Internal Medicine Residency News, August 29, 2016

What did I read this week?

Contributed by David Butterly, MD

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. C Wanner, SE Inzucchi, et al for the EMPA-OUTCOME Investigators. NEJM 374: 323-334 July, 2016

This article appeared in last month’s NEJM. Blake Cameron presented the paper for our Nephrology Journal Club which gave our division a chance to discuss the findings in detail.  The results are encouraging and I think you will find the article worth the read.

Background

As I know most of you are aware from rounding on Gen Med and Cardiology and other services caring for our patients with ESRD, Diabetic Kidney Disease is incredibly common. In fact, in patients with DM, even mild degrees of albuminuria and impaired GFR are associated with marked increased risk of cardiovascular morbidity and mortality. Up to 40% of patients with Diabetes (either Type 1 or Type 2) develop nephropathy and diabetes is the leading cause of ESRD in the US with roughly 40-50% of new starts to dialysis due to Diabetic Nephropathy. 

Interventions have predominantly focused on metabolic control along with treatment of hypertension. The DCCT and the UKPDS have demonstrated that improved glycemic control can delay or slow the progression of microvascular complications including nephropathy. The single most effective measure for delaying progression is the reduction of BP and multiple trials in both Type I and Type II DM have demonstrated the additional beneficial effects of inhibition of the renin angiotensin system.

The last decade has seen the development of many new agents for the treatment of Type II Diabetes. Three novel pharmacologic approaches have come to market: 1) the Glucagon-like peptide1 (GLP-1) agonists which stimulate insulin release, 2) the dipeptidyl peptidase 4 (DDP-4) inhibitors which act on the same path and inhibit GLP-1 breakdown and finally 3) the sodium-glucose cotransporters (SGLT-inhibitors) which prevent the resorption of glucose in the proximal tubule. Each of these agents has been demonstrated to improve glycemic control, but whether they impact microvascular complications including diabetic nephropathy, has not been rigorously studied.  The current study reports on the renal effects of an SGLT-Inhibitor- Empagliflozin- in a large cohort of patients with Type 2 DM and cardiovascular disease.

Methods

The study included patients with Type 2 DM, established cardiovascular disease, and a GFR > 30.  Patients were randomly assigned to receive either empagliflozin at 10 or 25 mg or placebo in addition to standard care.  The primary outcome of the EMPA-REG OUTCOME trial was a composite of 3 cardiovascular events: 1) death from CV event, 2) MI or 3) Stroke.

A secondary outcome of the trial was a composite of microvascular outcomes that included retinal events and nephropathy.  This study reports on the renal outcomes. 

Renal outcomes that were tracked included:

• Incident or worsening nephropathy
• Progression to Macroalbuminuria (> 300 mg/ gm Creatinine)
• A doubling of serum creatinine
• Initiation or renal replacement therapy
• Death with renal failure

In the study, patients with Type 2 DM and GFRs > 30 were randomly assigned to either Empagliflozin (10 or 25 mg) or placebo once daily. 

Patients

Baseline Characteristics are shown in Table 1 on page 327.

A total of 7020 patients were enrolled at 590 sites in 42 countries.  By design more than 99% had cardiovascular disease.  eGFR was 45-59 in 18%, 30-44 in 7.7%.  Nearly 30% had microalbuminuria and 11% had macroalbuminuria. 

The group with eGFR < 60 were older- 67 vs 61.  Diabetes management is outlined in Table 1.  60-80% were on Metformin and 45-60% were on insulin.  HgbA1C was 8 and did not differ between the groups.  80.7% of the group were on ACE-I or ARB.  BP at baseline averaged 130’s/70’s and did not differ between the groups.

Results

Figure 1 on page 329 shows Kaplan-Meier Analysis of renal outcomes.

The composite renal microvascular outcomes occurred in 577/4132 (14%) treated patients vs 424/2068 (20.5%) in the placebo group, a relative risk reduction of 38%.  Incident or worsening nephropathy occurred in 525/4124 (12.7%) in the Empagliflozin treated group versus 388/2061 (18.8%) in the placebo group. This represented a relative risk reduction of 39%. Progression to macroalbuminuria occurred in 459/4059 (11.2%) vs 330/2033 (16.2%).  A doubling of serum creatinine was seen in  70/4645 (1.5%)  vs  60/2323 (2.6%) in those treated with placebo, a relative risk reduction of 44%.  Initiation of renal replacement therapy was seen in only a small number (13//4687 vs 14/2333), but again was reduced by about 50% in the Empagliflozin treated group. 

Risk comparison of the seven renal outcomes is highlighted in Figure 2 pg 330.  Six of seven renal outcomes tracked were reduced in the Empagliflozin treatment arms.  Change in GFR over the 192 weeks of the study is shown in the 3 groups in Figure 3 A page 331.  Figure 3 B shows eGFR at conclusion of the study and at final study visit after coming off the medication.  Adverse events are detailed in Table 2 pg 332.  AKI and Hyperkalemia were not seen at any higher frequency in treatment groups. 

Conclusions

In summary, in patients with Type II Diabetes and high cardiovascular risk, the use of Empagliflozin, in addition to standard care, was associated with slower progression of CKD and lower rates of clinically significant renal events. The relative risk reduction of roughly 40% was consistently seen in all renal outcomes and is similar to the risk reduction seen in the pivotal trials evaluating treatment with ACE-I and ARBs in this patient population. 

The renal effects of this class of drugs are likely multifactorial but direct renovascular effects may play an important role. By inhibiting proximal tubular sodium resorption, Empagliflozin increases distal sodium delivery and through the process of tubuloglomerular feedback the net result is a decrease in glomerular hyperfiltration. This was previously demonstrated in a group of patients with Type I DM treated with Empagliflozin (Cherney Circulation 2014).  Importantly, although this class of drugs does alter glomerular hemodynamics, they do not inhibit RAAS and there was no increase in AKI or hyperkalemia seen when combined with ACE or ARB. Thus, the unique glomerular hemodynamic effects of this particular class of drugs may allow them to impact renal function beyond their effects on glycemic control. 

These results were seen in a group of patients whose BP was already well managed with RAAS blockade in the majority of participants.  Whether these results can be generalized to patients with a lower risk of CV disease and in African Americans (small sample size) remain in question and will require further investigation. More studies will be forthcoming but anything which can delay or slow the progression of CKD in this population would not only help our individual patients but could have a huge public health impact as well. 

 

Clinic Corner: Ambulatory Care

Contributed by Daniella Zipkin, MD

A few words from clinic land…

First, a big shout out to Leah Machen and Annie Reihman for their outstanding work representing the ResCo subcommittee on ambulatory care. They have brought energy and ideas and questions and are helping us take a fresh look at the full curriculum. Thanks to both of you, we are so glad to have you!

July was the hottest month on record on planet Earth. And, July turned out to be pretty rough in ambulatory world too – it was a perfect storm, a combination of the 4+2 schedule increasing the numbers of residents on ambulatory, template updates which have been in progress for the past few months not fully complete yet, and multiple faculty on vacation. If you have issues with your ambulatory week, please always let Aparna and me know so we can get on the fixes right away. Thanks for your patience with us!

Speaking of template updates, did you know there are now 17 ambulatory experiences available to JARs and SARs, including all medicine subspecialties and more? They are:

• Pulmonary
• Cardiology
• Renal
• GI
• Hematology-Oncology
• Rheumatology
• Endocrinology
• Allergy-Immunology
• Infectious diseases
• General Medicine
• Palliative Care
• Sports Medicine
• Dermatology
• Women’s Health
• ENT/Ophthalmology
• Lincoln Community Health Center
• and partial week experiences in Pain Medicine and Integrative Medicine

Please let us know if you have an interest in a particular ambulatory experience and haven’t done it yet. Aparna continues to work on expanding each template.

We are happy to introduce General Internal Medicine (GIM) Journal Club, coming soon to a faculty home near you. Come enjoy food and drink and time to hang out with your friends. All are welcome. Stay tuned for details.

I will be holding “Zipkin office hours” at the various sites, and please send me a message any time you want to meet up or talk. Next one is this Wednesday, August 31, 2pm at Prime Clinic. Hope to see some of you then.

Continuity Clinic Evaluations: thanks to everyone who filled out this evaluation last spring, we are actively using your responses to work on changes needed at each clinic site.

See you back at clinic!!

Dani

From the Chief Residents

Morning Report and MGR: August 29-September 2, 2016

Date	Topic	Lecturer	Time	Location
8/29/16	Anemia	Murat Arcasoy	7:15 a.m.	DUH 8253
8/30/16	Case presentation	Magana / Cohen	7:15 a.m.	DUH 8253
8/31/16	Cost-conscious medicine	Maselli / Klotman	7:15 a.m.	DUH 8253
9/1/16	Wellness activity	Jim Lefler	7:15 a.m.	DUH 8253
9/2/16	Medicine Grand Rounds: Systems pharmacogenomics of aspirin: A new take on an old drug	Deepak Voora, assistant professor of medicine (Cardiology, and Kevin Friede, hospitalist	8:00 a.m.	DUH 2002

 

Noon Conference: August 29-September 2, 2016

Date	Topic	Lecturer	Time	Location	Lunch
8/29/16	MKSAP Endocrinology	Aparna Swaminathan	12:00 p.m.	DUH 2002	Jason's Deli
8/30/16	SAR Lecture Series: Oncologic Emergencies: TLS/Spinal Cord Compression	Kahli Zietlow	12:00 p.m.	DUH 2002	Nosh
8/31/16	ITE		12:00 p.m.	Oregon St. Computer lab	China King
9/1/16	ITE: Mindfulness Workshop with Dr. Brantley		12:00 p.m.	Civitan Bldg., 2213 Elba Street, Room 229	Domino's
9/2/16	Chair's Conference	Sky Vanderburg	12:00 p.m.	DUH 8253	Bullocks BBQ

From the Residency Office

Have You Logged Your Duty Hours??

With the start of the 2016-17 academic year, the residency program is asking all house staff to log their duty hours on a daily basis.  This will allow us even closer oversight of duty hour compliance across the program.  In order to use the MedHub mobile Duty Hour app, you will need to know your actual MedHub log in as it will not accept your NetID/password log in.  If you have forgotten you main log in, please go to the main MedHub site, and select "Forgot my password."  You will then be able to re-set it via email.  Lynsey Michnowicz will be sending reminders each Wednesday to those who have not yet logged their duty hours for the week.  Thank you in advance for your attention to this task!

 

Office hours for program leaders

Please feel free to stop by during these times and of course always feel free to reach out to program leaders to set up a meeting outside of these times if needed.

• Aimee Zaas: Every Monday from 3:00 p.m. to 4:00 p.m. and Thursday from 10:00 a.m. to 11:00 a.m.
• Dani Zipkin: Wed., Aug. 31 from 2:00 p.m. to 3 p.m. in VA Prime clinic; Wed., Sept. 7 from 11 a.m. to 12 p.m. in Pickett Rd.

 

Global Health-Internal Medicine Residency Program recruiting eligible candidates

Internal Medicine Residents who have successfully completed PGY1 are eligible to apply for the Duke Global Health Pathway for Residents and Fellows, an extended residency that leads to a Master of Science in Global Health and a total of nine months providing clinical care and conducting mentored research at a Duke University international partner site. Visit www.dukeglobalhealth.org for an in-depth description of the core curriculum including sites, global health competencies, and program requirements as well as application instructions. Watch past global health internal medicine resident John Stanifer discuss his decision to pursue global health training at Duke in this video. Applications will be accepted on a rolling basis until Sept. 1, 2016. 

 

Opportunities for Wellness

Feeling down? Need to talk to someone? 

All trainees at Duke have FREE access to Personal Assistance Services (PAS), which is the faculty/employee assistance program of Duke University. The staff of licensed professionals offer confidential assessment, short-term counseling, and referrals to help resolve a range of personal, work, and family problems. PAS services are available free of charge to Duke faculty and staff, and their immediate family members. An appointment to meet with a PAS counselor may be arranged by calling the PAS office at 919-416-1PAS (919-416-1727), Monday through Friday between 8:00 A.M. and 5:00 P.M. For assistance after hours, residents and fellows can call the Blood and Body Fluid Hotline (115 inside DUH, 919-684-1115 outside) for referral to behavioral health resources. Another resource is Duke Outpatient Psychiatry Referrals at (919) 684-0100 or 1-888-ASK-DUKE. https://www.hr.duke.edu/pas/

Upcoming Dates and Events

• August 31 - Stead Trivia Night (Warren Society)
• September 1 - deadline for applications to the Global Health Pathway
• September 7 - Special lecture by Duke Nobel winner Paul Modrich. Registration is required.

• September 7 - Chief Happy Hour w/ Interns - Hope Valley Brewing

• October 8 - Stead Tread 5K Fun Run (Kempner Society)

Useful links

• GME Mistreatment Reporting Site
• Duke Health Influenza Policy
• http://duke.exitcareoncall.com/
• Main Internal Medicine Residency website
• Main Curriculum website
• Department of Medicine
• Confidential Comment Line Note (All submissions are strictly confidential unless you chose to complete the optional section requesting a response.)

Opportunities

• https://www.phs.wakehealth.edu/public/edu.cfm
• www.FloridayPhysicianWork.com
• www.bidmc.org/CentersandDepartments/Departments/BIDHC
• http://www.careermd.com/employers/latestbulletins.aspx