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Research digest
In Focus
With buses, we often wait for one for a long time, only for two to arrive together; so is the case, it seems, for trials. Following quickly on from the cardiovascular results of the EMPA-REG OUTCOME trial, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial investigators have now reported a 13% lower risk of cardiovascular events in 9340 patients with diabetes and high cardiovascular risk on once daily liraglutide injections compared with placebo over an average follow-up of 3·8 years. Cardiovascular death was unexpectedly lowered by 22%, whereas non-fatal myocardial infarction and stroke were nonsignificantly reduced by about 10%. At first sight, one might wonder why these results contrast with those from the ELIXA trial in which another GLP-1 receptor agonist, lixisenatide, was noninferior to, but also no better than, placebo after acute coronary syndrome in patients with diabetes. Thoughts turn to the different populations studied, the shorter mode of action of lixisenatide, the shorter duration of ELIXA, or perhaps combinations of these elements. Interestingly, nephropathy was also reduced by more than 20% on liraglutide, driven mostly by reduced progression of albuminuria. In terms of safety, liraglutide was reassuringly not associated with any increased risk of pancreatitis (a topic previously hotly debated) nor with more heart failure, although acute gallstone disease was more common on liraglutide, as were nausea and vomiting, as expected. On the plus side, liraglutide recipients experienced a third fewer severe hypoglycaemia events, probably because there was far greater commencement of insulin and sulfonylureas on placebo. Interestingly, this differential uptake of new diabetes treatments seems greater in LEADER than in other recent cardiovascular endpoint trials—the much higher baseline HbA1c is a likely explanation.
Recently published evidence about genetic variants in the GLP-1 receptor also hint at the potential cardiovascular benefit of such treatments. But, as to the potential mechanisms of benefit observed in LEADER, which emerged much more slowly than seen with empagliflozin, these are anyone’s guess. The trial investigators suggested an anti-atherosclerotic benefit, perhaps linked to the combined modest improvements in glycaemic control, weight, and blood pressure reductions. However, the potentially greater benefit of liraglutide on cardiovascular death than on non-fatal cardiovascular events suggests that a direct cardiac or vascular effect of liraglutide and lower rates of hypoglycaemia might be relevant. Time will tell. EMPA-REG OUTCOME was a clinical trial designed to compare the effect of treatment with two different doses of the SGLT2 inhibitor, empagliflozin, with placebo on cardiovascular outcomes in a secondary prevention population with diabetes. Results reported in late 2015 showed that empagliflozin reduced cardiovascular events, most substantially cardiovascular death and hospital admission for heart failure. Current thinking is that this pattern of clinical benefit is linked to an improvement in the disturbed glomerular blood flow that accompanies diabetes, resulting in haemodynamic changes. This intriguing paradigm suggested the possibility that this treatment might also offer renal benefit. However, this view was tempered by concern that early fluid depletion with enhanced urinary glucose loss might prompt acute renal failure in susceptible individuals. The investigators randomly assigned 7020 patients of whom a quarter had baseline estimated glomerular filtration rates (eGFRs) of less than 60 mL/min per 1·73 m² and 40% had microalbuminuria or macroalbuminuria. Newly published results confirm remarkable reductions in renal
www.thelancet.com/diabetes-endocrinology Vol 4 August 2016
outcomes. Empagliflozin treatment led to a 40% reduction in nephropathy over 3·1 years, a benefit that was evident across all subgroups. Although empagliflozin treatment led to an initial drop in eGFR, reflecting modest fluid depletion, this was followed by an unexpected stabilisation of eGFR in contrast to the eGFR of placebo recipients, which fell consistently over time. By the end of the trial, average eGFR was in fact 2–3 mL/min per 1·73m² higher in empagliflozin recipients than in those given placebo. More intriguingly, about a month after all study treatment had been stopped, this difference had become even greater. Few participants progressed to requiring renal replacement therapy during the trial, but these results suggested a 55% reduction on empagliflozin. There was also no excess in either acute renal failure or hyperkalaemia; rather, both were reduced on empagliflozin. We now have evidence of both cardiovascular and renal benefit for two diabetes drugs in two different classes when used in patients with diabetes and cardiovascular disease. Of course, physicians will be keen to see if other drugs in each class will yield similar results and whether similar benefits occur in other populations, and we will not have to wait too long for such data, with several new trials coming rapidly down the line. Over time, and especially if other trials add support, these positive results will influence guideline recommendations regarding the choice of diabetes drugs to be used in combination with metformin initially in the secondary prevention setting. Important considerations for physicians and payers will be the route of administration, the frequency of dosing and, inevitably, cost which currently stands at about £37 per month for empagliflozin and more than three times as much for liraglutide.
Naveed Sattar, David Preiss
Neil Bennet
Research digest
Published Online July 8, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30161-9 For the LEADER trial see N Engl J Med 2016; published online June 13. DOI:10.1056/ NEJMoa1603827 For the EMPA-REG OUTCOME renal results see N Engl J Med 2016; published online June 14. DOI:10.1056/NEJMoa1515920
NS has consulted for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, Janssen, Merck, Sanofi, and Amgen. DP declares no competing interests.
651
With buses, we often wait for one for a long time, only for two to arrive together; so is the case, it seems, for trials. Following quickly on from the cardiovascular results of the EMPA-REG OUTCOME trial, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial investigators have now reported a 13% lower risk of cardiovascular events in 9340 patients with diabetes and high cardiovascular risk on once daily liraglutide injections compared with placebo over an average follow-up of 3·8 years. Cardiovascular death was unexpectedly lowered by 22%, whereas non-fatal myocardial infarction and stroke were nonsignificantly reduced by about 10%. At first sight, one might wonder why these results contrast with those from the ELIXA trial in which another GLP-1 receptor agonist, lixisenatide, was noninferior to, but also no better than, placebo after acute coronary syndrome in patients with diabetes. Thoughts turn to the different populations studied, the shorter mode of action of lixisenatide, the shorter duration of ELIXA, or perhaps combinations of these elements. Interestingly, nephropathy was also reduced by more than 20% on liraglutide, driven mostly by reduced progression of albuminuria. In terms of safety, liraglutide was reassuringly not associated with any increased risk of pancreatitis (a topic previously hotly debated) nor with more heart failure, although acute gallstone disease was more common on liraglutide, as were nausea and vomiting, as expected. On the plus side, liraglutide recipients experienced a third fewer severe hypoglycaemia events, probably because there was far greater commencement of insulin and sulfonylureas on placebo. Interestingly, this differential uptake of new diabetes treatments seems greater in LEADER than in other recent cardiovascular endpoint trials—the much higher baseline HbA1c is a likely explanation.
Recently published evidence about genetic variants in the GLP-1 receptor also hint at the potential cardiovascular benefit of such treatments. But, as to the potential mechanisms of benefit observed in LEADER, which emerged much more slowly than seen with empagliflozin, these are anyone’s guess. The trial investigators suggested an anti-atherosclerotic benefit, perhaps linked to the combined modest improvements in glycaemic control, weight, and blood pressure reductions. However, the potentially greater benefit of liraglutide on cardiovascular death than on non-fatal cardiovascular events suggests that a direct cardiac or vascular effect of liraglutide and lower rates of hypoglycaemia might be relevant. Time will tell. EMPA-REG OUTCOME was a clinical trial designed to compare the effect of treatment with two different doses of the SGLT2 inhibitor, empagliflozin, with placebo on cardiovascular outcomes in a secondary prevention population with diabetes. Results reported in late 2015 showed that empagliflozin reduced cardiovascular events, most substantially cardiovascular death and hospital admission for heart failure. Current thinking is that this pattern of clinical benefit is linked to an improvement in the disturbed glomerular blood flow that accompanies diabetes, resulting in haemodynamic changes. This intriguing paradigm suggested the possibility that this treatment might also offer renal benefit. However, this view was tempered by concern that early fluid depletion with enhanced urinary glucose loss might prompt acute renal failure in susceptible individuals. The investigators randomly assigned 7020 patients of whom a quarter had baseline estimated glomerular filtration rates (eGFRs) of less than 60 mL/min per 1·73 m² and 40% had microalbuminuria or macroalbuminuria. Newly published results confirm remarkable reductions in renal
www.thelancet.com/diabetes-endocrinology Vol 4 August 2016
outcomes. Empagliflozin treatment led to a 40% reduction in nephropathy over 3·1 years, a benefit that was evident across all subgroups. Although empagliflozin treatment led to an initial drop in eGFR, reflecting modest fluid depletion, this was followed by an unexpected stabilisation of eGFR in contrast to the eGFR of placebo recipients, which fell consistently over time. By the end of the trial, average eGFR was in fact 2–3 mL/min per 1·73m² higher in empagliflozin recipients than in those given placebo. More intriguingly, about a month after all study treatment had been stopped, this difference had become even greater. Few participants progressed to requiring renal replacement therapy during the trial, but these results suggested a 55% reduction on empagliflozin. There was also no excess in either acute renal failure or hyperkalaemia; rather, both were reduced on empagliflozin. We now have evidence of both cardiovascular and renal benefit for two diabetes drugs in two different classes when used in patients with diabetes and cardiovascular disease. Of course, physicians will be keen to see if other drugs in each class will yield similar results and whether similar benefits occur in other populations, and we will not have to wait too long for such data, with several new trials coming rapidly down the line. Over time, and especially if other trials add support, these positive results will influence guideline recommendations regarding the choice of diabetes drugs to be used in combination with metformin initially in the secondary prevention setting. Important considerations for physicians and payers will be the route of administration, the frequency of dosing and, inevitably, cost which currently stands at about £37 per month for empagliflozin and more than three times as much for liraglutide.
Naveed Sattar, David Preiss
Neil Bennet
Research digest
Published Online July 8, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30161-9 For the LEADER trial see N Engl J Med 2016; published online June 13. DOI:10.1056/ NEJMoa1603827 For the EMPA-REG OUTCOME renal results see N Engl J Med 2016; published online June 14. DOI:10.1056/NEJMoa1515920
NS has consulted for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, Janssen, Merck, Sanofi, and Amgen. DP declares no competing interests.
651