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The modes of action and clinical implications of several of the newest classes of antidiabetic drugs used as monotherapy and as add-on therapy have been extensively reviewed in recent publications.1 2 Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (eg, empagliflozin) belong to one such novel class and act via interference with proximal renal tubular reabsorption of glucose; about 90% of such reabsorption depends on this cotransporter. They therefore reduce blood glucose concentrations, promote weight reduction and lower blood pressure through glycosuria and osmotic diuresis. Moreover, since their activity is independent of insulin, they are efficacious even in the presence of pancreatic beta cell failure, which is in marked contrast to many other antidiabetic drugs. Furthermore, polyuria and polydipsia are uncommon. Gliptins (eg, saxagliptin) form another new class of oral antidiabetic agents that reduce glucagon secretion but promote insulin release by interfering with the degradation of incretins (intestinal hormones produced in response to ingested meals), and are generally well tolerated. Glucagon-like-peptide 1 (GLP1) receptor agonists (eg, exenatide) are incretin mimetics that constitute yet another class of new antidiabetics and, together with SGLT2 inhibitors, are the only antidiabetic drugs that have a favourable weight loss effect. Subcutaneous administration and gastrointestinal side effects are distinct disadvantages. In contrast to many other antidiabetic agents, treatments with drugs in these three classes and metformin confer a lower risk of hypoglycaemia.
Type 2 diabetes mellitus (T2DM) is more than just a disorder of glucose metabolism. Patients with T2DM die prematurely because of cardiovascular disease and renal failure. The goal of drug treatment of diabetes should therefore be more than just controlling the blood glucose. In the aftermath of the rosiglitazone controversy,3 the United States Food and Drug Administration required new antidiabetic drugs to demonstrate cardiovascular safety. The EMPA-REG OUTCOME trial was therefore conducted on the new SGLT-2 inhibitor empagliflozin,4 to fulfil this requirement.
This was a multicentre, placebo-controlled, randomised, double-blind clinical trial that reported significantly improved mortality and other outcomes in adults with T2DM treated with empagliflozin. Recruited patients had: (1) established cardiovascular disease and (2) glycated haemoglobin levels 7–9% (if on glucose lowering treatment) or 7–10% (if not on hypoglycaemic therapy). Study patients received other treatment for diabetes and cardiovascular risk factors as necessary. The primary endpoint, and to some extent the secondary endpoints, were selected with a view to being able to demonstrate statistically significant benefits. Although the study entailed 10 and 25 mg/day empagliflozin dosage arms, the trial investigators pooled the results as the hazard ratios were so similar.
To appreciate the clinical significance of the benefits of empagliflozin, it is imperative to view them in absolute terms such as number-needed-to-treat (NNT), which is, mathematically, the reciprocal of the absolute risk reduction. As previously described,5 unadjusted relative risk (RR) and NNT values and corresponding 95% CIs for EMPA-REG trial endpoints can be readily calculated. Moreover, recourse to NNT/year values facilitates comparison with absolute benefits from other long-term interventions.
Table 1 shows RR and NNT/year values for fatal and non-fatal outcomes and putative adverse reactions among the 4687 empagliflozin recipients and 2333 placebo-treated patients. NNT/year was calculated using the median follow-up time of 3.1 years rather than the median treatment duration of 2.6 years. Using the latter figure reduces all corresponding values by about 16% (eg, the NNT/year for all-cause-deaths becomes 101), making all absolute benefits (or harms) appear all the more impressive.
The most striking absolute benefit was the reduction in all-cause deaths; respective RR and NNT/year values were 0.69 (95% CI 0.57 to 0.83) and 120 (95% CI 79 to 249). Only hospitalisation for heart failure or cardiovascular death (except fatal stroke) yielded a statistically significantly lower NNT/year of 109. The reduction in all-cause mortality associated with empagliflozin treatment is reassuring, as it indicates that the reduction in cardiovascular deaths was not at the expense of non-cardiovascular deaths.
Remarkably, the NNT/year of 120 for preventing any death was lower than in many other long-term treatment interventions. Thus, in the 4S and CARE statin trials, the respective values were 163 and 639.5 In the LIPID trial and the MRC/BHF Heart Protection Study, moreover, respective 6.1-year and 5-year all-cause mortality NNTs for statin treatment were 33 and 57,6 7 resulting in corresponding NNT/year values of 202 and 286 that also indicate smaller absolute benefits. Furthermore, as around 81% and 95% of the EMPA-REG patients, respectively, were already taking lipid-lowering and antihypertensive drugs, the mortality benefit due to empagliflozin must have been additional. The reduction in all-cause mortality without a significant reduction in non-fatal events (barring hospitalisation for heart failure) was surprising, but could be explained by conversion of some fatal to non-fatal events and prevention of some non-fatal ones, thus resulting in no significant net reduction in the latter.
SGLT2 inhibitors are remarkably safe and well tolerated, although urogenital infections, fluid depletion episodes, hypoglycemic events and others have been reported.1 2 In the EMPA-REG trial, the only significant adverse effect was an increase in genital infections; respective RR and ‘number-needed-to-harm’/year values were 3.57 (95% CI 2.57 to 4.96) and 67 (95% CI 56 to 83). One notable but rarely encountered adverse effect of this drug class is euglycaemic diabetic ketoacidosis, which tends to occur in patients with insulin deficiency. These patients may present with nausea, vomiting, abdominal pain, malaise and hyperventilation but, as their blood glucose is not grossly elevated, the diagnosis could be missed by the unwary. Furthermore, trial patients are highly selected and closely monitored. In the real world, a wider spectrum of individuals gets treated and so more frequent adverse effects should be anticipated.
As to whether the benefits conferred by empagliflozin on cardiovascular outcomes and overall mortality could be a class effect, the available evidence from meta-analyses of phase II and III studies does not fully support this proposition.8 For example, the effect of empagliflozin on relative risk reductions for fatal and non-fatal cardiovascular outcomes is substantially greater than for dapagliflozin and canagliflozin (52% vs 18% and 9%, respectively). However, such differences could be due to differing patient entry criteria into the trials, differences in SGLT receptor subtype selectivity, or potency non-equivalence of the doses being compared. Ongoing trials with SGLT2 inhibitors may indicate what role they could have in patients with type 1 diabetes as well as in those with T2DM taking them with a view to promoting weight loss, preserving renal function and tackling hypertension and heart failure. Compared with the outcome benefits attributed to other relatively new antidiabetic drugs, those reported for empagliflozin appear impressive. Moreover, a pre-specified secondary analysis of EMPA-REG trial patients demonstrated slower progression of renal disease in empagliflozin recipients.9 To date though, no other clinical trials with empagliflozin have reported on hard outcomes. While hard outcome benefits have been reported for treatment with GLP1 receptor agonists compared with placebo in the LEADER and SUSTAIN-6 trials,10 11 in absolute terms their impact on all-cause mortality was much smaller or non-existent; respective unadjusted NNT/year and 95% CI values calculated for death from any cause amount to 264 (145 to 1424) and −1618 (−139 to 168).
The SGLT-2 inhibitors mark a new era in the treatment of T2DM. As a treatment to lower glucose their efficacy is modest, but their ancillary effects include weight reduction, lowering of blood pressure and renal protection. In the EMPA-REG trial at least, all these effects ultimately translated into a clinically significant reduction in mortality, although this has yet to be established for other drugs in this class.
Contributors CRK: Acquired relevant data, undertook its analysis and interpretation of findings; conceived the message for the editorial and produced the first draft; critically revised the manuscript and approved the final version; agrees to be accountable for the contents, including its integrity and accuracy.
KCBT: Provided necessary reference material; critically revised the manuscript and approved the final version; agrees to be accountable for the contents, including its integrity and accuracy.
BMYC: Contributed to the conception of the message; drafted sections of the manuscript and reviewed data interpretation; critically revised the manuscript and approved the final version; agrees to be accountable for the contents, including its integrity and accuracy.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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