Sodium-glucose co-transporter 2 inhibitors: game changers when handled with care?

Abstract

Recent years have seen a paradigm shift in the management of patients with diabetes mellitus. Rather than good glycaemic control being the sole primary aim, the therapeutic focus has broadened to consider potential additional cardiovascular and renal benefits. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, canagliflozin and dapagliflozin, have gained increasing prominence, with evidence suggesting significant improvement in outcomes in patients with established cardiovascular and renal disease. Here, we discuss the benefits and relative risks of these novel agents and highlight important clinical issues of relevance to general physicians.

Keywords

SGLT-2 inhibitors cardiovascular disease diabetes mellitus chronic kidney disease

Inhibitors of sodium-glucose co-transporter 2 (SGLT-2) have gained prominence over recent years. Although developed as hypoglycaemic agents for use in type 2 diabetes mellitus, several studies have demonstrated major benefits in other areas such as cardiovascular death, hospitalisation for heart failure and progression of chronic kidney disease. However, safety concerns have been raised, particularly risks of diabetic ketoacidosis, amputation and limb fracture, but these appear to be small. These drugs will therefore be of interest to many clinicians including endocrinologists, cardiologists, nephrologists, geriatricians and general practitioners. Ongoing trial evidence and clinical experience are likely to increase the use of these drugs further. In this article, we present an overview of the current role of these agents in clinical practice.

Search strategy

The PubMed database was searched for clinical human studies that were published up to May 2020 relating to efficacy and safety of the use of SGLT-2 inhibitors. Search terms included: SGLT-2 inhibitors, diabetes, chronic kidney disease, cardiovascular death, myocardial infarction, stroke, heart failure, ketoacidosis, genitourinary infections, bladder cancer, volume depletion, acute kidney injury, obesity, hyperuricaemia, amputations, bone and fractures. The reference lists of cited articles were also reviewed for additional relevant publications.

Mechanism of action

SGLT-2 is expressed by proximal renal tubular cells and is responsible for sodium and glucose reabsorption.¹ Inhibition of SGLT-2 activity results in increased natriuresis and glycosuria and an osmotic diuresis, and several potential cardiovascular and metabolic benefits such as volume contraction, blood pressure reduction, weight loss and improved glycaemic control.^1,2 Since renal glucose excretion depends on glomerular filtration in patients receiving these agents, their hypoglycaemic action is lessened in moderate to severe renal impairment, especially when glomerular filtration rate (GFR) falls below 45 mL/min/1.73 m². The risk of hypoglycaemia has also been reported to be minimal compared to other agents, given that the underlying mechanism is non-insulin-dependent.³

In addition to their glycaemic effects, SGLT-2 inhibitors have other potential benefits within the kidney, particularly by modulating intra-glomerular haemodynamics. These are largely mediated through tubulo-glomerular feedback, whereby tubular fluid composition leads to effects on afferent and efferent glomerular arterioles, in turn influencing intra-glomerular pressure and GFR.² Tubulo-glomerular feedback is initiated via the macula densa (in the distal nephron) where changes in tubular fluid sodium and chloride concentration are detected and the effects fed back to glomerular arterioles through mediators including angiotensin II, nitric oxide and bradykinin. Proximal tubular SGLT-2 blockade promotes sodium and chloride delivery to the macula densa, resulting in afferent arteriolar vasoconstriction and thus reduction in intra-glomerular pressure and glomerular hyperfiltration.^2,4 Since hyperfiltration is known to promote progression of chronic kidney disease by increasing proteinuria and fibrosis, SGLT-2 inhibitors offer a theoretical role in slowing this process. In addition to this haemodynamic mechanism, it has been reported that SGLT-2 inhibitors may have significant anti-inflammatory and anti-fibrotic properties in the kidney and heart. This may explain why cardio-renal benefits have still been observed in patients with advanced kidney disease despite the reduced effect on glucose excretion.⁴

Indications and relative contraindications

Primary and secondary care clinicians are increasingly encouraged to prescribe SGLT-2 inhibitors for patients with type 2 diabetes, particularly in view of the potential additional cardio-renal benefits. However, it is important to be aware of possible adverse effects and necessary precautionary measures. Indications and relative contraindications:^5–11

Indications

Type 2 diabetes with established cardiovascular disease or at high risk of developing cardiovascular disease.

Type 2 diabetes with diabetic nephropathy with moderate to severe albuminuria (urine albumin:creatinine ratio >3 mg/mmol).

Type 2 diabetes, chronic kidney disease and estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m².

Type 2 diabetes with moderate to severe heart failure.

Type 2 diabetes requiring additional therapy to achieve glycaemic targets, especially when standard agents are inadvisable due to intolerance, risk of hypoglycaemia or renal impairment.

Relative contraindications

eGFR < 30 mL/min.

Type 1 diabetes.

Recurrent genital/urinary tract infection.

Previous history or high risk of diabetic ketoacidosis.

Previous history of amputation or at risk of amputation due to significant arterial disease.

Active bladder cancer.

Haemodynamic compromise from volume depletion or intercurrent illness, e.g. infection.

Use of SGLT-2 inhibitors

SGLT-2 inhibitors in type 2 diabetes mellitus

As discussed above, the glucose-lowering action of SGLT-2 inhibitors is insulin-independent and occurs via promotion of glycosuria by blocking proximal renal tubular glucose reabsorption, particularly when plasma glucose exceeds the threshold for urinary glucose excretion.¹² However, as their hypoglycaemic action is dependent on glomerular filtration of glucose, this effect declines as GFR falls. Several international guidelines currently recommend them as an adjunct to other anti-diabetic agents for patients with inadequate glycaemic control.^5,8,10 More recently, KDIGO (the Kidney Disease – Improving Global Outcomes group) has gone further and suggest that patients with type 2 diabetes, chronic kidney disease and eGFR ≥ 30 mL/min/1.73 m² be treated with an SGLT-2 inhibitor (level 1 A evidence) in addition to metformin.¹¹ Rarely, SGLT-2 inhibitors may be considered as monotherapy if no other suitable options are available, for example due to drug intolerance or fear of hypoglycaemia.⁹ It has also been reported that SGLT-2 inhibitors may work synergistically with glucagon-like peptide-1 (GLP-1) receptor agonists (e.g. dulaglutide, exenatide, liraglutide), improving not only glycaemic control but also cardiovascular and renal outcomes.¹³ The relative risk of hypoglycaemia from SGLT-2 inhibitors appears to be low, of particular benefit in elderly patients or others with poor hypoglycaemic awareness.¹⁴ However, the risk of hypoglycaemia should still be considered in patients treated with these agents.

SGLT-2 inhibitors in cardiovascular disease

Cardiovascular disease is a significant problem in patients with type 2 diabetes mellitus, affecting one-third of patients in one study.¹⁵ There has been growing recognition of improved cardiovascular outcomes in patients treated with SGLT-2 inhibitors, for example in the form of better blood pressure control, reduced hospital admissions for heart failure, decreased rates of non-fatal myocardial infarction and non-fatal stroke, and reduction in deaths due to cardiovascular disease. In the EMPA-REG trial, 7020 patients with type 2 diabetes and underlying cardiovascular disease were treated with empagliflozin or placebo and followed up for over three years. There was a 38% reduction in cardiovascular death and a 14% reduction in all cardiovascular events compared to placebo.¹⁶ The cardiovascular benefits of dapagliflozin were demonstrated in the DECLARE-TIMI 58 trial, in which more than 17,000 patients received dapagliflozin or placebo over a four-year period. There was a substantial decline in cardiovascular death and hospital admission rates for heart failure in the treatment cohort.¹⁷ Similar cardiovascular benefits were observed in the CANagliflozin cardioVascular Assessment Study (CANVAS), in which 10,142 study participants were treated with canagliflozin or placebo over a median follow-up period of 2.4 years. This study found significant reductions in event rates for heart failure hospitalisation and primary outcomes (cardiovascular death, non-fatal myocardial infarction or stroke) – 33% and 14%, respectively.¹⁸ Zelniker et al. conducted a meta-analysis of these three controlled trials (which included a total of 34,322 patients, 60.2% with established atherosclerotic cardiovascular disease), and concluded that there were significant reductions in major cardiovascular events/cardiovascular disease-related mortality or hospitalisation for heart failure (11% and 23%, respectively).¹⁹ Interestingly, the reduction in the cardiovascular disease event rate was only observed in patients with atherosclerotic cardiovascular disease and not in those without, whereas reductions in mortality and hospitalisation for heart failure were similar in patients with or without atherosclerotic cardiovascular disease or previous heart failure.

In the more recent DAPA-HF trial, 4744 patients with mild to moderate left ventricular systolic dysfunction, with or without diabetes, were randomised to receive either dapagliflozin or placebo (in addition to optimised medical therapy for heart failure) with a median follow-up of 18.2 months. There were significant reductions in all-cause mortality (hazard ratio [HR]: 0.83, 95% confidence interval, [CI]: 0.71–0.97), cardiovascular death (HR: 0.82, 95% CI: 0.69–0.98) and hospitalisation for heart failure (HR: 0.70, 95% CI: 0.59–0.83) in the dapagliflozin group, regardless of diabetes status.²⁰

Based on available trial data, empagliflozin and canagliflozin appear to have better cardiovascular risk reduction profiles than dapagliflozin.^16–18 However, as no head-to-head comparisons have yet been made, this observation could be related to differences in trial design such as inclusion criteria and baseline patient characteristics, particularly severity of pre-existing kidney disease and degree of proteinuria (patients with more advanced kidney disease were noted to have more prominent benefits).²¹ Overall, there appears to be a reproducible class effect of SGLT-2 inhibitors on cardiovascular and renal endpoints and safety profiles.²¹

SGLT-2 inhibitors in diabetic kidney disease

SGLT-2 inhibition has proven to be beneficial in patients with diabetic kidney disease, particularly those at an early stage, through reduction in albuminuria and consequent slowing progression to end-stage kidney disease. As discussed above, this is largely mediated through tubulo-glomerular feedback. SGLT-2 inhibitors have had been demonstrated to improve several renal endpoints. In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, wherein 4401 patients with type 2 diabetes and chronic kidney disease (eGFR 30–89 mL/min) together with albuminuria of >300 mg/day (despite renin-angiotensin inhibition) were randomly assigned to canagliflozin or placebo. The trial was terminated early because statistically significant reductions in primary composite outcomes (including progression to end-stage kidney disease, doubling of serum creatinine and renal/cardiovascular death) of approximately by 30%, and end-stage kidney disease specifically by 32%, were achieved.²² A recent meta-analysis, combining four randomised controlled trials (including CREDENCE) studying over 38,000 individuals with diabetic kidney disease, convincingly demonstrated substantial reno-protective benefits, including reduction of end-stage kidney disease and renal-related mortality, in the SGLT-2 inhibitor treatment groups.²³

SGLT-2 inhibitors in obesity

SGLT-2 inhibition promotes weight reduction in obese patients with diabetes mellitus by reducing glucose reabsorption in the kidney.²⁴ However, the extent of weight loss has been reported to be modest, up to only 1–2 kg.²⁵ This effect can, however, be potentiated when used in combination with GLP-1 receptor agonists.²⁴ Recent studies suggest that SGLT-2 inhibitors are also effective for weight reduction in non-diabetic individuals.^26,27

SGLT-2 inhibitors in hyperuricemia

SGLT-2 inhibition appears to lower uric acid levels, thus reducing the risk of gout attacks. The mechanism is not fully understood and is likely explained by modification of glucose transport in renal tubules, promoting uric acid excretion.²⁸ In a subgroup analysis of the CANVAS study, canagliflozin-treated patients had greater reduction in serum urate concentration and less frequent gout flares than the placebo group.¹⁸ Recently, a large population-based cohort study found that patients on SGLT-2 inhibitors had a 30%–40% reduction in the incidence of gout compared to those taking GLP-1 agonists.²⁹ Taken together, SGLT-2 inhibitors could be considered as an option in the management of gout, especially for patients who are intolerant of or have contraindications to standard uric acid lowering agents. Furthermore, as hyperuricaemia is in itself a risk factor for cardiovascular disease, this effect may contribute to the improved cardiovascular outcomes seen in patients treated with SGLT-2 inhibitors.³⁰

Risks of SGLT-2 inhibitors

Genitourinary infections

Patients with diabetes mellitus are at increased risk of genital and urinary tract infections due to promotion of bacteriuria by glycosuria, increased bacterial attachment to uroepithelium, impaired glycaemic control leading to a lower threshold for fungal infections (particularly Candida albicans) and general impairment of immune function.³¹ Since SGLT-2 inhibitors increase glycosuria, there has been concern that patients on these agents are at higher risk. Several studies, including some meta-analyses, reported no significant differences in episodes of urinary tract infection in patients treated with SGLT-2 inhibitors.^32–34 However, genital fungal infections such as vulvovaginitis and balanitis do appear more common, particularly in post-menopausal women, uncircumcised men and those with prior history of such infections.^35,36 The majority of these patients achieve a good clinical recovery with oral or topical anti-fungal agents and rarely require withdrawal of SGLT-2 inhibitor treatment.^3,37 Recently, there has been growing concern following reports of patients on SGLT-2 inhibitors developing necrotising fasciitis of the genitalia or perineum (Fournier’s gangrene). When this occurs or is suspected, SGLT-2 inhibitors should be stopped immediately and standard interventions such as surgical debridement and antibiotics instituted.³⁸

Volume depletion and the risk of acute kidney injury

The osmotic diuresis caused by SGLT-2 inhibitors can lead to intravascular volume depletion, especially in patients at particular risk such as the elderly, others with multiple co-morbidities, those on diuretic therapy and patients with pre-existing renal impairment.^39,40 Reassuringly, no increased risk of acute kidney injury has yet been observed in meta-analyses of available controlled trials.^41,42 Importantly, since SGLT-2 inhibitors reduce intra-glomerular pressure by limiting blood flow into the afferent renal arteriole, an initial transient rise in serum creatinine may be expected in the first few weeks after initiation (similar to angiotensin converting enzyme inhibitors or angiotensin receptor blockers). Renal function usually then stabilises, and retardation of progression of chronic kidney disease may be observed thereafter.⁴³ However, as a precautionary measure, volume status and renal function should be monitored, temporary reduction or suspension of diuretic therapy may be necessary, and appropriate counselling regarding maintenance of good oral fluid intake and following sick day rules should be undertaken.⁴⁴

Lower limb amputation and bone fracture

Conflicting evidence on the incidence of lower limb amputation and bone fracture after SGLT-2 inhibitor use in patients with diabetes has been reported. Canagliflozin was reported to increase the risk of these adverse events in the CANVAS study.¹⁸ Recent meta-analyses, comprising CANVAS and other studies, found that these incidents appeared more common with canagliflozin than with other SGLT-2 inhibitors.^45,46 However, in the CREDENCE trial, rates of limb amputation and fracture were similar for canagliflozin and placebo groups.²² A further retrospective cohort study of over 100,000 new users of SGLT-2 inhibitors (75% on canagliflozin) revealed no higher risk of lower limb amputation compared to other hypoglycaemic agents.⁴⁷ The underlying mechanisms for these complications are yet to be unravelled. Unsurprisingly, patients with diabetic foot syndromes, autonomic neuropathy, prior history of amputation or established peripheral arterial disease are at increased risk of amputation,^39,45 and elderly patients with frequent falls (often exacerbated by volume depletion, postural hypotension and high-dose diuretics) are more prone to fractures.⁴⁵ These issues should be taken into consideration prior to initiation of SGLT-2 inhibitors, and patients require regular foot examination, integrated care with a diabetic foot team and a low threshold for discontinuing the SGLT-2 inhibitor if any complications occur.

Euglycemic diabetic ketoacidosis

Diabetic ketoacidosis has been increasingly recognised as a serious untoward effect of SGLT-2 inhibitor use, often requiring cessation of treatment. As a result of the reduced renal glucose excretion threshold and increased glycosuria, the majority of reported cases of ketoacidosis presented with euglycaemia or only a modest rise in blood glucose level.⁴⁸ This may result in a delay in diagnosis and initiation of effective diabetic ketoacidosis management. Elevation in blood ketones by SGLT-2 inhibition may be explained by several different mechanisms: reduced renal glucose reabsorption leading to decreased insulin secretion and increased glucagon production, in turn promoting free fatty acid formation and ketosis; direct pancreatic islet cell stimulation; and reduction in urinary ketone clearance.⁴⁹ Data surrounding the incidence of diabetic ketoacidosis related to SGLT-2 inhibitor use are largely derived from post-marketing surveillance, with over 2500 cases reported to the US Food and Drug Administration Adverse Event Reporting System in 2016.⁵⁰ In one retrospective study, the rate of diabetic ketoacidosis within six months of commencement of SGLT-2 inhibitors was around twice than in patients on dipeptidyl peptidase-4 inhibitors.^29,51 In landmark clinical trials, the increased diabetic ketoacidosis risk appeared to be similar in patients on canagliflozin and empagliflozin,^16,22 and was higher in the dapagliflozin-treated population;¹⁷ overall incidence across all trials ranged from 0.2 to 1.2 per 1000 patient-years. It is advised that clinicians have a high index of suspicion of diabetic ketoacidosis when patients with diabetes on SGLT-2 inhibitors present with non-specific symptoms such as nausea, vomiting, abdominal pain and lethargy, with or without accompanying hyperglycaemia, especially in the setting of high catabolic states (e.g. infection, stress, major surgery, other acute medical illness). A protocol-based treatment plan should be formulated, including intensive monitoring of clinical and laboratory parameters, variable or fixed rate insulin and dextrose infusion and suspension of the causative drug.⁵² Prior to SGLT-2 inhibitor introduction, individuals’ risk of diabetic ketoacidosis should be assessed. Patient education is paramount to advise on good oral fluid and carbohydrate consumption, cessation of SGLT-2 inhibitors in the event of acute illness or before a planned operation or procedure that requires a period of fasting, and to seek early medical attention when symptoms of possible ketoacidosis occur.⁵²

Bladder cancer

Concerns have been raised over a potential association between SGLT-2 inhibitors and risk of malignancy, particularly bladder cancer. However, evidence is limited and no convincing mechanism has been postulated. Current clinical trial data are not considered strong enough to form a definitive conclusion, partly due to lack of screening for risk of malignancy before randomisation, and also because of relatively short follow-up.⁵³ In a meta-analysis of 47 randomised controlled trials including over 30,000 patients followed up for a mean of 61 weeks, no evidence of increased cancer risk was found. Moreover, canagliflozin was associated with reduced risk of gastrointestinal cancers.⁵⁴ Nevertheless, a cautious approach is required until more reliable long-term data are available. For now, SGLT-2 inhibitors may not be the most attractive option in patients with past history of bladder cancer or unexplained haematuria, and decisions should be made on a case-by-case basis.

Potential future roles of SGLT-2 inhibitors

Even though SGLT-2 inhibitors have a proven role in improving renal prognosis, current international guidelines only recommend use for patients with eGFR of >30 mL/min.^5,8–10 The promising CREDENCE trial data may lead to broadening of the indications to include patients with more advanced chronic kidney disease.²² Also, given that cardio-renal protective benefits offered by SGLT-2 inhibitors appear to be independent of their glucose-lowering effect, they may be of benefit in the non-diabetic chronic kidney disease population. Two large-scale clinical trials – DAPA-CKD (NCT03036150) and EMPA-KIDNEY (NCT03594110) – are underway to determine the efficacy and safety of SGLT-2 inhibitors in patient groups including non-diabetic chronic kidney disease, eGFR < 30 mL/min and non-proteinuric chronic kidney disease.⁵⁵ At present, SGLT-2 inhibitors are not licensed for use in patients with type 1 diabetes mellitus in view of the risk of diabetic ketoacidosis; future safety outcome trials may elucidate this issue.¹⁴ A further potential area for investigation is that of new onset diabetes after kidney transplantation (NODAT) to assess whether SGLT-2 inhibitors may be of benefit in reducing cardiovascular risk.⁵⁶ At present, use in this group is limited by the fear of increased risk of genitourinary tract infection in these immunosuppressed transplant recipients and the fact that the anticipated decline in GFR (due to haemodynamic changes) may be difficult to distinguish clinically from graft rejection.

Conclusion

Although initially developed as hypoglycaemic agents, SGLT-2 inhibitors are likely to see their role continue to develop following the observation of their substantial but unanticipated cardiovascular and renal benefits together with favourable metabolic effects including reduction in weight and uric acid levels. Despite some safety concerns, particularly the risk of diabetic ketoacidosis, genital infections and limb amputation, SGLT-2 inhibitors are considered safe to use when appropriate precautions and monitoring are undertaken. Ongoing studies will strengthen the evidence base regarding the efficacy and safety of these drugs, allowing use for a wider variety of indications and in more complex clinical scenarios.

Footnotes

Declarations

Acknowledgements

None.

Provenance

Not commissioned; peer reviewed by Ratnasingam Nithiyananthan, Joana Rigor, MD Bashar.

ORCID iD

Zay M Htet

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