Greetings from New Orleans, where ADA 2016 wrapped up this morning with a flurry of notable data, valuable commentary, and a good old torrential Louisiana downpour. Today’s highlights include more details on the full EMPA-REG renal results demonstrating a significant 39% risk reduction for diabetic nephropathy, new sub-analysis data showing that the heart failure and CV death outcomes of the EMPA-REG trial were consistent across age groups, and valuable commentary from University of Michigan’s Dr. William Herman on the caveats of the EMPA-REG OUTCOME results. We also have a covariate mediation analysis (!) of the EMPA-REG OUTCOME results suggesting that increased hematocrit contributed to cardiac death risk reduction, and secondary endpoint analyses from the IRIS trial demonstrating a 52% risk reduction for progression to type 2 diabetes with the TZD pioglitazone. On the tech side, we have updated full results from the Bionic Pancreas team’s placebo-controlled, double-blind, glucagon-only study in patients with type 1 diabetes, where time spent in hypoglycemia declined 78% overall and 93% overnight (!) - Ms. Courtney Balliro of MGH did an especially great job delivery these standout results that were part of the eight Presidential late-breakers. We also have thought-provoking DPP follow-up data suggesting that physical activity – independent of weight loss – can help reduce cumulative diabetes incidence. See below for our top seven highlights, followed by detailed discussion and commentary. It was particularly moving in the sessions this morning to see ADA Chief Scientific Officer Dr. Bob Ratner and ADA CEO Kevin Hagan at the back of the room watching the science – we feel that so much work goes into this meeting that none of us probably fully realizes and we send a special thanks to them for their commitment to science.
Tomorrow morning, we bid NOLA and the magic of ADA goodbye and jet back to San Francisco where we’ll be hard at work on our ADA 2016 full report that we plan to send you before the July 4 weekend! In the meantime, see our Days #1, #2, #3, #4, and initial coverage of LEADER for a look at the week in review.
Top Seven Highlights
1. Dr. Christoph Wanner (University of Würtzburg, Germany) presented full renal outcomes results from EMPA-REG OUTCOME demonstrating a significant 39% risk reduction for diabetic nephropathy with Lilly/BI’s Jardiance (empagliflozin).
2. Dr. Bernard Zinman (Mount Sinai Hospital, University of Toronto, Ontario, Canada) presented new sub-analysis data, showing that the heart failure and cardiovascular death outcomes of the EMPA-REG trial for Lilly/BI’s Jardiance (empagliflozin) were consistent across age groups. It is always reassuring to see this leader stand before us and we especially appreciated his comments.
3. Discussing both the cardiovascular and renal outcomes results, Dr. William Herman (University of Michigan, Ann Arbor, MI) argued that EMPA-REG OUTCOME is a game-changer but one with important caveats.
4. Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT) presented a covariate mediation analysis of the EMPA-REG OUTCOME results, suggesting that increased hematocrit (presumably as a reflection of plasma volume) was a significant (but still just a partial) contributor to the impressive 38% risk reduction for cardiac death with Lilly/BI’s Jardiance (empagliflozin).
5. Ms. Courtney Balliro (MGH, Boston, MA) presented updated, full results from the Bionic Pancreas team’s placebo-controlled, double-blind, glucagon-only study in patients with type 1 diabetes. Time spent in hypoglycemia declined 78% overall and 93% overnight.
6. Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT) presented secondary endpoint analyses from the IRIS trial demonstrating a 52% risk reduction for progression to type 2 diabetes and reductions in insulin resistance and fasting plasma glucose (FPG) with TZD pioglitazone in patients with elevated insulin resistance and high cardiovascular risk. IRIS had recently reported in the New England Journal of Medicine a 24% reduction from pioglitazone in stroke and MI in this cohort.
7. Dr. Andrea Kriska (University of Pittsburgh, PA) presented new follow-up data from the Diabetes Prevention Program (DPP) study, which suggested that physical activity – independent of weight loss – can help reduce cumulative diabetes incidence. We would love to see more focus on this topic, particularly exercise prescriptions.
Top Seven Highlights
1. Full EMPA-REG Renal Results – 39% Risk Reduction for Incident or Worsening Nephropathy with Empagliflozin
Dr. Christoph Wanner (University of Würtzburg, Germany) presented full renal outcomes results from EMPA-REG OUTCOME demonstrating a significant 39% risk reduction for diabetic nephropathy with Lilly/BI’s Jardiance (empagliflozin). The results were also published in the NEJM this morning. The hazard ratio for the main renal endpoint of incident or worsening nephropathy (progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m2 or renal replacement therapy or death due to renal disease) was 0.61 (95% CI: 0.53-0.70; p<0.001). As with the cardiovascular outcomes, the effect appeared early and was sustained throughout the trial; there was no difference between the 10 mg and 25 mg doses of empagliflozin. The results were essentially the same for the combined endpoint of incident or worsening nephropathy or CV death (HR = 0.61; 95% CI: 0.55-0.69; p<0.001). Subgroup analyses demonstrated a consistent effect in subgroups divided by CKD stage, age, sex, race, diabetes duration, A1c, BMI, blood pressure, and concomitant medications. New onset macroalbuminuria was the most common event and therefore demonstrated the most robust results (HR = 0.62; 95% CI: 0.54-0.72; p<0.0001). The effect for hard renal outcomes (doubling of serum creatinine, renal replacement therapy, or death due to renal disease) took longer to appear but was also highly significant by the end of the trial (HR = 0.54; 95% CI: 0.40=0.75; p<0.001). There was no significant risk reduction for incident albuminuria in patients with normal urinary albumin levels at baseline, suggesting that the benefit is likely exerted later in the progression of CKD. There was no signal for adverse events including hypoglycemia, urinary tract infections, acute kidney injury, bone fractures, hyperkalemia, or DKA in patients with impaired kidney function, which we speculate should help support a label update to remove the current contraindication for patients with renal impairment.
- Dr. Wanner outlined one potential mechanism for the positive renal effects, centered around a reduction in glomerular hypertension. He explained that diabetes leads to increased reabsorption of sodium and glucose in the proximal tubule and decreased delivery of sodium to the macula densa. Because the macula densa regulates the glomerular filtration rate based on the amount of sodium it senses, the abnormally low delivery of sodium leads to hyperfiltration. With SGLT-2 inhibition, more glucose and sodium reaches the macula densa, leading to an initial drop in glomerular pressure and glomerular filtration rate. While this short-term decline in GFR initially led to concerns that SGLT-2 inhibitors might be harmful to the kidneys, over the long term the restoration of tubulo-glomerular feedback and reduced glomerular hypertension appears to be quite beneficial. This model is the closest thing to a consensus hypothesis we have heard for the mechanism of renal protection with SGLT-2 inhibitors, though we also heard an intriguing alternative hypothesis related to fuel energetics earlier this week.
2. EMPA-REG Sub-Analyses Demonstrate Consistent Outcomes Across Age Groups
Dr. Bernard Zinman (Mount Sinai Hospital, University of Toronto, Ontario, Canada) presented new sub-analysis data, showing that the heart failure and cardiovascular death outcomes of the EMPA-REG trial for Lilly/BI’s Jardiance (empagliflozin) were consistent across age groups. Also presented in two posters, the analyses stratified the results by three baseline age groups (<65, 65-75, ≥75 years). For cardiovascular death, the hazard ratios were 0.72, 0.54, and 0.55 for the age groups, respectively by increasing age group (p=0.484 for the treatment by age group interaction). Regarding hospitalization for heart failure, hazard ratios were 0.73, 0.66, and 0.45 for the respective increasing age groups (p=0.488 for the treatment by age group interaction). In addition, the analyses calculated the collective hazard ratios for heart failure hospitalization or cardiovascular death: 0.79, 0.59, and 0.52 for the respective increasing age groups (p=0.240 for the treatment by age group interaction). The time to cardiovascular death and heart failure hospitalization appeared to remain mostly consistent across baseline age groups. The analyses also found that reported adverse events were consistent with the known safety profile of Jardiance across age subgroups. The percentage of participants reporting one or more adverse events in the empagliflozin arm was 89.1%, 91.8%, and 90.8% in the <65, 65-75, and ≥75 years age groups, respectively. Specifically, the proportion of participants who reported events consistent with urinary tract infection (15% vs. 20% vs. 26%), volume depletion (4% vs. 7% vs. 7%), and bone fracture (3% vs. 5% vs. 5%) tended to increase with increasing age. These findings support the broad use of Jardiance by age group and should provide further color on how to incorporate the EMPA-REG findings into treatment algorithms, as we look forward to further sub-analyses to provide stronger evidence on the guidance for better personalizing therapy.
3. EMPA-REG OUTCOME: Game-Changer with Caveats
Discussing both the cardiovascular and renal outcomes results, Dr. William Herman (University of Michigan, Ann Arbor, MI) argued that EMPA-REG OUTCOME is a game-changer but one with important caveats. He stressed that the very impressive results need to be interpreted strictly in the context of the eligibility criteria for the trial, meaning they should be applied only to older patients with established CVD. He also noted that the results could reflect the reduced use of potentially harmful medications like insulin and sulfonylureas rather than a specific beneficial effect of empagliflozin. Dr. Anne Peters (USC, Los Angeles, CA) offered a similar theory yesterday with regard to the LEADER results for Novo Nordisk’s Victoza (liraglutide). It is an interesting theory in both cases, though it seems unlikely that it would explain the entire benefit in EMPA-REG OUTCOME given the lack of a hypoglycemia difference between the groups and the dramatic and specific benefits on heart failure and CV death with empagliflozin. For patients with earlier-stage type 2 diabetes, Dr. Herman suggested that selection of SGLT-2 inhibitors as a second-line therapy should still be based on the criteria outlined in the ADA guidelines, including efficacy (moderate), hypoglycemia risk (low), weight effect (beneficial), side effects (genitourinary infections), and cost (expensive). In terms of the mechanism of benefit, Dr. Herman suggested that a sum of small effects (on A1c, weight, blood pressure, etc.), decreased plasma volume, renal effects, or alternative fuel sources are all plausible hypotheses. Several of these issues were discussed in more detail during Q&A – see below for a full transcript.
4. EMPA-REG OUTCOME Mediation Analysis Suggests Hematocrit Could be Mediator of Cardiovascular Death Risk Reduction
Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT) presented a covariate mediation analysis of the EMPA-REG OUTCOME results, suggesting that increased hematocrit (presumably as a reflection of plasma volume) was a significant (but still just a partial) contributor to the impressive 38% risk reduction for cardiac death with Lilly/BI’s Jardiance (empagliflozin). The analysis looked at several potential mediators of the effect related to glycemia (A1c, fasting plasma glucose [FPG]), vascular tone (systolic blood pressure, diastolic blood pressure, heart rate), lipids (HDL cholesterol, LDL cholesterol, triglycerides), renal factors (log urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate [eGFR]), adiposity (weight, BMI, waist circumference), volume status (hematocrit), and other (uric acid). The analyses involved a “change from baseline” analysis to determine if a covariate may have an acute effect on the outcome and a “updated mean” analysis to determine if it may have a chronic effect on the outcome. The change from baseline analysis found that adjustment for hematocrit levels produced a hazard ratio of 0.791 for cardiovascular death, suggesting that decrease in plasma volume could potentially explain nearly 52% of the overall effect of empagliflozin on cardiovascular death. Adjustment for uric acid levels yielded the second largest change in effect (24%), suggesting it may also have some role, though Dr. Inzucchi noted that any percent change in effect under 30%-40% is unlikely to indicate a significant major mediator of the cardiovascular death effect.
- In the updated mean analysis of potential chronic factors, hematocrit levels once again emerged as a significant potential mediator of the effect. Adjustment for hematocrit produced a hazard ratio again of 0.791 for cardiovascular death, also a 52% change in the overall effect. Analysis for other volume-related factors such as hemoglobin and albumin also suggested a potential effect: hemoglobin levels accounted for 45.7% of the overall effect and albumin levels for 31.6% of the overall effect. In this analysis, A1c and FPG appeared to affect the outcome more than in the “change from baseline” analysis, with adjustment resulting in a 23% and 29% change in effect, respectively. Overall, however, Dr. Inzucchi concluded that hematocrit appeared to by the most likely potential mediator for the effect, warranting further study to investigate this hypothesis. He did, however, acknowledge that there could be other factors not measured in the EMPA-REG OUTCOME trial that could have mediated some of the effect on cardiovascular death. Others have proposed that a slight increase in ketone bodies produced by SGLT-2 inhibitors may provide a more efficient fuel source for the heart and that this may be an important mediator as well.
5. Bionic Pancreas Glucagon-Only Study Shows Massive Drop in Time Spent in Hypoglycemia versus Control
Ms. Courtney Balliro (MGH, Boston, MA) presented updated, full results from the Bionic Pancreas team’s placebo-controlled, double-blind, glucagon-only study in patients with type 1 diabetes. Time spent in hypoglycemia declined 78% overall and 93% overnight. The study enrolled 22 people with type 1 diabetes, who wore a Bionic Pancreas at home for 14 days that administered glucagon-only on seven of those days vs. placebo-only on seven of those days, interspersed in random order (insulin was self-regulated). Results were just as impressive as those first presented by Dr. Steven Russell at AADE 2015 – time spent in hypoglycemia (<60 mg/dl) was reduced from 5.8% with placebo to 1.3% with glucagon for the entire day (a 78% reduction). The overnight improvement was even more striking – 7.9% time spent <60 mg/dl with placebo vs. 0.5% with glucagon, a 93% improvement! Glucagon administration reduced hypoglycemia exposure (area over the curve and less than 60 mg/dl) by 77% (p<0.001) relative to placebo administration without affecting mean blood glucose (mean: ~154 mg/dl, in both arms). Performance was not at the expense of hyperglycemia, as time spent >180 mg/dl was not significantly different – 28% (glucagon) vs. 29% (placebo) (p=0.7) – nor due to greater insulin utilization – 39 units/day (glucagon) vs. 37 units /day (placebo) (p=0.12).
- Ms. Balliro stressed that the Bionic Pancreas did not deliver excessive glucagon (~0.48 mg/day – on par with previous studies) and noted that there were no differences in self-reported nausea. The team continues to show strong data on this front, countering those arguing that glucagon administration may prove problematic on nausea.
- The other big question is the effects of chronic glucagon exposure, and it will take some time to get an answer. We learned from Dr. Ed Damiano on Saturday that the team will use Zealand’s liquid stable glucagon analog and plans to begin clinical trials with the iLet device in 2H16. As we noted on Day #2, the pivotal studies of the insulin-only iLet are still expected to start in 2Q17. The bihormonal pivotal trial, which will begin after the start of the insulin-only pivotal trial, will require that a subset of the study cohort use the iLet for 12 months in order to gain chronic glucagon exposure data for the FDA. Dr. Damiano has forecasted an end of 2017 insulin-only PMA submission, with a potential PMA supplement to add glucagon in early 2019.
- Ms. Balliro confirmed that the Bionic Pancreas team plans to test its glucagon-only Bionic Pancreas in patients with post-bariatric hypoglycemia and chronic hyperinsulinemia “in the next year or so.” The device could be particularly suited to the former group given that carbohydrate intake was reduced 35% in the glucagon arm. That said, Dr. Balliro stressed that the near-term focus is on bringing the dual-hormone device to the market – no surprise there – but it was terrific to hear that the team thinks a glucagon-only system does have commercial application. For those that suffer from acute severe hypoglycemia, this could also be a product, depending on how payers feel (we assume they would be enthusiastic as ER visits cost so much).
- Glucagon-only study design: Patients wore a Bionic Pancreas at home for 14 days that administered glucagon-only on seven of those days vs. placebo-only on seven of those days, interspersed in random order (insulin was self-regulated). Patients were not restricted in their daily activities and were blinded to which days they were on glucagon vs. placebo, which Ms. Balliro noted was effective: patients were able to distinguish glucagon from placebo treatment on < 50% of days [i.e., less than chance].
6. IRIS Trial Secondary Analysis Finds Pioglitazone Reduces Risk of New Diabetes Diagnosis by 52% and Has a Greater Effect in Participants at Higher Risk for Type 2 Diabetes
Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT) presented secondary endpoint analyses from the IRIS trial demonstrating a 52% risk reduction for progression to type 2 diabetes and reductions in insulin resistance and fasting plasma glucose (FPG) with TZD pioglitazone in patients with elevated insulin resistance and high cardiovascular risk. The five-year, placebo-controlled trial (n=3,876) enrolled participants without diabetes with a history of recent stroke or transient ischemic attack (TIA), and insulin resistance (defined as HOMA-IR >3.0). The hazard ratio for new diagnosis of type 2 diabetes in the pioglitazone group was 0.48 (95% CI: 0.33-0.69, p<0.0001), with 3.8% of those in the pioglitazone group developing type 2 diabetes compared to 7.7% in the placebo group. Furthermore, Dr. Inzucchi presented new data demonstrating a significant improvement in insulin resistance for the pioglitazone-treated group, as measured by HOMA-IR. HOMA-IR at one year decreased to 4.1 (-24%) in the pioglitazone-treated group and increased to 5.7 (+7%) in the placebo group (baseline HOMA-IR=5.4, p<0.0001). Pioglitazone treatment also produced improvements in fasting plasma glucose (FPG) compared to placebo: after one year, mean FPG was 95.1 mg/dl in the pioglitazone-treated group and 99.7 mg/dl in the placebo group (baseline FPG=98.2 mg/dl, p<0.0001). Furthermore, the analysis revealed that pioglitazone’s preventive effect for new diabetes diagnosis was more potent in participants at higher risk for type 2 diabetes (with impaired fasting glucose, higher A1c, more insulin resistance, and metabolic syndrome) – see the detailed results below. It appears that pioglitazone can ameliorate the increased risk of diabetes associated with high cardiovascular risk and perhaps intervene in the additive risk effect of concurrent cardiovascular disease and type 2 diabetes. Dr. Inzucchi highlighted the fact that pioglitazone is now the only oral glucose-lowering agent demonstrated to reduce atherosclerotic events and the only one shown to prevent diabetes and improve cardiovascular outcomes in the same trial. The side effects of TZDs are not minor (though Dr. Inzucchi has asserted they can be managed), but there does appear to be a significant upside to this medication for the right patients.
- The relative and absolute risk reduction for progression to type 2 diabetes was greater for participants with prediabetes (defined as FPG ≥100 mg/dl at baseline or A1c ≥5.7%), with the highest insulin resistance, or with metabolic syndrome. For patients with impaired glucose tolerance and FPG ≥100 mg/dl, pioglitazone produced a 59% relative risk reduction (HR=0.41; 95% CI: 0.30-0.57; p<0.0001, absolute risk reduction [ARR]=8.5%), while it only produced a 31% non-significant relative risk reduction in participants without impaired glucose tolerance (HR=0.58, 95% CI:0.39-1.23; p=0.21, ARR=0.8%). In participants with baseline A1c ≥5.7%, pioglitazone treatment demonstrated a 54% risk reduction (HR=0.46; 95% CI: 0.34-0.62, p<0.0001; ARR=5.6%), compared to a non-significant risk reduction of 42% in participants with A1c<5.7% (HR=0.58; CI: 0.27-1.28; p=0.17; ARR=1.0%). By insulin resistance level, those with a HOMA-IR ≥4.6 experienced a relative risk reduction of 60% (HR=0.40, 95% CI: 0.29-0.57; p<0.0001; ARR=6.3%), compared to a non-significant risk reduction of 37% in participants with HOMA-IR <4.6 (HR=0.66; 95% CI: 0.40-1.08; p=0.10; ARR=1.4%). For those with metabolic syndrome (as defined by National Cholesterol Education Program [NCEP] criteria), pioglitazone treatment offered a 54% risk reduction (HR=0.46, 95% CI: 0.33-0.63, p<0.0001, ARR=5.9%), though risk reduction for those without metabolic syndrome remained significant at 57% (HR=0.43, 95% CI: 0.23-0.80, p<0.006, ARR=2.1%). Tests for interaction were non-significant in each of these cases, but Dr. Inzucchi nonetheless emphasized that primary protection from new diabetes diagnosis was driven by the highest-risk participants. Interestingly, treatment with pioglitazone reduced the Kaplan-Meier curve for participants with high insulin resistance to the point where it was nearly superimposable with that of the placebo-treated group with lower insulin resistance.
- The IRIS trial previously demonstrated that pioglitazone treatment produced a relative risk reduction of 24% for the composite primary endpoint of fatal and non-fatal stroke and MI (HR=0.76; CI: 0.62-0.93, p<0.007). 9.0% of patients in the pioglitazone-treated group experienced a stroke or MI during the trial period, compared to 11.8% of those in the placebo-treated group. However, other secondary endpoints besides new diabetes diagnosis (stroke, acute coronary syndrome, three-point MACE [stroke, MI, and heart failure], and death) were not significantly reduced with pioglitazone when compared with placebo. That said, Dr. Inzucchi has previously emphasized that this is fairly typical in such trials, driven by the lower number of events for these secondary endpoints. He pointed out that, while not statistically significant, each of these endpoints was less frequent in pioglitazone-treated patients. Adverse events associated with pioglitazone were as expected, including weight gain, edema, and bone fractures.
7. DPP Follow-Up Data Show Physical Activity’s Impacts on Diabetes Incidence
Dr. Andrea Kriska (University of Pittsburgh, PA) presented new follow-up data from the Diabetes Prevention Program (DPP) study, which suggested that physical activity – independent of weight loss – can help reduce cumulative diabetes incidence. In this 12-year investigation (n=1,793), participants wore an activity monitor for one week, completed a yearly interviewer-administrated physical activity questionnaire (Modifiable Activity Questionnaire), and performed an annual oral glucose tolerance test and semi-annual fasting plasma glucose tests to determine diabetes status. According to Dr. Kriska, the findings showed that, in the hree treatment groups combined (lifestyle, metformin, placebo), diabetes incidence was lower for those who were more physically active, regardless of changes in weight. Specifically, there was a 2% decrease in diabetes incidence for each 6 Met-hr/week increase in physical activity (~1.5 more hours/week of activity similar to a brisk walk) – this association was examined using Cox proportional hazards models controlling for weight and other factors. Notably, this protective effect of physical activity was greater in participants who were relatively less active at baseline (stratified at <150 minutes/week of reported physical activity at baseline). Not surprisingly, the lifestyle intervention group had the greatest cumulative physical activity levels (p=0.003) of the treatment groups, as well as the lowest cumulative incidence of diabetes after 12 years. These findings may be valuable in helping the field identify the at-risk individuals who would benefit the most from such programs and may even influence how the DPP is delivered within the community. In addition, these results remind us of the need to look beyond weight and also consider ones physical activity levels in prevention efforts.
Detailed Discussion and Commentary
Symposium: Update from the EMPA-REG OUTCOME Trial
Q: The known factors like blood pressure are very important here. As Dr. Wanner pointed out, the IDNT and RENAAL studies controlled for blood pressure. The FDA requires control of blood pressure for renal endpoints. Even if the FDA didn’t care to control for blood pressure in this setting, why didn’t the sponsor? We’re left with a choice between the Cox analysis and scratching our heads.
Dr. Bernard Zinman (Lunenfeld-Tanenbaum Research Institute, Toronto, Canada): The vast majority of patients with type 2 diabetes do have hypertension and the vast majority are on two or three blood pressure medications. I think the blood pressure we reported here was very similar to other studies like this. I think this is the reality of the kind of blood pressure we can achieve in a global setting. I’m not sure whether you’re implying we should’ve intensified blood pressure therapy before randomization? When you look at the difference in blood pressure, there was no difference in the outcome.
Q: Why wasn’t it treated to target in both arms?
Dr. Zinman: It was.
Q: Not successfully.
Dr. Zinman: The target A1c is <7% and I’d like to know how many people in this audience have all their patients under 7%. We didn’t actively intervene on blood pressure or lipids; we left it to the local physicians and they did the best they could. It didn’t in any way affect the outcome.
Dr. Matthew Riddle (OHSU, Portland, OR): This was a relatively advanced CV risk population and quite a few with existing nephropathy. Was this a surprising systolic blood pressure for this population?
Dr. Christoph Wanner (University of Würtzburg, Germany): I’m quite happy with the blood pressure we achieved. Remember in the IDNT and RENAAL trials they had higher blood pressure and the committee hammered on the investigators to bring the blood pressure down. Here we are in a range where we have quite sophisticated blood pressure-lowering agents. A meta-analysis in CKD did not indicate that further lowering would have a benefit. It’s not proven in type 2 diabetes but at least in CKD that’s true.
Q: I understand the mechanism is unclear, but Dr. McGuire suggested that the mechanisms were different for LEADER and EMPA-REG OUTCOME so the combination might be beneficial. If the alternative fuel hypothesis is true, liraglutide shuts down beta-hydroxybutyrate production, so you might lose at least this part of the effect. You shouldn’t just combine them. If you think we should, we need a combined study.
Dr. Zinman: I can’t agree more. You don’t know until you actually do it. A good example is combining ACE inhibitors and ARBs. I already asked how many people in the room are using GLP-1 agonists and SGLT-2 inhibitors and 60% of hands went up. It’s being done, but you’re correct that we need to study it more. It will take awhile, but we need to look at surrogates, hemodynamic responses, and metabolic responses. Several companies are initiating combination studies. We can’t just assume it will be additive.
Q: One thing you mentioned in your slide was oxidative stress, but it wasn’t further discussed, probably because it’s hard to measure. There are ways to measure the end products of oxidative stress if samples are available, and we had two posters here showing that it was correlated with cardiovascular endpoints in the VADT. If samples are available, some investigation could be telling.
Dr. Silvio Inzucchi (Yale University, New Haven, CT): I agree. These trials teach you that you should have saved more samples. We’re somewhat restricted to what we measured at baseline. We don’t have blood left over. It’s led to a lot of speculation.
Q: It’s interesting that the renal effects of empagliflozin were maintained in patients with a GFR under 45. That’s the level at which we’re not meant to be using the drug according to the label. Was there an analysis of cardiovascular outcomes in that subgroup?
Dr. Inzucchi: There was no heterogeneity of effect based on sub-category of GFR. There was a consistent effect for heart failure hospitalization and CV death in those patients.
Q: You showed that for an eGFR <60. What about under 45?
Dr. Wanner: If you look at stage 3 CKD, the reduction in CV outcomes was similar in the two sub-categories and very consistent. CV outcomes were reduced in even stage 3b, which is eGFR <45. But the n was small.
Q: Do you think the hematocrit increase or plasma volume decrease could also explain the imbalance in stroke?
Dr. Inzucchi: It’s a reasonable proposal. One caution is that when we looked at the stroke outcomes, most of the imbalance occurred in patients who had stopped the study drug. We’re still analyzing it but it is a bit of a curious finding. But a reduction in circulating plasma volume and the potential for sludging from increased hematocrit is something we’ve considered. A change in hematocrit from a mean of about 41 to about 44 shouldn’t really change plasma viscosity, but there certainly could be outliers. We are now looking at that specific question – were hematocrit or volume-related adverse events associated with stroke – so far, the answer is no.
Q: As a clinician I’m being persuaded to use this drug. Do you have advice on how to treat mycotic infections? Do you stop the drug if they occur?
Dr. Zinman: In the trial there were not a lot of recurrent infections. Patients tend to treat themselves with over the counter drugs. My own practice is that if a patient had recurrent infections as part of their history of diabetes, I wouldn’t use this class. Similarly, if they have a history of pancreatitis I tend not to use DPP-4 inhibitors. You need to individualize, but in my experience it’s not a big problem. The one patient I had with recurrent infections was a male who got balanitis and although it was treated he got a recurrence and stopped the drug. It’s generally not a problem.
Dr. Inzucchi: I agree that if there are recurrent adverse events from any medication, you need to avoid them. I treat the infections with topical antifungals.
Q: What is your explanation for the increase in creatinine at the onset of treatment?
Dr. Wanner: The increase in creatinine and drop in GFR is because of the reduction in intraglomerular pressure and hyperfiltration. It varies; it can be neutral but it can be quite substantial initially. We know from the ACE inhibitors, where we have a longer history of looking into this, that the more intraglomerular pressure or GFR drops at the beginning, the more the patient benefits long term in terms of RAS blockade. We have to look into it in terms of the SGLT-2 inhibitors, but for the moment I would assume it’s the same.
Q: Hepatic injury was statistically reduced. What was the definition and absolute numbers?
Dr. Zinman: We didn’t specifically measure hepatic injury. I really can’t give greater detail on that. I think it’s worth looking into. Weight-reducing agents can improve hepatic fat and liver enzymes, and it’s definitely going to the left, but I don’t have more details to provide.
Q: Taking your point that this may be a cardiac drug, and you can argue whether it’s really a renal drug, you may or may not need diabetes to have a benefit. Do you have any data on individual patients who had virtually no A1c response vs. a greater response? Was there any difference in outcomes? As clinicians, if we’re using this for diabetes and there’s no A1c improvement, should we withdraw or keep going because glucose is not what we’re actually treating?
Dr. Darren McGuire (UT Southwestern, Dallas, TX): That comment was a bit tongue in cheek, but I believe gauging efficacy by A1c is cutting it well short. There are many plausible beneficial effects and I don’t personally think A1c has anything to do with it.
Dr. Inzucchi: I agree. What you’re proposing is looking at data split by change in A1c. We know baseline A1c doesn’t predict the effect on CV mortality. It would be interesting to look at the impact of the delta in A1c.
Dr. Riddle: This was an interesting and thought-provoking mediation analysis. Will you do a similar analysis for the renal outcomes? Do you have a feeling whether it would show the same or different patterns?
Dr. John Lachin (George Washington University, Washington, DC): The first phase of the analysis is not complete and it will include looking at heart failure and renal outcomes.
-- by Melissa An, Adam Brown, Helen Gao, Varun Iyengar, Emily Regier, Ava Runge, and Kelly Close