This chapter of our EASD report focuses on oral agents, which were often discussed in the context of combination therapy at EASD 2016. Conference planners saved some of the best for last, with full results from DURATION-8 for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) in combination with once-weekly GLP-1 agonist Bydureon (exenatide) presented at the very last session of the meeting. We were also excited to hear full results from the VERTIS SITA2 trial for Merck’s ertugliflozin in combination with metformin and with DPP-4 inhibitor Januvia (sitagliptin). There was no shortage of conversation on EMPA-REG OUTCOME (given that the landmark CVOT was first-presented at EASD 2015 in Stockholm) – the highly-esteemed Drs. Bernard Zinman, David Fitchett, Christoph Wanner, Hertzel Gerstein, Silvio Inzucchi, and David Cherney all had something to say about SGLT-2 inhibitors and their cardio- and renal protective effects. We’ve captured all of this and more in our conference report dedicated to oral diabetes drugs.
Talk titles highlighted in yellow were some of our favorites from the meeting, reflecting what we found to be most notable. Talk titles highlighted in blue are new full report additions, and were not part of our daily highlights coverage during the conference.
Future and Impact of Cardiovascular Outcomes Trials
- Following an exciting year of positive cardiovascular outcomes trial (CVOT) results, much discussion centered on how they should affect drug labeling, regulatory processes, and clinical practice. We heard opinions from numerous esteemed experts on what needs to happen in order for EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 data to realize its real-world implications. Dr. Juris Meier (Ruhr University of Bochum, Germany) pushed for multi-agent CVOTs and head-to-head comparisons of newer drugs with relatively older agents. Data showing the relative CV benefits of different available diabetes drugs would be tremendously valuable for high-risk patients, he argued, and would give CVOT findings more direct purpose in clinical decision-making. Dr. Meier also advocated for a greater emphasis on primary CV prevention. Participants in published CVOTs have largely been very high-risk (understandably, as this helps a trial reach the necessary number of CV events for a sufficiently small confidence interval in a shorter amount of time), but enrolling lower-risk participants will be important for the future of CVOTs, Dr. Meier explained, noting that AZ’s DECLARE (for SGLT-2 inhibitor dapagliflozin) and EXSCEL (for GLP-1 agonist exenatide) will each include a cohort of patients without prior CV history. In his view (and ours), positive results on primary CV prevention could be a major win in two ways: (i) by promoting greater utilization of these agents across a much wider spectrum of the diabetes patient population, and (ii) by providing even more compelling evidence for cardioprotection in a broader population. Maybe this is what we need to get positive CV data on drug labels. We see expanding CVOTs into primary prevention as a worthwhile goal, although we acknowledge the associated cost would be enormous.
EMPA-REG OUTCOME: One Year Later
- We heard much discussion on the potential mechanism of cardioprotection seen in EMPA-REG OUTCOME, one-year after the groundbreaking CVOT was presented at EASD 2015. Dr. Silvio Inzucchi (Yale University, New Haven, CT) – who also presented the cardiovascular outcomes from the study at last year’s meeting – admitted that the initial thinking on why empagliflozin might offer CV benefit was off-base. “With a great deal of modesty, we had it all wrong.” The early divergence of the Kaplan-Meier curves suggests that the SGLT-2 inhibitor works not by an overarching atherosclerotic effect (which is more likely for GLP-1 agonist liraglutide based on LEADER data), but rather by some other mechanism. Dr. Bernard Zinman (University of Toronto, Canada) later presented a univariate mediation analysis of EMPA-REG OUTCOME (first presented at ADA 2016), which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit is independent of glycemic effects. Dr. Zinman shared that a multivariate analysis, which will prove more accurate in illuminating mechanism, is underway – we’re glad to see this hypothesis-generating work underway, though we recognize it may be quite a while before we have a consensus mechanism for the cardioprotective benefit.
- On the other hand, many speakers wondered aloud: how crucial is it that we understand mechanism? Several speakers felt that while it’s interesting and important to investigate the mechanism, it’s not so crucial that we must wait for a definitive answer before affecting clinical practice or adding positive CV results to drug labels for Lilly/BI’s Jardiance (empagliflozin) or Novo Nordisk’s Victoza (liraglutide). Dr. Inzucchi urged the committee charged with authoring the next iteration of the ADA/EASD diabetes treatment guidelines to consider EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6, and even IRIS (for the TZD pioglitazone), despite lingering mechanism questions. Having data from EMPA-REG OUTCOME and LEADER readily available on the label for these drugs would be hugely helpful for patients and HCPs, and so we agree wholeheartedly with what these renowned thought leaders had to say:
- “A stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.” – Dr. Hertzel Gerstein
- “One excuse at the Jardiance Advisory Committee was ‘we’re not quite sure about the mechanism’ – who cares?! While I applaud conservatism, it’s time to take action.” – Dr. Neil Poulter
- “At a certain point it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.” – Dr. Juris Meier
Renal Outcomes in CVOTs
- We noticed growing interest in renal complications of diabetes at this year’s EASD, as highlighted by encouraging renal outcomes results from the SUSTAIN-6 trial and a new sub-analysis of the LEADER trial. In SUSTAIN-6, renal complications appeared at a rate of 3.6% in the semaglutide group (59 events) vs. 6.0% in the placebo group (99 events), an impressive 36% risk reduction. The renal benefit was driven primarily by a difference in the diagnosis of persistent macroalbuminuria, which occurred at a rate of 2.5% in the semaglutide group, versus 4.9% with placebo. This parallels the 22% risk reduction in renal complications reported in the LEADER trial (HR=0.88; 95% CI: 0.67-0.92, p=0.003), which were driven by a 26% reduction in the onset of persistent macroalbuminuria (HR=0.74, 95% CI: 0.60-0.91) and a 19% reduction in urinary albumin-creatinine ratio, a measure of microalbuminuria (HR=0.31, 95% CI: 0.76-0.86). Two new findings from the ongoing subgroup analysis of the LEADER trial’s renal data further revealed that: (1) Among participants with kidney disease (eGFR <60 ml/min/1.73 m2) there was a 22% reduction in time to first renal event (HR: 0.78; 95% CI: 0.56-1.09); (2) Among participants with severe kidney disease (30-60 ml/min/1.73 m2) or end-stage renal disease there was a 27% reduction in time to next additional composite renal outcome (HR: 0.73; 95% CI: 0.50-1.07). These two findings provide the intriguing suggestion that liraglutide’s renal benefits may be particularly applicable to patients already experiencing renal disease.
- Renal complications are among the costliest of diabetes complications, so it is very encouraging to see evidence of renal-protective effects in not one but two members of the GLP-1 agonist class. As of now it remains unclear whether these renal benefits are due to improvements in glucose control and blood pressure or are instead the product of a direct effect of semaglutide on the kidney. We will be awaiting further dissection of these renal findings, and perhaps even a dedicated chronic kidney disease trial for liraglutide and semaglutide. We were also impressed by the renal outcomes from EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), first presented at ADA 2016. We’re hopeful that improvements in our understanding of the renal impact of diabetes drugs can direct patients with diabetic nephropathy to treatment options most likely to help address this area of high unmet need.
- Several talks at EASD discussed the use of multiple diabetes therapies in combination, with a particular spotlight on dual therapy with GLP-1 agonists and SGLT-2 inhibitors – assessed for the first time in the DURATION-8 trial. Results from the DURATION-8 trial showed improved glycemic control and cardiovascular risk factors with dual therapy consisting of AZ’s once-weekly GLP-1 agonist Bydureon (exenatide) and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either drug as monotherapy. After 28 weeks, patients (n=695) in all three arms of the study – exenatide and dapagliflozin, exenatide alone, and dapagliflozin alone – experienced impressive reductions in A1c: -2.0% (95% CI: -2.1 to -1.8), –1.6% (-1.8 to -1.4), and -1.4% (-1.6 to -1.2) respectively (baseline A1c=9.3%). However, the exenatide/dapagliflozin dual therapy reduced baseline A1c to a significantly greater extent than either monotherapy: a -0.4% improvement versus exenatide (95% CI: -0.6 to -0.1; p=0.004) and a -0.6% improvement versus dapagliflozin (95% CI: -0.8 to -0.3; p<0.001). Furthermore, exenatide/dapagliflozin dual therapy demonstrated superiority to either monotherapies for all secondary endpoints, including fasting plasma glucose, postprandial glucose, systolic blood pressure, and weight loss.
Fixed-Dose and Fixed-Ratio Combinations
- Interest in fixed-ratio and fixed-dose combinations ran high at this year’s EASD, as in previous years. We heard several oral presentations focused on GLP-1 agonist/basal insulin or SGLT-2 inhibitor/DPP-4 inhibitor products for type 2 diabetes, with speakers consistently emphasizing improvements in composite endpoints (A1c reduction with weight loss and no hypoglycemia, for example) as an advantage of combination therapy, driving home the point that a fixed-dose of two agents can often do more than one agent alone. As Dr. Timothy Bailey (UCSD, San Diego, CA) articulated in a presentation on the LIRA-SWITCH trial, composite endpoints are “most meaningful to patients.” Real-world patients want – and deserve – a drug that goes beyond A1c-lowering in its efficacy; patients care about weight loss, blood pressure, avoiding hypoglycemia, and quality of life. Dr. Vanita Aroda (Medstar Health Research Institute, Washington, DC) also highlighted composite endpoints in her discussion of a LixiLan-L post-hoc analysis, positioning Sanofi’s iGlarLixi (lixisenatide/insulin glargine) as a GLP-1 agonist/basal insulin product that can get type 2 diabetes patients to A1c goal without causing weight gain or hypoglycemia. In a presentation of the full results from Merck’s VERTIS SITA2 trial, Dr. Brett Lauring (Merck, Kenilworth, NJ) showed how SGLT-2 inhibitor ertugliflozin added-on to DPP-4 inhibitor Januvia (sitagliptin) and metformin yields significant improvements in glycemic control (the primary endpoint) but also significant and clinically meaningful improvements on secondary endpoints such as weight loss, fasting plasma glucose, and systolic blood pressure. We were very happy to see this recognition of composite and secondary outcomes beyond A1c, as we continue to push for drug developers, healthcare providers, clinical trialists, and regulators to consider metrics that matter most to patients in their daily lives. (This was the takeaway from a recent FDA workshop on outcomes beyond A1c, and notably, we also heard much conversation on the limitations of A1c at ADA 2016.)
- New data from the VERTIS program for Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin renewed interest in SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combinations. Dr. Brett Lauring (Merck, Kenilworth, NJ) presented full results from VERTIS SITA2, demonstrating that treatment with ertugliflozin in patients on a background of sitagliptin (Merck’s Januvia) and metformin led to significantly greater A1c reductions (0.8% with a 5 mg dose and 0.9% with a 15 mg dose) vs. placebo (p<0.001). In addition, 32% of patients on 5 mg ertugliflozin reached an A1c target <7% in 26 weeks, compared to an even higher 40% of the 15 mg group and only 17% of the placebo group (p<0.001 for both doses based on adjusted odds ratio). Importantly, ertugliflozin add-on therapy also caused significantly greater weight loss, reductions in fasting plasma glucose, and reductions in systolic blood pressure vs. placebo. Results from the VERTIS FACTORIAL study were presented on a poster: In patients on metformin, a 15 mg dose of ertugliflozin alongside a 100 mg dose of sitagliptin caused a mean 1.5% A1c reduction at 26 weeks vs. 1.1% for 100 mg sitagliptin alone and 1.1% for 15 mg ertugliflozin alone (p<0.001 for both comparisons). Fasting blood glucose, proportion of patients reaching target A1c, and body weight all trended in the same direction and achieved statistical significance as well, supporting the efficacy of an ertugliflozin/sitagliptin fixed-dose combination. Indeed, a Merck press release issued when Dr. Lauring’s presentation began announced that the company will submit fixed-dose ertugliflozin/sitagliptin and ertugliflozin/metformin to the FDA. We’d certainly be excited about another SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combination on the market, as data continues to underscore the therapeutic potency of this particular combo. As of now, the only such fixed-dose combination available in the US is Lilly/BI’s Glyxambi (empagliflozin/linagliptin), while AZ’s Qtern (dapagliflozin/saxagliptin) is approved in Europe. That said, we haven’t seen widespread adoption of these particular combinations as of yet, largely due to cost and access concerns – we hope that positive composite endpoint data from these trials may help convince payers of the value of these combinations.
Detailed Discussion and Commentary
Oral Presentations: SGLT-2 Inhibitor Trials
Efficacy and Safety of Ertugliflozin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on the Dual Combination of Metformin and Sitagliptin: The VERTIS SITA2 Trial
Brett Lauring (Merck, Kenilworth, NJ)
Dr. Brett Lauring presented findings from the phase 3 VERTIS SITA2 trial demonstrating significant A1c reductions for Merck’s SGLT-2 inhibitor candidate ertugliflozin as an add-on to DPP-4 inhibitor Januvia (sitagliptin) and metformin in patients with type 2 diabetes (n=463). A 5 mg dose of ertugliflozin lowered A1c by a mean 0.8% after 26 weeks, while a 15 mg dose lowered A1c by 0.9% (baseline A1c=8%, p=0.001 for both vs. placebo). For comparison, the placebo group experienced a substantially smaller 0.1% A1c reduction. The between-group difference in glucose-lowering was apparent at six weeks and increased through the end of the 26-week study period. Among patients treated with 5 mg ertugliflozin, 32% achieved A1c <7% vs. 17% in the placebo group (p<0.001 for both doses based on adjusted odds ratio). An even higher 40% of patients in the 15 mg ertugliflozin group achieved this A1c target (p<0.001). Ertugliflozin treatment added to sitagliptin and metformin also demonstrated a significant improvement on a number of secondary endpoints, namely (i) weight loss; (ii) reductions in fasting plasma glucose; and (iii) reductions in systolic blood pressure. Weight loss amounted to an average of 3.3 kg (~7.3 lbs) in the 5 mg arm (p<0.001) and 3 kg (~6.6 lbs) in the 15 mg arm (p<0.001), compared to 1.3 kg (~2.9 lbs) in the placebo arm. Fasting plasma glucose was 25 mg/dl lower after 26 weeks in the 5 mg ertugliflozin group and 31 mg/dl lower in the 15 mg group compared to placebo (p<0.001 for both). There was a 4 mmHg drop in systolic blood pressure, on average, for patients given a 5 mg dose of ertugliflozin vs. a 1 mmHg drop for patients on placebo (p=0.019). Patient taking the 15 mg dose experienced a mean 5 mmHg decline in systolic blood pressure (p=0.002).
- Dr. Lauring noted that the higher dose trended better on most primary and secondary outcome measures. The exception was weight loss, which was similar for both doses.
- Ertugliflozin was well-tolerated, showing no increased risk of urinary tract infections (4, 7, and 3 subjects in the 5 mg, 15 mg, and placebo groups, respectively), symptomatic hypoglycemia (6, 1, and 4 subjects in the 5 mg, 15 mg, and placebo groups, respectively), or hypovolemia (1, 0, and 1 subjects in the 5 mg, 15 mg, and placebo groups, respectively). As expected, the incidence of genital mycotic infections was higher in both males and females and the differences from placebo were statistically significantly different (p<0.05) for the 5 mg dose for males and the 15 mg dose for females (6, 9, and 1 subjects in 5 mg, 15 mg and placebo for females and 4, 3, and 0 subjects in 5 mg, 15 mg and placebo for males). All four of these adverse events types were pre-specified for further analysis in VERTIS SITA2, according to Dr. Lauring, because of concerns related to SGLT-2 inhibitor agents more generally.
- According to an announcement released as soon as Dr. Lauring’s presentation began, Merck and partner Pfizer will submit NDAs for standalone ertugliflozin, ertugliflozin/sitagliptin and ertugliflozin/metformin by the end of 2016. Further regulatory submissions in international markets are expected in 2017.
- In an interview with Dr. Sam Engel (Merck, Kenilworth, NJ), Associate VP of clinical research in diabetes and endocrinology, we learned that Merck views ertugliflozin as part of a larger strategy of developing diabetes therapies that patients can use at any point during the course of their care. In other words, the people who could benefit from ertugliflozin and its combinations would span a wide spectrum encompassing patients regardless of diabetes duration, whether newly-diagnosed as a first-line therapy or already a few decades into diabetes management in need of therapy intensification. On a similar theme, Dr. Lauring argued during Q&A following his presentation that bringing a fourth SGLT-2 inhibitor to market would benefit patients by expanding choice. Ertugliflozin would join Lilly/BI’s Jardiance (empagliflozin), Janssen’s Invokana (canagliflozin), and AZ’s Farxiga (dapagliflozin).
- Dr. Lauring shared enthusiasm for the therapeutic potential of a SGLT-2 inhibitor/DPP-4 inhibitor combination product. Right now, the only such fixed-dose combination available in the US is Lilly/BI’s Glyxambi (empagliflozin/linagliptin), while AZ’s Qtern (dapagliflozin/saxagliptin) was recently approved in Europe. We expect the very neutral CV safety results for the sitagliptin component of the ertugliflozin/sitagliptin combination will be reassuring for many providers, though we expect much of the buzz for SGLT-2 inhibitors will continue to center around the empagliflozin franchise, at least until further CVOTs are able to confirm a cardiovascular class effect.
Questions and Answers
Q: We already have three SGLT-2 inhibitors, so was there a reason why you embarked on producing a fourth? Do we expect anything better here?
A: With more agents on the market, there are always better choices for patients. As in other drug classes, differentiation among agents emerges over time. We’re running a large CVOT program within this program, so we’ll have to wait and see. With our emerging profile for ertugliflozin, we’re very happy with what seems like a comparable efficacy profile. Plus, development of a fixed-dose combination with sitagliptin might be an attractive option for many patients.
Q: I see there was a small drop in eGFR noted, which is fairly typical. Were there any patients who reached criteria for acute kidney injury?
A: Using laboratory tests, we found one subject with a substantial drop in eGFR, and I think that was in the placebo arm. No, we didn’t see any adverse kidney injuries resulting in hospitalization, or anything like that.
Q: Did any patients develop DKA?
A: We did not observe any acute cases of ketoacidosis in this trial, but I’ll remind you that it was a six-month study with ~500 patients. For ethical purposes, we did provide rescue therapy. Over the course of 26 weeks, ~16% of participants in the placebo arm received rescue therapy, and this percentage was much lower in the treatment arms.
Q: Looking more closely at the genital infection rates – here, the rates seem relatively low (~10%) compared to the VERTIS MONO trial (~20%). Do we have evidence to suggest that a SGLT-2/DPP-4 combo may be less aversive in this regard than an SGLT-2 inhibitor alone?
A: Yes, there was a higher incidence of genital mycotic infections in VERTIS MONO (which, for anyone who is curious, is abstract 727 at this meeting). The patient populations of these two studies were very similar, and we used the same definition. So we think it was just normal variation. In VERTIS MONO, we saw greater rates in both groups – treatment and placebo. My personal opinion is that this is just random variability from trial to trial.
Oral Presentations: SGLT-2 Inhibitors: Metabolic Effects
canagliflozin Slows Progression of Renal Function Decline Independent of Glycemic Effects
Hiddo Heerspink, MD (University Medical Center Groningen, the Netherlands)
Dr. Hiddo Heerspink (University Medical Center Groningen, Groningen, the Netherlands) presented a compelling new post-hoc analysis of CANTATA-SU to support a glucose-independent, renal-protective benefit for the SGLT-2 inhibitor canagliflozin (Janssen’s Invokana). The analysis was published recently in the Journal of the American Society of Nephrology. CANTATA-SU was a phase 3, double-blind, head-to-head study of canagliflozin (100 or 300 mg/day) vs. sulfonylurea glimepiride (titrated to 6-8 mg/day) over 24 months in patients with type 2 diabetes (n=1,450) on metformin monotherapy. In the post-hoc analysis, eGFR declines throughout the trial were smaller with both doses of canagliflozin compared to glimepiride (declining 0.5 ml/min in the canagliflozin 100 mg group [p=0.01] and 0.9 ml/min in the canagliflozin 300 mg group [p=0.01], compared to a 3.3 ml/min reduction in the glimepiride group. The results suggest that canagliflozin, compared with glimepiride, slows the progression of renal disease in type 2 diabetes patients over two years. Canagliflozin furthermore produced reductions in urinary albumin:creatinine ratio (UACR) compared to glimepiride (5.7% reduction with the 100 mg dose and 11.2% reduction with the 300 mg dose, p=0.01). This was especially pronounced in the subgroup of patients with baseline UACR above 30 mg/g, who experienced a 31.7% (p=0.01) decline in this ratio with canagliflozin 100 mg and a 49.3% (p=0.01) decline in this ratio on the 300 mg canagliflozin dose compared to glimepiride treatment. Further post-hoc analysis revealed that the treatment effect of canagliflozin on albuminuria persisted even after statistically controlling for the differences in A1c reduction, systolic blood pressure, body weight, or the combined changes in all three of these factors between the canagliflozin and glimepiride arms. This suggests that canagliflozin’s effect on albuminuria occurs independently of its glycemic effects – wow! We’re intrigued by the suggestion of renal-protection for canagliflozin demonstrated by these analyses and our curiosity is piqued regarding the mechanism by which SGLT-2 inhibitors achieve this renal-protective effect. Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) recently demonstrated impressive renal-protective benefits in EMPA-REG OUTCOME and we’re certainly looking forward to more renal outcomes data from other products in the class – as well as for GLP-1 compounds. Diabetic nephropathy is an extremely costly complication of diabetes, both in human and economic terms, and the availability of glucose-lowering drugs with additional renal-protective benefits is a major win for patients. We look forward to hearing more on renal impact of diabetes drugs in the coming days at EASD.
- An astute comment during the ensuing Q&A session pointed out that this study lacks a sufficient control group. Thus it is impossible to tell whether the renal benefits of canagliflozin over glimiperide are due to canagliflozin being beneficial or glimiperide being harmful. To resolve this issue, we would love to see similarly-designed trials in the future that includes a third, placebo-controlled arm. Also, just in general, we’d love to see SFUs used in more outcomes trials. Though it may make more patients not want to participate in the trials, we think that more data is needed to show the negativity of SFUs – so many patients are forced to be on SFUs still and there is not enough data for patient advocates to try to push back for these patients. For some group of course, lower-dose SFUs may be fine, but we think the combination of weight gain and hypoglycemia and fracture risk and beta cell burnout is quite negative for most.
- The CREDENCE trial is underway to assess the effects of canagliflozin (100 mg/day) on renal endpoints in patients with diabetic kidney disease. With nearly 4,000 subjects enrolled, Dr. Heerspink explained that the CREDENCE trial will be powered to definitively show whether canagliflozin has renal-protective effects. According to ClinicalTrials.gov, this trial is estimated to complete in January 2020.
Effect of Empagliflozin (EMPA) on Bone Fractures and DKA in Patients with Type 2 Diabetes
Stefan Kaspers, MD (Boehringer Ingelheim, Germany)
In a completely packed, at-capacity session, Dr. Stefan Kaspers presented results from two meta-analyses examining the impact of treatment with Lilly/BI’s Jardiance (empagliflozin) on diabetic ketoacidosis (DKA) and bone fracture rates across the body of clinical trial data available. The results were very reassuring overall, demonstrating no clear association between empagliflozin and increased DKA or bone fracture event rates in a clinical trial setting. The completely packed, large presentation room and the audience’s rapt attention is a testament to both the interest in the SGLT-2 inhibitor class and the concerns many providers have about the relationship between SGLT-2 inhibitors and these two adverse events. We expect these reassuring results, coupled with the compelling EMPA-REG OUTCOME data demonstrating potential cardioprotective and renal-protective benefits for empagliflozin, might lead to some providers and patients preferring empagliflozin over other SGLT-2 inhibitors in the class (though, of course, many prescribing decisions today are too often dictated by reimbursement and access as well).
- The DKA meta-analysis found DKA event rates were very low and balanced between empagliflozin-treated and comparator groups, though increased urinary ketones was more common among participants treated with empagliflozin. The analysis was conducted with data from 18 randomized phase 1-3 clinical trials for empagliflozin (including the EMPA-REG OUTCOME cardiovascular outcomes trial) and from six extension studies. The analysis was based on investigator-reported outcomes and included a total of 15,677 patients. In total, the analysis included over 19,000 patient-years of exposure to empagliflozin. The DKA meta-analysis found only 12 cases of DKA in all of the clinical trials combined: 5 events among participants treated with the 10 mg dose of empagliflozin, 2 events among those treated with 25 mg of empagliflozin, and 5 events among those in the comparator groups. The event rate of each of these groups per 100 patient-years was 0.06, 0.02, and 0.05, respectively. 10 of these DKA events were classified as serious, 5 in those treated with 10 mg empagliflozin, 1 in those treated with 25 mg empagliflozin, and 4 in those treated by comparators (events rates were 0.06, 0.01, and 0.04 per 100 patient-years, respectively). Of the seven participants who experienced a DKA event while on empagliflozin, only two discontinued the study drug (none of the five participants who experienced a DKA events on placebo discontinued). The meta-analysis also showed that, based on regular urinary ketone tests from these trials, the vast majority of patients either never experienced a positive ketone test (76% of patients in empagliflozin-treated arms and 82% in comparator arms) or never experienced higher than trace levels of ketones (14%-15% of those in the empagliflozin-treated arms and 14% in the comparator arms. That said, a greater proportion of participants treated with empagliflozin experienced elevated urinary ketones across the studies than those in comparator arms (10% in the empagliflozin-treated arms compared to 4% in the comparator arms).
- The bone fracture meta-analysis found that the proportion of patients experiencing bone fractures was comparable between empagliflozin-treated groups and comparators overall and in all age, gender, and eGFR subgroups. The bone fracture meta-analysis was conducted with data from 15 placebo-controlled phase 1-3 clinical trials and four extension studies – one trial, the EMPA-REG H2H-SU head-to-head study of empagliflozin vs. sulfonylurea glimepiride, was discussed separately. The main meta-analysis was based on investigator-reported outcomes and included a total of 12,620 patients. The overall bone fracture event rate per 100 patient-years was 1.55, 1.36, and 1.69 with empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively (absolute event rates were 2.8%, 2.5%, and 2.9%, respectively). The event rate per 100 patient-years and the absolute rate were similarly comparable across empagliflozin and placebo groups for serious bone fractures (0.38 [0.7%] with empagliflozin 10 mg, 0.47 [0.9%] with empagliflozin 25 mg, and 0.59 [1%] with placebo). For bone fractures leading to discontinuation, the rate per 100 patient-years and absolute rate remained comparable and were even lower across the board (0.08 [0.1%] with empagliflozin 10 mg, 0.10 [0.2%] with empagliflozin 25 mg, and 0.23 [0.4%] with placebo). Bone fractures were similarly comparable regardless of type (upper limb, lower limb, thoracic cage, spinal, skull and facial, pelvic, or other). The subgroup analyses found that bone fractures were more frequent in both empagliflozin and placebo arms among females, increasingly older patients, and those with decreasing renal function. Dr. Kaspers emphasized that within these subgroups of increased risk, bone fracture rates among empagliflozin-treated participants were comparable to rates among the placebo groups. Dr. Kaspers also pointed out that there were no changes in calcium or phosphate levels with empagliflozin or placebo and no notable differences in changes in other bone markers between empagliflozin and placebo groups. Analysis of bone fracture rates in EMPA-REG H2H-SU found similar results regarding the comparability of bone fracture rates between the empagliflozin and glimepiride groups. Furthermore, EMPA-REG H2H-SU included measures of bone mineral density from femoral neck and lumbar spine DXA scans after 52, 104, 156, and 208 weeks of treatment. The results demonstrated that bone mineral density remained stable throughout the four years of empagliflozin treatment and were comparable between those treated with empagliflozin and those treated with glimepiride. We’re certainly glad that the potential relationship between SGLT-2 inhibitors and bone fracture risk does not appear to be a class effect – where it has been seen to date may have been spurious correlation and we look forward to more data all around. As a reminder, the FDA strengthened the label warning on bone fracture risk with J&J’s Invokana (canagliflozin) last year.
Metabolic Mechanisms of Increased Plasma Ketones with Dapagliflozin
Carolina Solis-Herrera, MD (Texas Tech University Health Sciences Center, San Antonio, TX)
Dr. Carolina Solis-Herrera delivered a fascinating presentation on the molecular mechanisms underlying the action of the SGLT-2 inhibitor dapagliflozin. In a randomized, double-blind, placebo controlled trial, participants were randomized to 10 mg/day dapagliflozin or matching placebo. At baseline and at the culmination of the 14-day treatment period, participants underwent a euglycemic clamp procedure and indirect calorimetry tests. Fourteen days of treatment with dapagliflozin caused: (i) a shift from glucose oxidation to lipid oxidation; and (ii) an increase in the plasma glucagon to insulin ratio, increasing hepatic glucose production, and (iii) an increase in urinary glucose excretion thereby decreasing plasma glucose. Dr. Solis-Herrera contextualized these findings, explaining that a shift from glucose to fat oxidation increases the product of fatty acid oxidation, acetyl CoA, which either can enter the TCA cycle or be converted to ketones, the latter being favored by the SGLT2 inhibitor induced stimulation of glucagon secretion. Moreover, the increased glucagon insulin ratio will downregulate the enzyme Acetyl CoA Carboxylase resulting in a decreased conversion from acetyl CoA to malonyl CoA. Malonyl coA is the downregulator of CTP1 (carnitine palmitoyltransferase), the enzyme that allows acetylCoA to enter the mitochondria and start beta oxidation. When malonyl CoA is low, the activity of CPT1 increases and this will increase beta oxidation and ketogenesis. The downstream consequence of these SGLT-2 inhibitor-mediated changes is increased ketogenesis – a process that, paradoxically, is harmful for precipitating DKA, but potentially beneficial in cardiovascular terms. Ketogenesis seems to increase cardiac efficiency and reduces oxygen consumption and oxidative stress; Dr. Solis-Herrera argued that these effects are potentially the driving force underlying the cardiovascular benefits seen with a different SGLT-2 inhibitor, empagliflozin, in the EMPA-REG OUTCOME trial. This is largely the thrust of Dr. Ele Ferrannini’s “thrifty substrate” hypothesis regarding the mechanism of empagliflozin’s cardioprotective benefit, which was presented at ADA 2016 and published in Diabetes Care. While this hypothesis is clearly very speculative at this point, the replication of this potential mechanism and pathway with dapagliflozin lends tentative support to the notion that the cardioprotection might be a class effect. Dr. Solis-Herrera’s overarching message was the importance of appreciating the complexity of dapagliflozin’s ketogenesis-promoting mechanism; future work with SGLT-2 inhibitors should carefully weigh the costs and benefits of ketogenesis-associated cardioprotection and DKA.
Questions and Answers:
Q: You said that SGLT-2 inhibitors may improve beta cell function. Is this via the ketogenesis mechanism, or does dapagliflozin have an independent beneficial effect on the beta cell?
A: We do not know if it is a direct effect on the beta cell.
Q: There might be differences in the propensity to develop DKA between the different SGLT-2 inhibitors. Do you think this may have to do with the different effects on lipid and glucose oxidation?
A: We believe our findings regarding lipid and glucose metabolism represent a class effect. Different does with different drugs may produce a more marked effect, but it is nevertheless a something that we expect to see in all SGLT-2 inhibitors.
Q: Do you have any information as to the onset of these metabolic shifts, and whether they continue at the same level? Is there change or accommodation over time to different substrate availability?
A: We have noticed that there is an acute effect immediately upon drug exposure and it persists for the first 48 hours.
Q: We have learned that DKA incidence is low in well-controlled studies. It seems probable that many patients are getting SGLT-2 inhibitors who shouldn’t be.
A: I think we need to learn more about these drugs to assess this. It is hard to say if they will be approved for type 1 diabetes.
Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function
David Sjöström, MD, PhD (AstraZeneca, Göteborg, Sweden)
Dr. David Sjöström (AstraZeneca, Gothenburg, Sweden) presented the results of a meta-analysis examining whether the effects of dapagliflozin vary in patients with varying eGFR levels, given a 2014 study suggesting that dapagliflozin’s A1c lowering efficacy is attenuated in patients with low eGFR (≥30-59 ml/min/1.73 m2). The pooled analysis, which included 11 phase 3 trials (n=4404), found that treatment with dapagliflozin 10 mg for 24 weeks consistently reduced body weight, systolic blood pressure, pulse pressure, and urine albumin to creatinine ratio (UACR) – regardless of baseline eGFR. According to Dr. Sjöström, the presence of these eGFR-independent effects offers the fascinating suggestion that dapagliflozin’s mechanisms of action is mediated in part by processes independent of urinary excretion of glucose. He hypothesized that one such mechanism may be reduction of sodium reabsorption in the proximal tubule of the nephron, since this process commonly occurs due to dampened action of the NHE3, a protein co-localized with the SGLT-2 protein and thus likely impinged upon by SGLT-2 inhibiting agents like dapagliflozin.
Symposium: Combination Treatment with SGLT-2 Inhibitors/GLP-1 Receptor Agonists
DURATION-8 Study: dapagliflozin and Exenatide QW Combinaton
Cristian Guja, MD (University of Medicine and Pharmacy, National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania)
Dr. Cristian Guja (University of Medicine and Pharmacy, Bucharest, Romania) presented the results of the DURATION-8 trial demonstrating improvement of glycemic control and of some cardiovascular risk factors with dual therapy consisting of AZ’s once-weekly GLP-1 agonist Bydureon (exenatide) and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either drug as monotherapy. After 28 weeks, patients (n=695) in all three arms of the study – exenatide and dapagliflozin, exenatide alone, and dapagliflozin alone – experienced impressive reductions in A1c: -2.0% (95% CI: -2.1 to -1.8), –1.6% (-1.8 to -1.4), and -1.4% (-1.6 to -1.2) respectively, from a baseline A1c of 9.3%. Interestingly, Dr. Guja noted that the trial enrolled participants with a baseline A1c of 8%-12% to minimize the risk of potential hypoglycemia if the trial enrolled participants with a lower A1c. The A1c reduction of 1.4% in the standalone dapagliflozin arm is certainly very robust for an SGLT-2 inhibitor, which is undoubtedly at least partly attributable to the high baseline A1c. That said, the exenatide/dapagliflozin dual therapy reduced still produced a significantly greater A1c reduction than either monotherapy: a -0.4% improvement versus exenatide (95% CI: -0.6 to -0.1; p=0.004) and a -0.6% improvement versus dapagliflozin (95% CI: -0.8 to -0.3; p<0.001). Given the potential for additive CV risk reduction stemming from both classes (this still has to be proven, of course), the positives in taking the two compounds together may be even larger. Although no labels have yet been updated in the US concerning cardiovascular or renal risk reduction, we imagine this is a “when” not “if” and the number of trials to happen in combinations in the coming years should provide great learning and excitement for now to improve public health. The full results from the trial were simultaneously published in The Lancet Diabetes and Endocrinology.
- In a conversation with AZ’s VP of Global Medicines Development, Dr. Elisabeth Bjork, we learned more about the additive effects of Bydureon and Farxiga on A1c. Namely, Dr. Bjork articulated how diabetes drugs are mostly baseline-dependent – as one product in this combination improves a patient’s glycemic control, the second will have a marginally smaller impact on A1c, although the essential takeaway is that exenatide and dapagliflozin in combination achieved superior A1c reductions vs. either agent alone. Dr. Bjork also remarked that there is interesting potential for the additive cardioprotective effects of Bydureon and Farxiga, especially since the dominant thought is that SGLT-2 inhibitors and GLP-1 agonists operate through distinct mechanisms of action when it comes to cardioprotection. There’s no CVOT in the works for this combination per se, although EXCEL (for exenatide) and DECLARE (for dapagliflozin) are ongoing and will reveal any impact of these drugs on MACE events and CV mortality. Finally, Dr. Bjork explained that the baseline A1c of 9.3% was an important piece of this study because these are the patients who might benefit most from a combination therapy when uncontrolled on metformin alone.
- Exenatide/dapagliflozin dual therapy demonstrated superiority to either monotherapies for all secondary endpoints. Dual therapy produced significantly greater reductions in fasting plasma glucose (FPG) than exenatide or dapagliflozin monotherapy (-3.61 mmol/l [65 mg/dl] vs. -2 mmol/l [36 mg/dl] and -2.7 mmol/l [49 mg/dl]; p<0.001). The same was true for reductions in postprandial glucose (PPG) (-4.83 mmol/l [87 mg/dl] vs. -3.31 mmol/l [87 mg/dl] and -3.41 mmol/l [61 mg/dl]; p<0.0001) and reductions in systolic blood pressure (-4.2 mmHg vs. -1.3 mmHg and -1.8 mmHg; p<0.007).
- Furthermore, dual therapy with exenatide and dapagliflozin produced greater weight loss (-3.41 kg [~7.5 lbs] vs. -1.54 kg [~3.4 lbs] and -2.19 kg [~4.8]; p<0.001) and a greater proportion of patients with weight loss of 5% or more (33% vs. 14% and 20%; p<0.001). Dr. Guja noted that the weight loss effects of the co-administration appear to be additive. Notably, participants with a baseline A1c between 8% and 9% appeared to experience a greater, more additive weight loss benefit from the co-administration of the two products. In this subgroup, participants treated with both dapagliflozin and exenatide experienced a mean 4.5 kg (~10 lbs) weight reduction, compared to 1.9 kg (~4.2 lbs) in the standalone exenatide group and 2.2 kg (~4.9 lbs) in the standalone dapagliflozin group (p<0.001 for the combination compared to both exenatide and dapagliflozin). In comparison, participants with a baseline A1c³9% treated with both dapagliflozin and exenatide experienced a mean weight loss of 2.6 kg (~5.7 lbs), compared to 1.2 kg (~2.6 lbs) in the standalone exenatide group and 2 kg (~4.4 lbs) in the standalone dapagliflozin group (p<0.01 vs. exenatide, non-significant vs. dapagliflozin). Based on these promising results, we’d be especially eager to see a trial of co-administration of the two products in patients with lower A1cs down to 7.5%.
- Adverse events occurred with approximately equal frequency in each group: exenatide plus dapagliflozin (57%), exenatide alone (54%), and dapagliflozin alone (52%). Respectively, serious adverse events occurred evenly across all groups (4% vs. 3% and 4%), as did adverse events leading to discontinuation (4% vs. 5% and 2%). The most commonly-occurring adverse events were: (i) diarrhea (4% vs. 6% and 3%); (ii) injection-site nodules (8% vs. 6% and 5%); (iii) nausea (5% vs. 7% and 3%); and (iv) urinary tract infections (4% vs. 5% and 6%). No major, minor, or severe hypoglycemia events occurred throughout the trial. There was only one case of diabetic ketoacidosis in the trial that occurred in the standalone exenatide arm. There was one case of pancreatitis in the standalone exenatide arm and one case in the combination treatment group. As expected, the rate of genital mycotic infections in the co-administration and standalone dapagliflozin arms were higher than in the exenatide arm (4%, 6%, and 2%, respectively). Overall, this adverse event profile seems very positive.
Pathophysiological Basis of SGLT-2 Inhibitor/GLP-1 Agonist Combination
Ele Ferrannini, MD (University of Pisa, Italy)
In a discussion immediately preceding the discussion of the DURATION-8 results, the highly renowned Dr. Ele Ferrannini (University of Pisa, Italy) argued that co-administration of GLP-1 agonists and SGLT-2 inhibitors is both rational and likely to work. He emphasized the distinct mechanisms of action of the two drugs (pointing out SGLT-2 inhibitors’ non-insulin-dependent glucose lowering) and the impressive benefits both classes appear to offer in terms of weight loss and potential cardioprotection. Notably, pointing out that it would be impossible for us to empirically evaluate every single possible combination of diabetes drugs with rigorous randomized controlled clinical trials, Dr. Ferrannini advocated for a “rational” approach to determining which drugs should be used together in combination therapy – SGLT-2 inhibitors and GLP-1 agonists certainly seem to fit the bill and there’s already been some very cogent discussion by Professor Philip Home on how it may be possible to profile cohorts of patients by their profile (complications etc).
Symposium: EMPA-REG OUTCOME: One Year Later
Introduction and Context
Bernard Zinman, MD (University of Toronto, Canada)
Dr. Bernard Zinman (University of Toronto, Canada) set the tone for this session, a one-year later update on EMPA-REG OUTCOME, by focusing attention on mechanism. Whenever the field sees a robust clinical finding, he explained, we’re understandably eager to know the underlying biology. Dr. Zinman reviewed data from a univariate mediation analysis of EMPA-REG OUTCOME which attributed 52% of the cardioprotection finding to volume contraction, as reflected by an increase in hematocrit. The analysis attributed 25% to decreased uric acid concentration and only 3% to between-group A1c differences – this last point underscores that the CV benefit of Lilly/BI’s Jardiance (empagliflozin) is independent of glycemic effects. That said, Dr. Zinman mentioned a few caveats: (i) this univariate analysis was post-hoc and should only be considered hypothesis-generating; (ii) variables that weren’t factored into the analysis, such as ketone bodies, might play a mediating role between empagliflozin and reduced CV death; and (iii) a multivariate model of combined mechanisms would be more accurate, though this analysis is also much more complicated. He remarked that a multivariate analysis is underway.
Macrovascular and Heart Failure Outcomes: An Update
David Fitchett, MD (University of Toronto, Canada)
Dr. David Fitchett (University of Toronto, Canada) discussed an interesting post-hoc analysis to EMPA-REG OUTCOME, zooming in on heart failure burden. He also presented these post-hoc results at this year’s European Society of Cardiology Congress in Rome. The recent analysis showed that empagliflozin reduces the risk of a variety of heart failure measures by a substantial margin: (i) the risk of investigator-reported heart failure declined by 30% with empagliflozin treatment; (ii) the risk of a composite endpoint of hospitalization for heart failure or investigator-reported heart failure also declined by 30%; (iii) the introduction of loop diuretics was delayed by 38%; and (iv) the risk of a composite endpoint of hospitalization for heart failure and introduction of loop diuretics declined by 37%. Dr. Fitchett emphasized that these risk reductions are clinically meaningful. He also underscored that the decrease in CV death with empagliflozin vs. placebo was similar in patients with and without heart failure at baseline or during the trial. For more on this data, see our coverage from ESC 2016.
Microvascular and Renal Outcomes
Christoph Wanner, MD (University of Würzburg, Germany)
Dr. Christoph Wanner (University of Würzburg, Germany) outlined findings on the positive renal effects of empagliflozin treatment regardless of baseline kidney function. He described how patients with healthy kidneys, microalbuminuria, or macroalbuminuria all experience clinically significant changes in urinary albumin creatinine ratio (UACR) over the course of 192 weeks on empagliflozin. Among patients who at baseline showed normoalbuminuria, there was a mean 7% decline in UACR at 12 weeks (p<0.05 vs. placebo) and a mean 21% decline at 192 weeks (p<0.01 vs. placebo). For patients with baseline microalbuminuria, these values were 25% (p<0.001) and 40% (p<0.001), respectively, while patients with baseline macroalbuminuria experienced an average 32% drop (p<0.001) and 38% drop (p<0.05) in UACR at 12 and 192 weeks, respectively. Though UACR is not yet accepted as an outcome parameter, Dr. Wanner emphasized that it is connected to renal outcomes and thus should hold weight in evaluations of empagliflozin’s renal benefits. Continuing on, he shared incidence rate ratios for adverse events, breaking down the study population into baseline eGFR <60 ml/min/1.73m2 and >60 ml/min/1.73m2. In patients with lower eGFR, signaling a higher risk for kidney complications or disease, the hazard ratios for adverse events, serious adverse events, and severe adverse events all favored empagliflozin vs. placebo. In fact, the only hazard ratios near unity were urinary tract infections (UTI) and complicated UTIs. Genital infections were markedly more common in the empagliflozin group. These trends were similar among patients with higher baseline eGFR. The important takeaway from this additional data, according to Dr. Wanner, is that there were pronounced benefits to empagliflozin among the patients at risk for kidney complications in EMPA-REG OUTCOME. Treatment with the SGLT-2 inhibitor slowed the progression of kidney disease and reduced clinically relevant renal events. Dr. Wanner ended his presentation with a brief explanation of the glomerular hypertension hypothesis for mechanism of renal protection, which he also discussed in relation to empagliflozin at ADA 2016. The expanded renal results presented at EASD were certainly encouraging and reassuring – we would love to see Lilly/BI tackle a dedicated renal outcomes trial for empagliflozin and potentially pursue a diabetic nephropathy indication given the high unmet need in this area. We’d also like to better understand regulatory requirements on this front – previously they have been quite challenging.
Implications for the Management of Patients with Type 2 Diabetes and High CV Risk
Hertzel Gerstein, MD (McMaster University, Ontario, Canada)
How important is the explanation of mechanism? Dr. Hertzel Gerstein (McMaster University, Ontario, Canada) suggested that understanding mechanism of cardioprotection for empagliflozin (Lilly/BI’s Jardiance) shouldn’t be a prerequisite for using this knowledge of the drug’s CV benefits in clinical practice. While he acknowledged that we need to support research to find out more about mechanism, he argued that this lingering uncertainty shouldn’t stop us from applying this evidence toward optimal diabetes care for patients with type 2 diabetes and high CV risk. “Empagliflozin reduces some extremely serious health outcomes,” he put simply, and even though “we’re not sure why, that shouldn’t stop us from offering these benefits to patients.” We so appreciated this commentary as we’d love to see improved prognosis for patients, especially those at high risk for CV morbidity and mortality who stand to benefit most from empagliflozin therapy. It seems like such a shame to be sitting on compelling evidence for cardioprotection without harnessing the latest clinical data to provide better patient care. Dr. Gerstein summed it up perfectly: “A stone falls today the same way that it fell 200 years ago, but our theory of gravity has changed dramatically. You don’t need to know how a drug works to benefit from it.”
EASD/ADA Symposium: Changing Paradigms: The Role of SGLT-2 Inhibitors
SGLT-2 Inhibition and Cardiovascular Outcomes
Silvio Inzucchi, MD (Yale University, New Haven, CT)
Dr. Silvio Inzucchi (Yale University, New Haven, CT) presented cardiovascular results from EMPA-REG OUTCOME at last year’s EASD in Stockholm, Sweden – he returned this year with a focus on mechanism, and started off by admitting “with a great deal of modesty, we had it all wrong.” Dr. Inzucchi explained how the initial thinking on Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) was that the agent would confer CV benefits through an overarching atherosclerotic effect. The early divergence of the Kaplan Meier curves in EMPA-REG OUTCOME suggests otherwise. Results from blood pressure and statins trials demonstrate that an atherosclerotic mechanism shows up as divergence much later, around 12-18 months, which is also what was seen in the LEADER trial for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Despite lingering questions surrounding mechanism of cardioprotection, Dr. Inzucchi called upon the ADA and EASD to consider powerful CVOT data in drafting the next position statement for the diabetes field. He urged the committee charged with authoring the next ADA-EASD treatment guidelines to look closely at EMPA-REG OUTCOME and other recent CVOTs, including LEADER, SUSTAIN 6 (for GLP-1 agonist semaglutide), and even IRIS (for the TZD pioglitazone, perhaps at low doses), because in his view, these CV benefits should be making their mark and improving real-world diabetes care.
Questions and Answers
Q: Can you pick up on heart failure data from DPP-4 inhibitor CVOTs, SAVOR and EXAMINE? The FDA has listed a warning, but on this side of the Atlantic, our European agency has posted a statement saying that the changes seen in heart failure are too small and should not alter practice. What are your thoughts on this?
A: The effect with alogliptin was not statistically significant. I still don’t completely understand why the FDA compelled that label to change. There’s no reason to believe a DPP-4 inhibitor could increase heart failure hospitalization rates, but the data is the data. Could it be a chance finding? Perhaps. We’re still obligated to follow drug labels in the US.
SGLT-2 Inhibitors and Renal Outcomes
David Cherney, MD (University of Toronto, Canada)
Dr. David Cherney (University of Toronto, Canada) picked up on the topic of SGLT-2 inhibition and continued the conversation on mechanism, but shifted focus from the heart to the kidneys. Post-hoc analysis of a composite renal endpoint in EMPA-REG OUTCOME found an impressive hazard ratio of 0.54 in favor of empagliflozin (Lilly/BI’s Jardiance), representing a 46% risk reduction with the SGLT-2 inhibitor therapy (p<0.001). More specifically, Dr. Cherney mentioned that the drug was associated with fewer cases of acute kidney injury and acute renal failure. What were the mechanisms responsible for improved renal outcomes? The short answer, as Dr. Cherney put it, is “we don’t know yet.” Still, he discussed in great detail what is known about the impact of SGLT-2 inhibitors – including empagliflozin, dapagliflozin (AZ’s Farxiga), and canagliflozin (J&J’s Invokana) – on kidney function, summarizing the leading hypotheses related to hyperfiltration and how agents in this class consistently reduce hyperfiltration, now evidenced through both animal and human data. He pointed out an interesting observation that 80% of patients enrolled in EMPA-REG OUTCOME were on a background of RAAS blockers. RAAS inhibition tends to dilate the kidney’s efferent arteriole, while SGLT-2 inhibition constricts the afferent arteriole. Therefore, one interesting theory for the renal protection seen in the CVOT is an additive effect of empagliflozin plus RAAS blockade, which may have more effectively lowered intraglomerular pressure to provide long-term kidney benefits. Another intriguing explanation is that empagliflozin delayed time to introduction of loop diuretics for participants (hazard ratio 0.62, p<0.001). Dr. Cherney also presented a combined renal-cardio hypothesis for the kidney and heart benefits seen in EMPA-REG OUTCOME. While cardioprotection has been getting more overt attention from the field of late, he suggested that renal preservation with SGLT-2 inhibitor therapy could be the gateway to lowering CV morbidity and mortality. Dr. Cherney outlined four potential pathways for this renal-cardio hypothesis: Lowering intraglomerular hypertension and albuminuria could (i) decrease blood pressure, arterial stiffness, cardiac afterload, and left ventricular remodeling, the last of which is cardioprotective; (ii) reduce renal systemic inflammation which decreases left ventricular remodeling; (iii) preserve sodium/water homeostasis which enhances maintenance of euvolemia, which is cardioprotective; and/or (iv) decrease cardiac preload, myocardial wall tension, and arrhythmogenesis, which is directly cardioprotective.
- Dr. Cherney picked up on Dr. Inzucchi’s call-to-action for guidelines committees as well. “In Canada, we do have exactly what’s suggested – in patients with high CV risk, SGLT-2 inhibitors are now indicated in guidelines as the next therapy of choice.” He endorsed this designation of SGLT-2 inhibitors as second-line therapy.
-- by Abigail Dove, Helen Gao, Payal Marathe, and Kelly Close