningful interaction with food or other medication. Experience of the class of drugs, at least in primary care and diabetes practice, is strong.

Caution should, however, be observed in patients who become ‘sick’ due to, for example, concurrent infection or who undergo surgical procedures, are insulinopenic or have a history of previous diabetic ketoacidosis, but otherwise there would appear to be little excuse for not seriously considering (and discussing with patients) the option of SGLT2 inhibitors for those with HFrEF, albuminuric chronic kidney disease or T2DM with (or at high risk) of atherosclerotic cardiovascular disease.

In patients without T2DM, the trials suggest that the only side effects that occurred more frequently than with placebo were genital infections – there was no increase in episodes of hypoglycemia, lower limb fracture, amputation or hypotension, volume depletion or renal dysfunction [4,6,11].

As the effects appear quickly, the sooner the patients start swallowing the tablets the sooner they will obtain the benefit.

Where & when should we prescribe SGLT2 inhibitors?

Many trials should report in the next few years [1] – including the registry-based randomized trial in those with left ventricular damage after acute myocardial infarction (DAPA-MI), HF with preserved ejection fraction (DELIVER and EMPEROR-Preserved) and acute HF (EMPULSE) – but two conclusions can be reached based on the evidence published to date:

• For those with T2DM: SGLT2 inhibitors should be part of the drug strategy for those with (or at high risk of) atherosclerotic cardiovascular disease, irrespective of the HbA1c level or target. This approach is currently supported in the USA and Europe [2,3]. The alternative option of a glucagon-like peptide-1 agonist or analogue (GLP1-RA) may also be considered, particularly for those with a history of vascular events such as myocardial infarction or stroke. Currently GLP1-RA therapy is delivered as a subcutaneous injection, but oral therapy may be available shortly.

• For those without T2DM (and we should always check for T2DM when we see patients with cardiovascular or renal risk factors): SGLT2 inhibition should be part of first-line therapies for HFrEF and for those with albuminuric chronic kidney disease. Benefits are not only in terms of disease progression (reduction in eGFR or hospitalization for HF) but also, at least for dapagliflozin, for CV and all-cause mortality.

Our patients would expect us to consider these drugs in these circumstances, and to discuss them with them. It is unlikely that head-to-head comparisons will be conducted between the different drugs in the class, so prescription should be based on comparison across the trials, and familiarity with the drugs. Prescription decision making should not be restricted to specialists – primary care physicians should also be enabled to prescribe, with appropriate decision support, to ensure more equitable and speedier implementation.

Seldom can one be so positive about a new class of drugs – but as each large CV outcome trial adds to the next we see confirmation of a consistent and important effect on CV risk reduction, particularly for people with HFrEF or chronic kidney disease. A class of drugs designed to improve diabetic control in those with T2DM has found an increasing role outside that area and it behoves guideline writers and prescribers to take the evidence seriously. I hope that we as a profession can get our house in order, so that few patients lose out on the potential added benefit.

Financial & competing interests disclosure

M Cowie has provided consultancy advice to AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Servier, Novartis and Bayer. He has not received any support to write this editorial. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.