Since 2008 the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have required new drugs for the treatment of diabetes to demonstrate cardiovascular safety, usually including a double-blind placebo controlled cardiovascular outcome trial (CVOT)1,2 as described in module 1. The primary end point required for the FDA was either the composite end point of major cardiovascular events (MACE), a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, or MACE plus, with the addition of hospitalisation for unstable angina. Hospitalisation for heart failure (HFH) was included as a secondary outcome but was not part of primary composite end point. Baseline heart failure was recorded in these diabetes CVOTs by the local clinical investigator but was not well characterised.
We now have multiple completed cardiovascular outcome trials for the new drugs classes of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The trials with DPP-4 inhibitors and GLP-1 receptor agonists are described in module 3. The positive outcomes that have been demonstrated by SGLT2 inhibitors for heart failure and renal composite outcomes in diabetes CVOTs have, in turn, stimulated dedicated cardiorenal outcome trials in patients with heart failure and patients with chronic kidney disease, including non-diabetic subjects.
SGLT2 inhibitor cardiovascular outcome trials
The landmark EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes mellitus Patients) was the first positive CVOT with a new anti-diabetes drug and included 7,020 patients with type 2 diabetes.3 All patients were supposed to have established atherosclerotic cardiovascular disease but a small number of subjects were randomised who were subsequently characterised as increased cardiovascular risk rather than established cardiovascular disease (CVD) (table 1). 10% of subjects had baseline heart failure. Subjects were randomised in a 1:1:1 ratio to empagliflozin 10 mg, empagliflozin 25 mg or placebo with a median follow up of 3.1 years. The empagliflozin groups were combined for analysis. In EMPA-REG OUTCOME:
- The primary MACE end point was significantly reduced in the empagliflozin group compared to the placebo group (10.5% vs. 12.1%; hazard ratio [HR], 0.86; 95% [confidence interval] CI 0.74 to 0.99; p=0.04 for superiority).3
- Compared with placebo, empagliflozin also resulted in a significant reduction in cardiovascular death, all-cause mortality and HFH.
- Empagliflozin was associated with a significant reduction in a prespecified renal end point, defined as ‘incident or worsening nephropathy’, a composite of progression to macroalbuminuria, doubling of serum creatinine level, initiation of renal-replacement therapy or death from renal disease.4
- Overall numbers of adverse events were similar between groups. As anticipated, there was a significant increase in genital fungal infections in the empagliflozin group (6% vs. 2%). There was no significant difference in occurrence of hypoglycaemia or diabetic ketoacidosis.
The CANVAS Program (CANagliflozin cardioVascular Assessment Study [CANVAS] plus CANVAS-Renal [CANVAS-R]) used a slightly different approach to other CVOTS. It combined the cardiovascular results of CANVAS and CANVAS-R trials into an integrated analysis.5 CANVAS was a cardiovascular safety trial and preliminary results were used to establish cardiovascular safety to get a licence in the US. CANVAS-R was designed as a CANVAS-like CVOT to be jointly analysed with CANVAS to meet a post-approval cardiovascular safety commitment of regulatory authorities. The CANVAS Program included 10,142 participants with established atherosclerotic CVD or two or more cardiovascular risk factors, who were followed for a mean of 188 weeks. 5,795 subjects received canagliflozin 100-300 mg, and 4,347 received placebo. In the CANVAS Program (table 1):
- There was a significant 14% reduction in MACE comparing canagliflozin and placebo (HR, 0.86; 95% CI 0.75 to 0.97; p=0.02 for superiority.5
- There was no statistically significant reduction in any of the components of MACE, or in total mortality, but it may have been underpowered to demonstrate significant reductions because of the unusual study design.
- HFH was significantly reduced (HR 0.67; 95% CI 0.52 to 0.87), as was a renal composite of 40% reduction in estimated glomerular filtration rate (eGFR), renal-replacement therapy or death (HR 0.60; 95% CI 0.47 to 0.77).
- An unexpected increase in amputations and lower extremity fractures was seen in the canagliflozin group. This has not been seen in other CVOTs with SGLT2 inhibitors.
DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) was the largest and longest of the diabetes safety trials with a SGLT2 inhibitor.6 It included 17,160 patients who were randomised to dapagliflozin 10 mg or placebo and followed for a median of 4.2 years. The majority of subjects were at increased cardiovascular risk whereas in the other three diabetes CVOTs the majority of subjects had established CVD (table 1). It also differed from the other trials by having co-primary end points of MACE and the composite of cardiovascular death and HFH. In DECLARE-TIMI 58:
- Dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR 0.93; 95% CI 0.84 to 1.03; p=0.17) but did result in a significantly lower rate of cardiovascular death or HFH (4.9% vs. 5.8%; HR 0.83; 95% CI, 0.73 to 0.95; p=0.005).6
- Prespecified analysis of subjects with a prior myocardial infarction (MI) at baseline showed significant reductions in MACE with dapagliflozin.7
- A renal event (sustained decrease in 40% or more in eGFR, new end-stage renal disease, or death from renal or cardiovascular causes) occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (HR 0.76; 95% CI 0.67 to 0.87; p<0.0001).8
- Genital fungal infections and diabetic ketoacidosis were more common with dapagliflozin, but there was no difference in the rate of fractures or amputations.
The most recent CVOT of an SGLT2 inhibitor in people with diabetes was VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial).9 This compared ertugliflozin 5 mg and 15 mg with placebo for a mean of 3.5 years in 8,246 patients with type 2 diabetes and atherosclerotic CVD. The initial intention was to recruit 4,000 subjects and to test for non-inferiority of MACE. Once the results of EMPA-REG OUTCOME were published, the VERTIS CV protocol was amended. The study was doubled in size allowing recruitment of more patients with clinically diagnosed heart failure (table 1). A key secondary outcome was added of superiority for a composite of cardiovascular death and HFH, followed by testing a renal composite outcome for superiority. In VERTIS-CV:
- MACE occurred in 653 of 5,493 patients (11.9%) in the ertugliflozin group and 327 of 2,745 patients (11.9%) in the placebo group satisfying the FDA criteria for non-inferiority (HR 0.97; 95% CI 0.85 to 1.11; p<0.001 for noninferiority).
- The composite of cardiovascular death and HFH was not significantly reduced (HR 0.88; 95% CI 0.75 to 1.03, p=0.11 for superiority), and the pre-specified renal composite outcome was not significantly reduced.
- While not a pre-specified hypothesis for statistical testing, a reduction in HFH was observed with ertugliflozin.
A recent meta-analysis has further examined cardiovascular and kidney outcomes with SGLT2 inhibitors in patients with type 2 diabetes.10 The largest benefit in the class was for HFH and kidney outcomes. MACE events were reduced in patients with and without prior atherosclerotic CVD. Of note, significant heterogeneity of associations with outcome was observed for cardiovascular death, with EMPA-REG OUTCOME being a possible outlier because of its strongly positive effect, VERTIS because of its lack of effect on cardiovascular death, or both.
Thus, CVOTS with SGLT2 inhibitors in people with diabetes have demonstrated major cardiovascular benefits with reductions in MACE, cardiovascular death, HFH, and renal composite events. The expected adverse event of an increase in genital fungal infections was observed, with slight increases in diabetic ketoacidosis.
Table 1. Cardiovascular outcome trials with SGLT2 inhibitors
|Drug||Trial||Key patient features||End point||Key results|
|Empagliflozin||EMPA-REG OUTCOME3,4||99% ASCVD
||MACE||MACE empagliflozin superior
CV and all-cause mortality reduced
Renal composite reduced
|Canagliflozin||CANVAS PROGRAM5||66% ASCVD
34% CV risk
|MACE||MACE canagliflozin superior
Renal composite reduced
60% CV risk
CV death/HFH dapagliflozin superior
Renal composite reduced
CV death/HFH (superiority)
CV death/HFH not superior
Renal composite no difference
|Key: ASCVD = atherosclerotic cardiovascular disease; CANVAS PROGRAM = CANagliflozin cardioVascular Assessment Study (CANVAS) plus CANVAS-Renal; CV = cardiovascular; DECLARE-TIMI = Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME = Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes mellitus Patients; HFH = heart failure hospitalisation; MACE = major adverse cardiovascular events; MI = myocardial infarction; SGLT2 = sodium-glucose co-transporter 2; VERTIS-CV = Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial|
Subsequent cardiorenal trials with SGLT2 inhibitors
Following on from the CVOTs performed to satisfy the FDA safety requirements for new-anti-diabetes drugs in people with diabetes, there has been a series of studies with SGLT2 inhibitors in dedicated populations of subjects with chronic kidney disease (CKD) and heart failure, including subjects with and without diabetes (tables 2 and 3). CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) investigated the effects of canagliflozin 100 mg versus placebo in 4,401 patients with type 2 diabetes and diabetic kidney disease (DKD), with a median follow-up of 2.6 years.11 The subjects who were recruited had much lower levels of eGFR than those in EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58. CREDENCE was stopped early on the recommendation of the data and safety monitoring committee after a planned interim analysis showed significant reductions in the risk of kidney failure and cardiovascular events. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation or eGFR <15 ml/minute/1.73m2), doubling of serum creatinine and death from renal or cardiovascular causes. In CREDENCE:
- The relative risk of the primary composite outcome was significantly reduced in the canagliflozin group compared with the placebo group, with event rates of 43.2 and 61.2 per 1,000 patient-years (HR 0.70; 95% CI 0.59 to 0.82; p=0.00001).
- The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% and the relative risk of end- stage kidney disease was lower by 32%.
- The canagliflozin group also had a lower risk of MACE (HR 0.80; 95% CI 0.67 to 0.95; p=0.01), and HFH (HR 0.61; 95% CI 0.47 to 0.80; p<0.001), but there was no significant difference in all-cause mortality.
- There were no significant differences in rates of amputation or fracture.
DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) extended the results of CREDENCE as it included a mixture of subjects with CKD with and without diabetes.12 DAPA-CKD examined the effects of dapagliflozin 10 mg versus placebo in 4,304 patients with CKD, with a median follow-up of 2.4 years. This trial was also stopped early on the recommendation of the data and safety monitoring committee because of clear efficacy, on the basis of 408 primary outcome events. The primary end point was slightly different from CREDENCE and was a composite of worsening kidney function defined as >50% decline in eGFR, as well as onset of end-stage kidney disease (dialysis, transplantation or eGFR <15 ml/minute/1.73m2), or death due to renal or cardiovascular causes. The results of DAPA-CKD were:
- There were 197 primary end point events with dapagliflozin and 312 with placebo. (HR 0.61; 95% CI 0.51 to 0.72; p=0.000000028).
- The benefit in the reduction of the primary end point was consistent in patients with and without type 2 diabetes.
- The dapagliflozin group also had a lower risk of cardiovascular death/HFH (HR 0.71; 95% CI 0.55 to 0.92; p=0.0089) and all-cause mortality (HR 0.69; 95% CI 0.53 to 0.88; p=0.0035).
Table 2. Cardiorenal outcome trials with SGLT2 inhibitors
|Drug||Trial||Key patient features||End point||Key results|
|Canagliflozin||CREDENCE11||T2DM, DKD (eGFR 30-<90 ml/minute/1.73m2, albuminuria)
||Primary renal composite canagliflozin superior
CV death/HFH reduced
|Dapagliflozin||DAPA-CKD12||CKD (eGFR 25-75 ml/minute/1.73m2, albuminuria)
||Primary renal composite dapagliflozin superior
CV death/HFH significantly reduced
All-cause mortality significantly reduced
|Sotagliflozin||SCORED16||T2DM, DKD (eGFR 25-60 ml/minute/1.73m2)
||Primary composite sotagliflozin superior
HFH/urgent visit for HF reduced
|Key: CKD = chronic kidney disease; CREDENCE = Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV = cardiovascular; CVD = cardiovascular disease; DAPA-CKD = Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; HF = heart failure; HFH = heart failure hospitalisation; MACE = major adverse cardiovascular events; MI = myocardial infarction; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus; SCORED = Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk|
The first dedicated outcome trial of a SGLT2 inhibitor in a heart failure population was the landmark DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial.13 DAPA-HF randomised 4,744 patients with New York Heart Association (NYHA) class II, III or IV heart failure and an ejection fraction of 40% or less to dapagliflozin 10 mg or placebo or a median of 18 months. Overall 11% of subjects were on sacubitril-valsartan at baseline. Subjects with diabetes (42% of the total population) were treated with a mixture of metformin, sulfonylureas, DPP-4 inhibitors and insulin, and only 1% were treated with GLP-1 receptor agonists. In DAPA-HF:
- The primary composite outcome of worsening heart failure (hospitalisation or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death occurred in 386 of 2,373 patients (16.3%) in the dapagliflozin group and in 502 of 2,371 patients (21.2%) in the placebo group (HR 0.74; 95% CI 0.65 to 0.85; p<0.001).
- Death from cardiovascular causes and death from all causes were also significantly reduced in the dapagliflozin group.
- Findings in patients with diabetes were similar to those in patients without diabetes.
- The risk of a renal composite outcome was also significantly reduced with dapagliflozin.
- Adverse events of volume depletion, renal dysfunction and hypoglycaemia did not differ between treatment groups, and diabetic ketoacidosis was not increased.
EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) was a similar study in 3,730 with NYHA class II, III or IV heart failure and an ejection fraction of 40%.14 Patients were randomised to empagliflozin 10 mg or placebo for a median of 18 months. The baseline usage of sacubitril-valsartan was higher than in DAPA-HF at 19%. At the same time that EMPEROR-Reduced was published, similar authors published a meta-analysis,15 which compared patient-level data from EMPEROR-Reduced and study-level data from DAPA-HF. In EMPEROR-Reduced:
- The primary composite outcome (hospitalisation for worsening heart failure or cardiovascular death) occurred in 361 of 1,863 patients (19.4%) in the empagliflozin group and in 462 of 1,867 patients (24.7%) in the placebo group (HR 0.75; 95% CI, 0.65 to 0.86; p<0.001), and the effect was consistent regardless of the presence or absence of diabetes.
- There was no difference in the rates of cardiovascular death or death from any cause comparing empagliflozin and placebo, but in the meta-analysis including DAPA-HF and EMPEROR-Reduced there was no heterogeneity of the effects on these outcomes.14,15
- The annual rate of decline in the eGFR was slower in the empagliflozin group than in the placebo group.
Sotagliflozin is an SGLT2 inhibitor that also inhibits gastrointestinal SGLT1. The development programme of sotagliflozin was halted in 2019 for commercial reasons. Sotagliflozin was being studied in two outcome trials that were stopped early in 2020 because of lack of funding plus the additional uncertainty relating to the effects of the COVID-19 pandemic on the trials. SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) compared sotagliflozin and placebo in 10,584 subjects with type 2 diabetes and diabetic kidney disease for a median of 16 months.16 SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) compared sotagliflozin and placebo in 1,222 subjects with type 2 diabetes who were recently hospitalised for worsening heart failure, for a median of nine months.17 For both trials the primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, HFH, and urgent visits for heart failure. With sotagliflozin:
- In SCORED the rate of the primary end point was significantly reduced in the sotagliflozin group (HR 0.74; 95% CI 0.63 to 0.88; p<0.001), but the trial was underpowered to look at renal events.
- In SOLOIST-WHF the rate of the primary end point was significantly reduced in the sotagliflozin group (HR 0.67; 95% CI 0.52 to 0.85; p<0.001) with no evidence of heterogeneity according to ejection fraction.
- In both trials, diarrhoea was more common in the sotagliflozin group than in the placebo group.
Table 3. Heart failure outcome trials with SGLT2 inhibitors
|Drug||Trial||Key patient features||End point||Key results|
||CV death/worsening HF dapagliflozin superior
CV & all-cause mortality reduced
Renal composite outcome reduced
|Empagliflozin||EMPEROR-Reduced14||Heart failure with EF <40% with or without T2DM
||CV death/HFH empagliflozin superior
CV death, all cause death no difference
||Primary composite sotagliflozin superior
HFH/urgent visit for HF reduced
|Key: CV = cardiovascular; DAPA-HF = Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; EF = ejection fraction; EMPEROR-Reduced = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; HF = heart failure; HFH = heart failure hospitalisation, MI = myocardial infarction; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus; SOLOIST-WHF = Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure|
Until recently, SGLT2 inhibitors have been used as anti-diabetic drug in people with diabetes to improve glycaemic control. Most of the clinical use has been in in people with type 2 diabetes, and a small amount of clinical use has been with dapagliflozin in people with type 1 diabetes.18 SGLT2 inhibitors are associated with increases in genital thrush infections. Patients starting an SGLT2 inhibitor should be given advice on genital hygiene, and if thrush occurs it usually responds to conventional treatments. The rate of diabetic ketoacidosis, which is a less common occurrence in people with type 2 diabetes, is also increased and diabetic patients should be given advice about temporarily discontinuing SGLT2 inhibitors at times of intercurrent illnesses as part of sick-day rules.
The pattern of cardiovascular benefits seen with SGLT2 inhibitors is different to the benefits that have been seen with GLP-1 receptor agonists (module 3) with a more rapid separation in MACE, and significant reductions in HFH. In addition, the renal benefits are a combination of reductions in albuminuria with significant effects in slowing the fall of eGFR. The phenotype of the patient with type 2 diabetes, who would be most suitable for a SGLT2 inhibitor, is therefore a patient with established CVD, including heart failure or atherosclerotic CVD, patients with diabetic kidney disease, or those at high cardiovascular risk without established CVD.
The results of the CVOTs in people with diabetes demonstrate clear reductions in cardiovascular events in addition to reducing HbA1c and weight. The results of these CVOTs are now incorporated into most guidelines on the management of type 2 diabetes, including the updated consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).19 A notable exception is the National Institute of Health and Care Excellence (NICE) guideline on the management of type 2 diabetes in adults from 2015 which did not include results of any of the CVOTs. This guideline is currently being updated with an expected publication date to be confirmed.20
Subsequent outcome trials with SGLT2 inhibitors have extended the evidence base into patients with heart failure and reduced ejection fraction, and patients with CKD. Previously SGLT2 inhibitors were not to be initiated in patients with a reduced eGFR as they are less effective at reducing HbA1c, but the licence for canagliflozin has now been changed and it can be initiated for treatment of diabetic kidney disease at a dose of 100 mg down to an eGFR of 30 ml/minute/1.73m2.
The licence for dapagliflozin has also changed recently and it is now approved in Europe for the treatment of symptomatic chronic heart failure with a reduced ejection fraction, with and without diabetes, including patients with heart failure and renal impairment. When starting SGLT2 inhibitors for patients with symptomatic heart failure, it is important to establish the diabetes status of the patient. To avoid hypoglycaemia, patients with a low HbA1c who are on sulfonylureas or insulin will require reductions in these when SGLT2 inhibitors are initiated. Patients with a very high HbA1c may need input from the diabetes team to avoid precipitation of ketoacidosis, and all patients with diabetes will require education on sick day rules.
The possible mechanisms of benefit of SGLT2 inhibitors have not been studied in any of these outcome trials. This is an area of intense research with many mechanistic studies in animals and humans due for completion over the next few years. Postulated mechanisms of cardiorenal benefit of SGLT2 inhibitors are detailed in figure 1.21-23 Mediation analysis has shown that the reductions in events cannot be explained by changes in HbA1c, weight or blood pressure, and the fact that reductions in heart failure and renal events are observed in subjects without diabetes indicates that the benefits are independant of effects on blood glucose.24,25
Thus, these trials have confirmed that the renal and heart failure benefits that were observed as secondary outcomes in EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 are present in dedicated populations with well-characterised CKD and heart failure with reduced ejection, and have shown that these benefits extend to people with and without type 2 diabetes. Dedicated trials in subjects with heart failure and preserved ejection fraction are expected to complete in the next few years (table 4), with outcome studies in other cardiovascular patients, such as patients with acute heart failure and post myocardial infarction to follow.
Table 4. Further trials with SGLT2 inhibitors
|Drug||Trial||Key patient features||End point|
|Empagliflozin||EMPEROR-Preserved||Chronic heart failure, EF >40%, elevated NT-proBNP, with or without T2DM||CV death/HFH|
|Dapagliflozin||DELIVER||Symptomatic heart failure, EF >40%, elevated NT-proBNP, with or without T2DM||CV death/HF events|
|Empagliflozin||EMPA-KIDNEY||CKD with or without T2DM, eGFR 25-45 ml/minute/1.73m2 or eGFR 45-90 ml/minute/1.73m2 with albuminuria||Renal composite outcome|
|Key: CKD = chronic kidney disease; CV = cardiovascular; DELIVER = Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure; EF = ejection fraction; eGFR = estimated glomerular filtration rate; EMPA-KIDNEY = The Study of Heart and Kidney Protection with Empagliflozin; EMPEROR-Preserved = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Preserved Ejection Fraction; HF events = heart failure hospitalisation or urgent heart failure visit; HFH = heart failure hospitalisation; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus|
- In patients with type 2 diabetes and atherosclerotic cardiovascular disease or who are at high risk of cardiovascular disease, empagliflozin, canagliflozin and dapagliflozin significantly reduced cardiovascular events
- Canagliflozin reduced the progression of diabetic kidney disease in patients with type 2 diabetes and chronic kidney disease (CKD), and dapagliflozin had similar effects in patients with CKD with and without diabetes.
- Dapagliflozin and empagliflozin reduced cardiovascular events in patients with heart failure and reduced ejection fraction, with and without diabetes.
- The clinical use of SGLT2 inhibitors now extends beyond controlling hyperglycaemia in people with diabetes, and SGLT2 inhibitors should be prescribed for suitable patients with heart failure and/or CKD.
1. Food and Drug Administration. Draft Guidance. Guidance for Industry. Diabetes mellitus: evaluating the safety of new drugs for glycemic control. Silver Spring, MS: US Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research, 2020. Available from: https://www.fda.gov/media/135936/download
2. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. London: EMA, 2012. Available from: https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf [last accessed 13th January 2021]
3. Zinman B, Wanner C, Lachin JM, et al. for the EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. https://doi.org/10.1056/NEJMoa1504720
4. Wanner C, Inzucchi SE, Lachin JM, et al. for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34. https://doi.org/10.1056/NEJMoa1515920
5. Neal B, Perkovic V, Mahaffey KW, et al. for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57. https://doi.org/10.1056/NEJMoa1611925
6. Wiviott SD, Bonaca MP, Mosenzon O, et al. for the DECLARE-TIMI 58 investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57. https://doi.org/10.1056/NEJMoa1812389
7. Furtado RHM, Bonaca MC, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and previous myocardial infarction. Subanalysis from the DECLARE-TIMI 58 trial. Circulation 2019;139:2516-27. https://doi.org/10.1161/CIRCULATIONAHA.119.039996
8. Mosenson O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of renal disease in patients with type 2 diabetes; an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019;8:606-17. https://doi.org/10.1016/S2213-8587(19)30180-9
9. Cannon CP, Pratley R, Dagogo-Jack S, et al. for the VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425-35. https://www.nejm.org/doi/full/10.1056/NEJMoa2004967
10. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. A meta-analysis. JAMA Cardiol 2020 (published online 7th October 2020). https://doi.org/10.1001/jamacardio.2020.4511
11. Perkovic V, Jardine MJ, Neal B, et al. for the CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306. https://doi.org/10.1056/NEJMoa1811744
12. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. for the DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46. https://doi.org/10.1056/NEJMoa2024816
13. McMurray JJV, Solomon SD, Inzucchi SE, et al. for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. https://doi.org/10.1056/NEJMoa1911303
14. Packer M, Anker SD, Butler J, et al. for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24. https://doi.org/10.1056/NEJMoa2022190
15. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in people with heart failure with reduced ejection fraction: a meta-analysis of the Emperor-Reduced and DAPA-HF trials. Lancet 2020;396:819-29. https://doi.org/10.1016/S0140-6736(20)31824-9
16. Bhatt DL, Szarek M, Pitt B, et al. for the SCORED Investigators. Sotagliflozin in patients with type 2 diabetes and chronic kidney disease. N Engl J Med 2021;384:129–39 https://doi.org/10.1056/NEJMoa2030186
17. Bhatt DL, Szarek M, Steg PG, for the SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28. https://doi.org/10.1056/NEJMoa2030183
18. National Institute for Health and Care Excellence (NICE). Dapagliflozin with insulin for treating type 1 diabetes. Technology appraisal guidance [TA597]. London: NICE, August 2019, updated February 2020. https://www.nice.org.uk/guidance/ta597 [last accessed 13th January 2021].
19. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63:221-8. https://doi.org/10.1007/s00125-019-05039-w
20. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management (update). In development [GID-NG10160] https://www.nice.org.uk/guidance/indevelopment/gid-ng10160 (last accessed 12th January 2021)
21. Heerspink HJL, Perkins BA, Fitchett SH Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation 2016;134:752–7. https://doi.org/10.1161/CIRCULATIONAHA.116.021887
22. Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the treatment of type 2 diabetes. Endocrine Reviews 2011;32:515–31. https://doi.org/10.1210/er.2010-0029
23. Sattar N, Petrie MC, Zinman B, Januzzi JL. Novel diabetes drugs and the cardiovascular specialist. J Am Coll Cardiol 2017;69:2646–56. https://doi.org/10.1016/j.jacc.2017.08.014
24. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2018;41:356–63. https://doi.org/10.2337/dc17-1096
25. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 2020;17:761–72. https://doi.org/10.1038/s41569-020-0406-8
26. Hirschberg B and Katz A. Cardiovascular outcome studies with novel anti diabetes agents: scientific and operational considerations. Diabetes Care 2013;36:S253-S258. https://doi.org/10.2337/dcS13-2041