July 6th, 2012
Screening (and Some Rescreening) for Aortic Aneurysms Found Cost Effective
A Danish study published in BMJ confirms the cost effectiveness of screening for abdominal aortic aneurysms in older men and explores the benefits of rescreening in those with increased aortic diameters. (The U.S. Preventive Services Task Force recommends one-time screening for men between age 65 and 75 who have ever smoked.)
Researchers used Danish national registries to characterize a theoretical cohort of 100,000 men at age 65. They then modeled screening versus no screening — and then, among those who were initially screened, a single repeat screening at 5 years versus screening every 5 years for life.
Screening was more cost effective than no screening. Using a cost-effectiveness threshold of roughly $30,000 for each quality-adjusted life-year gained, a single rescreening after 5 years seemed optimal in those with aortic diameters of 25 to 29 mm on the initial screen.
However, the authors cite “substantial uncertainty” and call for further research on the rates of aneurysm growth and rupture.
July 6th, 2012
Panel: How to Develop the Best Fellowship Application — Part I
Andrew M. Kates, MD, James De Lemos, MD and John Ryan, MD
Cardiology fellowship applications are due during the next few weeks. We sat down with moderators of our Fellowship Training blog to ask for their advice regarding the application process and how residents can best prepare for it.
We are joined by Dr. James de Lemos, past Cardiology Fellowship Program Director at UT Southwestern, Dr. Andrew Kates, Cardiology Fellowship Program Director at Washington University, St. Louis, and Dr. John Ryan, Cardiology Fellow at University of Chicago.
This is Part I of a two-part series. Part II concerns how having published research affects your competititiveness, whether you should differentiate yourself by stating a career path, and the new timing of the application cycle.
CardioExchange: What do programs look for in personal statements? What is the best way of approaching this aspect of the fellowship application?
de Lemos: These should be clear, succinct, and focused—please dispense with all BS! Too often, I read flowery descriptions of why someone wants to be a cardiologist. For us, this is a given — who wouldn’t love cardiology? Also, statements trying to be clever totally turn me off. Remember that the statement can hurt you much more than help you. It should describe your journey, focusing on aspects of your career to date that provide evidence of your future direction. If you’ve done research, this should be described in more detail, including your role in the project. You should clearly state a future direction, even if it is still vague in your head. We are looking for individuals who are organized enough, and plan well enough, to describe a clear path forward for their individual career trajectory. We all know it may change — even before you start your first day of fellowship! Finally, two don’ts:
(1) Never, ever go over one page.
(2) Be very careful about your personal stories—all of you have personal reasons for choosing cardiology, but too often the descriptions of these sound corny and self-serving.
Kates: We are looking to see that applicants can put together coherent thoughts in a clear way. I tell our residents to avoid waxing poetic or trying to write the next great novel. I also tell them to avoid the story of pursuing medicine as the wish of dear departed grandmother or other family member. Talk about your plans. Talk about what motivates you. The personal statement is the opportunity also to explain if you had taken a nontraditional pathway to medicine or if you took a year or two off or changed programs. What’s most important — unless you have a great story to tell, just be concise and be yourself.
Ryan: Whereas your resume is about what you have done, the personal statement is about what you are going to do. Creating a succinct, realistic plan about what you hope to achieve over the next 5-10 years is useful. To do this, I think you should look at junior faculty members who finished their residencies 5-10 years ago and use their achievements as an example of the type of physician you want to be.
CardioExchange: How should applicants decide who should write their letters, and do all the letter writers need to be cardiologists?
de Lemos: Remember one thing first and foremost. You are asking for a letter of recommendation — not an evaluation letter. Your program director or Chair will write the letter comparing you to your peers, but your other letter writers should all say you are a workhorse with a heart of gold and the intellect of Osler. When you identify possible letter writers, ask them whether they would be willing to write a very strong letter in support of your application — you need to know the answer to this before you get the letter. If they feel lukewarm about you, thank them for their honesty and ask someone else. There is nothing worse than faint praise. Since almost all of the letters exaggerate and inflate the candidate, yours needs to do the same to be competitive. In my opinion, they should all come from cardiologists and, if possible, from cardiologists with connections or reputations outside your institution. However, it is better to get a strong letter from someone who is not well known than a lukewarm letter from a national figure.
Kates: Letters should above all be from people who know you well. While not all letters need to be from cardiologists, the majority should be. The letter from your PD tends to be more of an advocacy letter than a letter of recommendation. Applicants want to get letters from famous names, but in reality a letter from a well-known person who spent a week with you on service says less than a letter from junior faculty who worked with you for two or three months. If you have done research with someone, get a letter from them – especially if the research was published.
Ryan: I think it is important that the letter writer truly knows you — the personal relationship should shine through, as a form letter can be obvious. Also, you must be confident in the fact that the referee is going to actually write a supportive letter. At times, residents ask the wrong person to write them a letter because he or she is well-known in the field but does not know the applicant well — this comes out easily. If you have done research during residency, then get a letter from the research supervisor who can highlight your skill as a researcher. Still, having a letter from a cardiologist known around the country is important (with the caveat that the cardiologist should know you well). When it comes to interview season, your letter writers will be your greatest asset in making and receiving phone calls supporting your application.
July 5th, 2012
Stem Cell Therapy Company Hypes Preliminary Results
Larry Husten, PHD
A biotech company has been accused of releasing preliminary and misleading information about a clinical trial. The company, Osiris Therapeutics, is the manufacturer of a cultured mesenchymal stem cell (MSC) therapy called Prochymal, which is being studied in a phase 2, placebo-controlled trial in post-MI patients. Earlier this week, Osiris issued a press release announcing preliminary results from the trial, in which 220 patients have been randomized, claiming that Prochymal “significantly reduces hypertrophy, arrhythmia and progression to heart failure in patients suffering a heart attack.” But Adam Feuerstein, a veteran biotech reporter for The Street, accuses the company of distorting the truth about the trial.
Osiris “disappeared” important data in its press release, Feuerstein writes in his detailed analysis. He quotes the press release:
Patients receiving Prochymal had significantly less cardiac hypertrophy, as measured by cardiac MRI, compared to patients receiving placebo (p [less than] 0.05). Patients treated with Prochymal also experienced significantly less stress-induced ventricular arrhythmia (p [less than] 0.05).
Feuerstein comments:
Sounds impressive except none of the Prochymal benefits disclosed by Osiris are predefined endpoints in the phase II trial. Osiris appears to have thrown out the real endpoints called for in the phase II trial and replaced them with new endpoints which just happen to show Prochymal in the best light. Why would Osiris do this? Perhaps the pre-defined endpoints in the study all failed? That’s a pretty safe assumption when companies decide to swap out trial endpoints with no disclosure or explanation.
Feuerstein points out that the primary endpoint of the trial, as listed on ClinicalTrials.gov, is left ventricular end systolic volume (ESV), while the secondary endpoints are left ventricular ejection fraction (LVEF), infarct size, and major adverse cardiovascular events. Writes Feuerstein: “Osiris’ silence on the outcomes of these two important endpoints [ESV and LVEF] should be deafening to investors — and not in a good way.”
The Osiris press release also claims “a statistically significant reduction in heart failure”:
In the study, seven patients who were treated with placebo have progressed to heart failure requiring treatment with intravenous diuretics, compared to none of the Prochymal patients (p=0.01). Furthermore, patients receiving placebo tended to require re-hospitalization for cardiac issues sooner than the patients receiving Prochymal (median 27.5 days vs. 85.5 days).
However, as Feuerstein writes, “these weren’t predefined endpoints”:
Importantly, Osiris doesn’t disclose the time point at which these purported benefits occurred, nor does the company tell us anything about the number of patients analyzed. How was heart failure defined? Osiris doesn’t say. What was the baseline incidence of heart failure in the study? Osiris doesn’t say. The study only allowed for a single infusion of Prochymal or a placebo immediately after the first heart attack but patients were followed for six months or a year, so how do follow-up therapies in each arm of the study compare? Were they balanced? Again, Osiris doesn’t say.
In the press release, a company official announces an extension of the trial’s duration:
Given the quality of the data and highly encouraging results observed thus far, we are extending the trial’s duration to capture a better understanding of the long-term clinical benefits of MSCs.
But the company offers no explanation for the extension. Writes Feuerstein:
Perhaps Osiris is extending the phase II study to delay the reporting of negative results? Again, that’s a pretty safe assumption absent a better explanation.
Update (July 6)– I have heard from several investigators in the trial that the Osiris press release was issued without any input or consultation from the site investigators. In fact, the site investigators, including several who are extremely experienced clinical trialists, have expressed frustration and disappointment because their input has not been sought at any point during the trial. In most multicenter trials it is common practice to consult with the sites, and in particular the top-enrolling sites. In this case, the highest enrolling sites have had no significant involvement in the trial design or conduct. One investigator said he “had never worked with a company like this.”
Another member of the steering committee told me that the committee had not met in a long time and has not seen the trial data. In fact, steering committee members were not even aware that Mark Vesely, an assistant professor at the University of Maryland, was the principal investigator of the study. One steering committee member said he’d never heard of him before reading the press release.
July 3rd, 2012
Many CHF Patients Not Receiving – Or Getting Benefits From – High Dose ACE Inhibitors and ARBs
Larry Husten, PHD
Although current guidelines recommend that ACE inhibitors and angiotensin-receptor blockers (ARBs) be used in high doses in patients with congestive heart failure, many CHF patients currently receive lower than recommended doses of these drugs. In a research letter published online in Archives of Internal Medicine, investigators in Montreal analyzed data from 43,405 patients with a first hospital admission for CHF in Quebec, 73% of whom received an ACE inhibitor and 27% an ARB.
Patients were classified as receiving low-, medium-, or high-dose drugs. Twenty-nine percent received a low dose. The groups were not evenly matched: patients in the high-dose group were more likely to have hypertension and diabetes, while patients in the low-dose group were more likely to have renal disease.
After adjusting for other factors, the risk of dying or being readmitted to the hospital was significantly reduced in the high-dose group. Here are the hazard ratios for ACE inhibitors and ARBs (medium dose serves as the reference):
ACE Inhibitor Mortality:
- Low dose: 1.16 (1.12-1.20)
- High dose: 0.90 (0.86-0.94)
ACE Inhibitor Mortality or CHF Readmission:
- Low dose: 1.09 (1.05-1.13)
- High dose: 0.93 (0.89-0.96)
ARB Mortality:
- Low dose: 1.15 (1.06-1.24)
- High dose: 0.93 (0.87-1.00)
ARB Mortality or CHF Readmission:
- Low dose: 1.18 (1.09-1.27)
- High dose: 0.95 (0.89-1.02)
The authors concluded that “physicians should strive, whenever possible, to treat patients with CHF with high doses of ACE inhibitors or ARBs to improve outcomes.”
July 2nd, 2012
Eroding Confidence in ASD Occlusion Devices
Richard A. Lange, MD, MBA and L. David Hillis, MD
The FDA has identified more than 100 cases of cardiac erosion following atrial septal defect occlusion (ASO) device implantation. All were associated with implantation of the AMPLATZER (AGA Medical/St. Jude Medical) or related cribriform ASO devices; none have been reported thus far with the GORE HELEX (Gore Medical) ASO device.
Although the estimated occurrence of cardiac erosion is 0.1% to 0.3%, the precise incidence is unknown, because ASO manufacturers aren’t required to register or report device implantations, and the reporting of device-associated complications in the FDA Manufacturer and User Facility Device Experience (MAUDE) database is sporadic.
Cardiac erosion has been observed as early as within 24 hours of device implantation and as late as 8.6 years after implantation, with ≈50% occurring in the first week, 61% in the first month, and 87% in the first year after device placement. The erosions typically occur at the domes of the atria near the aortic root and cause immediate hemodynamic compromise due to pericardial effusion, tamponade, or both; patients typically present with pericarditis, hypotension, or even sudden death. Occasionally, the process is chronic; fibrosis develops as erosion progresses, and an atrial-to-aortic fistula develops. These individuals typically present with heart failure or a new-onset murmur. Regardless of the manner of presentation, prompt recognition and surgical intervention are indicated.
Except for ASO device type, the risk factors that predispose to device-related erosions are unknown. A deficient anterosuperior atrial rim (<5 mm) seems to be a risk factor, but the FDA Circulatory Device Advisory Panel determined that the data supporting this association were inconclusive and made the uncharacteristic recommendation that St. Jude remove deficient anterosuperior rim — which occurs in ≈40% of patients with a secundum ASD — as a contraindication to ASO device closure.
Limitations in our understanding of this life-threatening complication highlight the fact that a device registry is needed. In the meantime, patients considering ASO device implantation should be informed of this potential complication and its symptoms, so they can decide whether to proceed with percutaneous ASD closure or, alternatively, to undergo surgical repair.
Will these reports of cardiac erosions following ASD occlusion device implantation affect your recommendations regarding their use?
July 2nd, 2012
Severe Blood Conservation Appears Safe in Cardiac Surgery for Jehovah’s Witnesses
Larry Husten, PHD
Severe blood conservation in conjunction with cardiac surgery is not associated with long-term adverse consequences, according to a new study published in the Archives of Internal Medicine.
Investigators from the Cleveland Clinic and the NHLBI compared 322 patients who were Jehovah’s Witnesses with an equal number of matched controls. Due to their religious beliefs, Witnesses do not receive blood transfusions, and therefore “provide a unique natural experiment in severe blood conservation,” according to the authors.
Compared with patients who had transfusions, Witnesses had better short- and long-term outcomes. They had fewer complications in the hospital and better survival out to 15 years.
- Perioperative MI: 0.31% for Witnesses vs. 2.8% for controls (p = 0.01)
- Operation for bleeding: 3.7% vs. 7.1% (p = 0.03)
- Prolonged ventilation: 6% vs. 16% (p < 0.001)
- Hours in the ICU (15th, 50th, and 85th percentiles): 24 vs. 24, 25 vs. 48, and 72 vs. 162 (p < 0.001)
- Survival at 5 years: 86% vs. 74%
- Survival at 10 years: 69% vs. 53%
- Survival at 15 years: 51% vs. 35%
The investigators conclude that although they “found differences in complications among Witnesses and control groups that received transfusions, current extreme blood management strategies do not appear to place patients at heightened risk for reduced long-term survival.”
In an accompanying commentary, Victor Ferraris points out that “Witnesses who undergo cardiac surgery are likely a healthier subgroup of Witnesses because those who are believed by their surgeons to require blood transfusion to survive cardiac surgery presumably never go to the operating room.” Nevertheless, “the finding that the Witnesses who did not receive transfusions did at least as well as, if not better than, those who received a transfusion raises questions about whether more patients might benefit from surgical strategies that minimize transfusion of blood products.”
July 2nd, 2012
Selections from Richard Lehman’s Literature Review: July 2nd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 27 June 2012 Vol 307
Pay for Performance (pg. 2595): Of all the things that made me glad to retire from general practice two years ago, pay for performance must top the list. Here’s a Viewpoint piece from the USA which explains why: “Focusing on specific outcomes does not reward skills or result in managing complexity, solving problems, or creativity. Indeed, Pink suggests such reward systems will undermine these desirable attributes.” Good old Pink: I like the cut of his jib. “Translating the ideas of Trisolini and Pink into a clinical medicine context leads to several recommendations: pay physicians a rewarding yet reasonable salary rather than piecework rewards, provide a direct ability to influence patient outcomes, and offer a continual sense of accomplishment and recognition. These would represent a more effective approach to motivating performance than specifically paying for production functions.” Good old Trisolini, too: nice jib. And here is the last paragraph of this excellent piece by Christine Cassell and Sachin Jain: “Efforts to assess physician performance are here to stay. The current system of care has invested a great deal in these measures, both financially and intellectually, and the goals they seek to achieve are critical to a high-functioning health care system. To reach sustainable quality goals, however, close attention must be given to whether and how these initiatives motivate physicians and not turn physicians into pawns working only toward specific measurable outcomes, losing the complex problem-solving and diagnostic capabilities essential to their role in quality of patient care, and diminish their sense of professional responsibility by making it a market commodity. Rewards should reinforce, not undermine, intrinsic motivation to pursue needed improvement in health system quality.” Amen.
Berwick’s Commencement Address (pg. 2597): And now from the man who has worked harder than anybody to improve health service quality – Donald Berwick’s address to Harvard medical graduates as they set out: “You will soon learn a lovely lesson about doctoring; I guarantee it. You will learn that in a professional life that will fly by fast and hard, a hectic life in which thousands of people will honor you by bringing to you their pain and confusion, a few of them will stand out.” The one who stands out for him is called Isaiah. He was a black child, addicted to cannabis at 5, crack at 14, by which time he had already done his first armed robbery. Berwick saved him from acute lymphoblastic leukaemia. He was found dead in the street 18 years later. “Society gives you rights and license it gives to no one else, in return for which you promise to put the interests of those for whom you care ahead of your own. That promise and that obligation give you voice in public discourse simply because of the oath you have sworn. Use that voice. If you do not speak, who will?”
tPA for Ischaemic Stroke in Warfarin-Treated Patients (pg. 2600): And now back to the kind of medicine that gets published in journals. A lot of people who get ischaemic stroke are taking warfarin, usually for atrial fibrillation. Is it safe to give these people intravenous tissue plasminogen activator (tPA) if they get an ischaemic stroke? The bottom line seems to be yes: “Conclusion: Among patients with ischemic stroke, the use of intravenous tPA among warfarin-treated patients (INR ≤1.7) was not associated with increased symptomatic intracranial haemorrhage risk compared with non–warfarin-treated patients.” But read that again. These patients were not being meaningfully anticoagulated with warfarin: their INRs were all 1.7 or less. Had their warfarin been properly monitored, they would probably never have had their stroke in the first place.
NEJM 28 June 2012 Vol 366
Surgery for Infective Endocarditis (pg. 2466): Infective endocarditis is a pleasing diagnosis to make, but not a good one to receive. Ever since I first read it at the age of 18, I’ve been haunted by this scene from the memoirs of Alma Mahler: “Chantemesse, who was a celebrated bacteriologist, now made a culture from Mahler’s blood and after a few days he came to us in great delight with a microscope in his hand. I thought a miracle had happened. He placed the microscope on the table. ‘Now, Madame Mahler, come and look. Even I – myself – have never seen streptococci in such a marvellous state of development.’… But I could not listen. Dumb with horror, I turned and left him.” In the trial reported here, patients with left-sided infective endocarditis, severe valve disease, and large vegetations were randomly assigned to early surgery (37 patients) or conventional treatment (39). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks after randomization. It was a small trial, but an easy win for surgery done within 48 hours.
Lancet 30 June 2012 Vol 379
The American Healthcare System (pg. 2412): Appalled by the prospect of the Supreme Court declaring Obama’s health act unconstitutional, Richard Horton is moved to fill the whole of Offline this week with an eloquent, coherent, historically informed view of America’s strange relationship with its health providers, and how this distorts the whole of global health provision. I never thought to write such praise of Offline; but I still prefer Victor Montori on Twitter: “Health care is a human right. Societies must protect and promote it. Debate how, not whether.”
BMJ 30 June 2012 Vol 344
Record Number of RECORD Studies: Those of us who are interested in the full disclosure of all data from clinical trials are not all paranoid geeks by nature. It has taken me the best part of fifteen years to realize how biased and incomplete the evidence base for common interventions can be, despite the efforts of the regulatory agencies. A classic case was rosiglitazone (Avandia) where cardiovascular harms were suspected from the start but were supposedly laid to rest in the open-label RECORD trial, sponsored by the manufacturers; in fact there is clear evidence of biased adjudication in this study, presented to the FDA two years ago and never explained since. I was therefore stunned to see the RECORD study appear in this meta-analysis of new oral anticoagulants following hip and knee replacement, again in the context of a seemingly biased adjudication. To quote in full: “However, major bleeding rates reported in the four pivotal RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) studies with rivaroxaban were 7-8 times lower than those in the enoxaparin groups of the remaining studies, which was attributed to the exclusion of most wound bleedings from the definition of major bleeding, as previously reported. This issue prevented the pooling of data on major bleeding reported in the publications of the RECORD studies. However, the major bleeding rates in the RECORD studies without excluding major wound bleedings were reported in an FDA review, and were similar to the major bleeding rates of the remaining studies.” Hmm. I thought there was only one RECORD study, which was nothing to do with rivaroxaban. In fact there are four others, sponsored by Bayer and Johnson and Johnson, in which the acronym stands for Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism. It is time for the BMJ to set the RECORD straight. As for the meta-analysis, it proves that it’s swings and roundabouts with dabigatran, rivaroxaban and apixaban for preventing VTE: the new oral agents may be slightly more protective than enoxaparin, but at the cost of slightly more bleeds.
June 29th, 2012
What Does the Supreme Court’s Upholding of Healthcare Reform Mean for Doctors and Patients?
CardioExchange Editors, Staff
CardioExchange invited clinicians and health policy experts to weigh in on what the upheld Affordable Care Act means–good or bad–for doctors and patients. Here are our initial responses. Share your thoughts with us and with your trusted colleagues.
Jack Lewin, MD (Principal, Lewin and Associates, Health Innovation Strategies; former CEO of the American College of Cardiology)
Given the surprising but very positive decision by the Supremes to uphold the Affordable Care Act, the challenge now is to work on improving outcomes at lower costs to help make our current unstable system sustainable. The ACA is already having powerful positive effects. One member of my family has a significant medical disability, for example, and without the ACA’s coverage of high risk “uninsurables” this person found getting insurance almost impossible previously. Many seniors who were patients of mine tell me they can now afford their necessary medicines more easily due to the Medicare “doughnut hole” coverage in the ACA. Thanks to Chief Justice Roberts for seeing the value to building on what is already in place, if imperfect. It’s real progress.
Harry Peled, MD (Medical Director of In-Patient Cardiology/Non-invasive Lab & Medical Director of Critical Care, St. Jude Medical Center in Fullerton, CA)
1.) I am grateful that my college-bound daughter can be insured for a reasonable cost
2.) Chief Justice Roberts has earned tremendous credibility for himself and the court
3.) The Act does absolutely nothing to control medicare costs or reduce either inappropriate care or industry influence. (see for example, my post on the wearable ICD). These issues pose serious dangers to our system. We have twice the average healthcare costs of the rest of the developed world, and rather than addressing this issue, the current law mostly shifts these costs around.
Sorry, there are no polls available at the moment.June 29th, 2012
A Watershed Court Case? The Affordable Care Act and the Role of the U.S. Government in Healthcare
Sandeep Mangalmurti, MD, JD
At first blush, the upholding of the Affordable Care Act (ACA) by the Supreme Court appears to preserve the status quo, at least until next year when there may be a different occupant in the White House. However, a closer look at the opinions reveals a potential fundamental shift in the relationship between federal and state governments. This shift may not be felt for years, but it may eventually change U.S. health care forever.
First, some background: The argument against the constitutionality of ACA was based on a less conventional interpretation of the Commerce Clause of the Constitution, which allows the federal government to “regulate interstate commerce.” Since the New Deal, the Commerce Clause has been interpreted quite broadly, allowing the federal government to involve itself in matters with only a tenuous relationship to commerce across state lines. In fact, it would not be an exaggeration to suggest that many scholars think this clause, with some limited exceptions, empowers the federal government to pass nearly any economic regulation it chooses. Since the New Deal, the Supreme Court has generally agreed with this interpretation; the Commerce Clause has almost never been used to rein in federal authority.
Others argue for a much more limited view of this clause, maintaining that it constrains federal regulatory power far more tightly than currently envisioned. Thus, they argue that an individual mandate is unconstitutional because forcing people to buy health insurance could not be reasonably be considered “regulating interstate commerce.”
With the Supreme Court’s decision on the ACA, a majority of the court agreed with that basic argument. Justice Roberts found the ACA constitutional not because he thought its individual mandate could be justified as “interstate commerce,” but because he felt it was a tax. He agreed with four of his brethren that the Commerce Clause was not a blank check, allowing the federal government the power to mandate or regulate anything it wishes.
Some think this is the beginning of a judicial effort to place clear constitutional limits on federal economic authority, a process that may unfold over many years. The implications for health care are vast. Take, for example, medical malpractice liability reform: Physician groups have been advocating for comprehensive tort reform at the federal level, including imposition of damage caps. The possible benefits of tort reform, including decreased defensive medicine, increase in physician supply, etc. become significant when implemented at a federal level. However, “federalizing” these reforms are likely contingent upon an expansive view of the Commerce Clause. If the Court is beginning to reject this view, would federal tort reform efforts survive judicial scrutiny? Time will tell….
June 29th, 2012
Linagliptin and Glimepiride Compared in Type 2 Diabetes
Larry Husten, PHD
Sulfonylureas are often added to metformin to improve glycemic control, but at the known risk of increasing hypoglycemia and weight gain. In a report published in the Lancet, more than 1,500 patients with type 2 diabetes taking metformin were randomized to the addition of either linagliptin, a dipeptidyl peptidase-4 inhibitor, or glimepiride, a sulfonylurea.
After two years, the trial achieved the prespecified criterion for noninferiority as treatment with both drugs resulted in a similar effect on HbA1c. Both hypoglycemia and weight gain were reduced in patients taking linagliptin. There was only one case of severe hypoglycemia in the linagliptin group, compared with 12 cases in the glimepridie group. In addition, although there were only a small number of cardiovascular (CV) events, a significant reduction was observed in the linagliptin group.
- Reduction in mean HbA1c: −0.16% for linagliptin vs. −0.36% for glimepiride (difference 0.20%, CI 0.09–0.30)
- Hypoglycemia: 7% for linagliptin vs. 36% for glimepiride (p<0.0001)
- Weight: −1.4 kg vs. +1.3 kg (p<0.0001)
- CV events: 12 vs. 26 events (RR 0.46, CI 0.23—0.91, p=0.0213)
The results, write the authors, “support the use of linagliptin in combination with metformin as a therapeutic option for treatment of type 2 diabetes.”
In an accompanying editorial, André Scheen and Nicolas Paquot discuss the potential benefits of linagliptin and other DPP-4 inhibitors. They note that the smaller reduction in HbA1c with linagliptin “might support the view of a slightly lower efficacy of DPP-4 inhibitors compared with sulphonylureas,” but say that only a trial with longer followup can assess the durability of glucose lowering with DPP-4 inhibitors. In the meantime, the effects on weight and the lower rate of hypoglycemia are “important to patients with diabetes” and can improve quality of life.
However, firm conclusions about the drugs can not be reached until long-term trials with cardiovascular outcomes are completed. These trials will “provide enough data for both efficacy (i.e., effects on diabetic complications) and safety (i.e., concerns about pancreatitis and pancreatic cancer) to draw firm conclusions about the real value of this new approach.”
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