A long awaited analysis of the renal outcomes from the EMPA-REG study was published in the New England Journal of Medicine on June 14th . As originally reported on UKidney, compared to patients taking placebo, the use of empagliflozin was associated with significant improvements in important renal end-points, namely doubling of serum creatinine and end-stage renal disease (ESRD). While these results are indeed very promising, some perspective is warranted when considering the potential nephroprotective properties of this drug, and of the SGLT2 inhibitor class in general.
UKidney Nephrology News and Insights
The SPRINT Study was received with great fanfare when it was published on November 26th in the New England Journal of Medicine. The primary results, summarized in the publication’s abstract are these:
"Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group."
The essential word in that abstract’s conclusion - and which prevents the application of these results - is ‘targeting’. The conclusion accepted by many is that aggressive blood pressure reduction, that is the achieved blood pressure, drove the observed results. However, it may well be that the act of targeting a low blood pressure, and using cardioprotective drugs to do so, explained the results rather than the reduction of blood pressure itself. And unravelling this nuance is the key to understanding whether SPRINT’s main message is applicable to the general population. I would argue that in its current form SPRINT suffers from a major methodological short-coming that leaves us in a quagmire.
As we continue to process data from the EMPA-REG renal outcomes presentation - which most importantly showed a 46% reduction in the composite of creatinine doubling, end-stage renal disease or renal death - speculation is well underway to explain the mechanism for renal protection. And the emerging story appears to be quite fascinating indeed.
Data from the EMPA-REG study were unveiled in Stockholm 6 weeks ago. In more than 7,000 adults with type 2 diabetes (T2D) at high risk for CV events, EMPA-REG OUTCOME met its primary endpoint and demonstrated superiority of JARDIANCE, when added to standard of care, in CV risk reduction. The primary endpoint was defined as time to first occurrence of either CV death, or non-fatal myocardial infarction or non-fatal stroke.
Canada becomes the first country outside Japan to approve JinarcTM (Tolvaptan) for the treatment of ADPKD. This medication, dosed twice daily, is the first of its kind to show a slowing in renal function decline as well as a slowing in kidney enlargement among patients with ADPKD.
Previously, UKidney News reported a possible link between calcium channel blockers and the development of breast cancer. Data from the Intermountain Medical Center Heart Institute study were presented at the 2014 American Heart Association Scientific Sessions in Chicago, dispelling some of this concern:
"We found no robust data that calcium channel blocker medications increase a person's risk of breast cancer," said Jeffery L. Anderson, MD, a cardiologist and researcher at the Intermountain Medical Center Heart Institute. "Given the important role calcium channel blocker medications play in treating heart conditions, we think it's premature to discontinue their use. At this point we recommend that patients continue taking these medications to treat their hypertension."
While it is very difficult to ever prove a negative association, these data do provide some reassurance to a large number of patients using this important antihypertensive.
Imagining the Dream RCT in nephrology is an important exercise, but not for the reasons you might think. For many, there might be the temptation to devise trials that will pave the way for future enhancements to patient care or to some other exciting, forward thinking outcome. For me however, the Dream RCT in nephrology is about shattering or affirming nephrology dogma - and in nephrology we seem to have more dogma influencing core tenets of our specialty than in other medical disciplines. There is a popular saying among those in the clinical epidemiology world - that you don’t need to conduct an RCT to prove that parachutes are required when jumping out of a plane. Unfortunately in nephrology, thought leaders have bestowed parachute status on too many interventions. I can think of no better example for this analogy than treating hyperphosphatemia in CKD/ESRD. And it is this topic that would underlie my Dream RCT.
Top-line results of the Symplicity 3 trial were revealed this week, showing that despite being safe, renal denervation was no better than a sham procedure at controlling blood pressure at 6 months. As reported on Medscape:
A report in JAMA - Internal Medicine raises important safety concerns about calcium channel blockers, one of the most widely prescribed classes of antihypertensives used world-wide.
In the population-based case-control study by Li et al, participants in the 3-county Seattle–Puget Sound metropolitan area were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls. The exposures studied were recency and use of antihypertensive medications while the main outcome measures were risks of invasive ductal and invasive lobular breast cancers.
As reported on UKidney, earlier in July 2013, Jamal et al published a systematic review comparing calcium-based phosphate binders with non-calcium-based phosphate binders in terms of their impact on cardiovascular outcomes. This pivotal work shows a small but statistically significant advantage of non-calcium-based binders over calcium vis-à-vis mortality outcomes in patients with chronic kidney disease and hyperphosphatemia.
Calcium dose has been implicated in the development of vascular calcification and in the excess cardiovascular morbidity common in patients with CKD, especially those on dialysis. The hope for non-calcium-based phosphate binders has always been that by limiting calcium intake, patients taking non-calcium-based binders would benefit from phosphate reduction without the exposure to potentially harmful dosages of calcium. While individual clinical trials have failed to show any clear advantage of non-calcium-based phosphate binders in terms of reducing cardiovascular morbidity and mortality, this latest systematic review now shows a statistically significant advantage of non-calcium-based phosphate binders over calcium in terms of limiting mortality in patients with CKD.
So where do we go from here? There will likely be discussion as to whether the finding in this systematic review is valid. Furthermore, even if the effect is indeed real, the cost of non-calcium-based binders over calcium-based binders is substantial. Nevertheless, it is likely time to consider whether calcium-based phosphate binders should be made obsolete. There are now substantial data supporting at least a modest effect of calcium dose on mortality and the rationale for using phosphate binders that are not calcium-based. An important question remains as to whether hyperphosphatemia should be treated at all – that is, with binders of any sort. It is entirely possible that non-calcium-based phosphate binders are superior to calcium simply because they limit calcium intake and that the drugs themselves do not offer any other outcome advantage - even if they lower phopshate.
And so, while this systematic review comes closer to answering a long-standing question in nephrology related to optimal phosphate binder class, it underscores an important lingering question as to whether hyperphosphatemia requires treatment at all. To answer this critical question, we require a long overdue placebo-controlled trial of hyperphosphatemia treatment. Objections to a placebo-controlled trial in this area have often centered around the ethics of withholding treatment for hyperphohsphatemia in the form of phosphate binders. However, there appears to be equipoise in this area; there is real uncertainty as to the saftey of calcium-based phosphate binders and whether hyperphosphatemia truly mediates cardiovascular illness in patients with CKD, or if it is only a disease association and nothing more.
Researchers from the University of Toronto and the University of Alberta add to existing data that calcium-based phosphate binders are harmful compared to binders that do not contain calcium. An updated systematic review on this topic that appears in the July 19th online version of the Lancet shows that patients with CKD across 8 studies (5 randomized) treated with non-calcium based binders had a 22% reduction in all-cause mortality compared to those taking calcium based binders.
Top-line results for the SAVOR trial were announced this week in which Saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) failed to demonstrate superiority over placebo in reducing a composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke when added to usual care in patients with type 2 diabetes with either a history of established CVD or multiple CVD risk factors. While the trial did demonstrate non-inferiority from a cardiovascular safety perspective, it failed to show any efficacy advantage. As reported originally on theheart.org:
Princeton, NJ and Wilmington, DE - The SAVOR-TIMI 53 trial has failed to demonstrate the superiority ofsaxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) over placebo in reducing a composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke when added to usual care in patients with type 2 diabetes with either a history of established CVD or multiple CVD risk factors .
The trial sponsors, Bristol-Myers Squibb and AstraZeneca, announced the top-line results from the trial early this morning. The full findings will be presented September 2, 2013 at the European Society of Cardiology(ESC) 2013 Congress. The trial did meet its "primary safety objective of noninferiority" vs placebo, a joint statement from the companies reads. SAVOR-TIMI-53 is part of an ESC hot-line session dedicated to risk factors and diabetes. The full schedule of ESC 2013 hot lines was published on the ESC website earlier this week.
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the US, Canada, Europe, and elsewhere as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Other, nonrandomized analyses had raised hopes that this class of drugs might have a protective effect on the vasculature of diabetes patients.
Saxagliptin was the first new diabetes drug to receive FDA approval after the issuance of new agency guidelines in July 2009, requiring companies to perform CV-outcomes studies with new diabetes drugs. The drug's clinical development program had been completed before the guidance, but because of the new rule, the company launched SAVOR-TIMI 53. The four-year-long trial had a target enrollment of 16 500 patients, and principal investigators for the trial are Dr Itamar Raz (Hadassah Medical Organization, Jerusalem, Israel) and Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA).
The High Impact Clinical Trials Session at this year's American Society of Nephrology Renal Week was the site of one of the most important and exciting nephrology developments to materialize in years. Researchers presented the results of a Phase 3 study using Tolvaptan (a vasopressin receptor antagonist) for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Previously a disease with no medical treatment, ADPKD accounts for 10% of the dialysis population and is associated with pain, hematuria, hypertension and a number of extra-renal manifestations.
The Tempo 3:4 Study randomized 1445 patients to receive a mean dose of 95 mg of Tolvaptan versus placebo over a 3 year period of observation. Patients receiving active drug experienced a slowing of kidney volume by 50% and also a slower deterioration in GFR, the primary and secondary outcomes of the study respectively. While there was a greater number of adverse effects related to the medication (polyuria, thirst, hyperuricemia, gout, hepatitis, hypernatremia), there were less ADPKD-related effects (pain, hemturia, urinary tract infection).
While the primary invstigator V. E Torrres was quick to temper enthusiasm until regulatory bodies such as the FDA weigh in on these findings, this study is a major breakthrough in the management of ADPKD and represents a shining example of bench to bedside research that will provide hope for a large group of patients who previously had no medical option for delaying the onset of end-stage renal disease in ADPKD. This will truly be a fascinating story to watch unfold as more study in this area continues.
Please see the New England Journal of Medicine publication here.
Some very disappointing news released today, as seen on Reuters:
Oct 18 (Reuters) - Abbott Laboratories Inc said its partner Reata Pharmaceuticals was discontinuing a late-stage trial of their potential blockbuster treatment for chronic kidney disease and diabetes based on safety concerns raised by an independent safety committee. The news for bardoxolone represents a major setback for Abbott just months before the planned Jan. 1 spinoff of its branded prescription drugs into a separate publicly traded company called AbbVie. Without the high-profile drug, Wall Street concerns about AbbVie's dependence on Abbott's $8 billion-a-year rheumatoid arthritis drug Humira could intensify. An independent data monitoring committee found excess serious adverse events and mortality in patients taking the oral anti-inflammatory drug, Abbott said in a regulatory filing.
Regulators were notified of the decision, and study participants were being informed, the company said.
Top-line results for the EVOLVE study using cinacalcet (Sensipar) in patients with end-stage renal disease (ESRD) were reported last week. In this phase 3 placebo-controlled randomized trial of 3,883 patients with secondary hyperparathyroidism, those on active treatment received a titrated dose of cinacalcet starting at 30 mg/day up to 180mg and were followed for approximately 4 years. Patients were evaluated for the composite primary outcome of all-cause mortality or first non-fatal cardiovascular event, including myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event. Despite very promising biochemical outcomes from earlier studies with cinacalcet, the reduction in the primary outcome, while numerically positive, was not statistically significant. A more detailed analysis of this study will be completed once the paper is published.
At the end of 2011, Novartis suspended the ALTITUDE Study, effectively ending the possibility that the direct renin inhibitor (DRI) Aliskiren will play a significant role in the management of patients with CKD already on an ACE or ARB. This development was disappointing but actually represents only part of a growing body of evidence that now casts major doubt on the use of microalbuminuria (MAU) as a treatment surrogate in patients with cardiovascular disease.
The use of MAU as a predictor of cardiovascular risk is sound and supported by a sizable evidence base. There is little doubt that patients with risks for cardiovascular disease who also have MAU are at far greater risk for adverse outcomes including death. In numerous studies, including the Heart Outcomes Prevention Evaluation (HOPE) Trial , MAU was the single most potent risk factor for adverse outcomes, with greater predictive power than diabetes, male gender, smoking and hypertension. The fascinating part of this observation is that even seemingly modest elevation in MAU was highly predictive of adverse events. It was very tempting then to anticipate a concomitant reduction in risk among patients whose MAU was targeted for therapeutic reduction with any of: (1) high dose ACE or ARB, (2) combination ACE and ARB, and most recently, (3) combination ACE or ARB with DRI. Unfortunately, recent prospective studies have essentially decimated this hypothesis and in all, proteinuria improved whereas patients did not or actually fared worse.
In a stunning development, Novartis said Tuesday that it will terminate the late-stage ALTITUDE study investigating Rasilez (aliskiren) in patients with type 2 diabetes and renal impairment on the recommendation of an independent data monitoring committee. The company indicated that the committee concluded that "patients were unlikely to benefit" from the addition of Rasilez to standard anti-hypertensives and also identified higher adverse events in this group (source: FirstWord).
On a personal and professional note, these results come as a great disappointment to me. Not only does it suggest no further protection for our patients prescribed this strategy in an effort to reduce the burden of cardiorenal disease, but I was a great believer in the hypothesis and taught about it extensively throughout my career.
Dr. Elizabeth Cohen, senior medical correspondent for CNN's Health, Medical and Wellness unit made a dangerously incorrect statement in her report on generic drugs in the US (Seen at approximately 1:37 of the following video).
Nephrology has become a field of medicine that is vastly expanding in knowledge and complexity. The number of students, residents considering the field of nephrology are declining every year. Lot of times the students consider nephrology as a difficult subject to grasp and hence have a "renal fear" to consider this field of medicine. To make nephrology more exciting and fun, and to add adjunctive tools of teaching, there have been attempts to develop interesting tools of teaching in nephrology. Websites like UKidney and others are one such example. E-learning can be used to enhance interest in nephrology. Other innovative tools have been tried as well ( crosswords, anagrams, role playing, concept maps) and we are hoping such tools will aid nephrology education and also enhancement of the field. Here are some links to publications that are reviewing some of these tools. Please give us your comments on these tools and how we can improve and make it more useful for all.