As new therapies emerge, the risk/benefit profile of each comes un-der scrutiny, creating a flood of sometimes conflicting data. The role of each emerging therapy also becomes more challenging to define as each takes its place in our list of indications, and eventually in our practice guidelines. Dr. Alice Cheng, the evening’s moderator, tackled these issues through a series of questions.

QUESTION 1 - Do incretin agents increase the risk of pancreatitis or pancreatic cancer?

Drs. Remi Rabasa-Lhoret and Goldenberg debated the pre-clinical literature to date – conflicting at best. Some studies have documented GLP-1 receptors in both the endocrine and exocrine pancreas and animal models exposed to in-cretins have sometimes shown ductal inflammation. Although there have been post-marketing reports of pancreatitis amongst incretin users, Dr. Goldenberg outlined the flaws and bias in the FDA Adverse Reporting System. Dr. Rabasa-Lhoret also criticized a recently publicized autopsy study of incretin users which recently found pre-malignant lesions in DPP4-i users who had died of unrelated causes. Unfortunately, the study was too unbalanced to lead to any reliable

From the Endocrinology & Diabetes Specialists of LMC Diabetes & Endocrinology. The opinions expressed in this paper are those of the authors and do not necessarily reflect

the opinions of LMC Diabetes & Endocrinology or the editorial board of Clinical Practice Update.

Ronald M. Goldenberg

MD, FRCPC, FACE

EditorRonnie Aronson

MD, FRCPC, FACE

ONTARIOBARRIE

Suzan Abdel-SalamHani Alasaad

BAYVIEWRonnie Aronson Andrew BorightLoren Grossman

Priya Narula (PA)Samantha Sandler

George SteinerAdam Telner

BRAMPTON

Harpreet BajajPrakash Chandra

ETOBICOKEHasnain Khandwala

Nadeem Aslam

MARKHAMNikhil Gupta

OAKVILLED. Y. Twum-Barima

Alex Barchan

THORNHILLJulie Daitchman

Ronald Goldenberg Gloria Rambaldini

Robert SchlosserNina Wine

QUEBECMONTRÉAL

Nouhad SalibaNahla Aris-Jilwan

Zeina Yared

ALBERTACALGARY

Akshay JainStuart Ross

in Diabetes Management: An Interactive Evening for Endocrinologists at Vascular 2013

Thursday, October 17, 2013, Montreal, Quebec

Part 2 – Glycemia Management in the Diabetes Patient

Clinical Controversies

Jordan WeinsteinMD, FRCPC

Remi Rabasa-Lhoret

MD, PHD

Ronnie Aronson

MD, FRCPC, FACE

C L I N I C A L P R A C T I C E U P D A T E I N

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glucose (and sodium) in the renal tubules. He further suggested that they resemble a diuretic in their effect – a modest loss of salt, sugar and water. The expected side ef-fects then, would include a modest BP drop, urinary frequency and theoretical volume contraction.

Dr. Weinstein also pointed out that BP reduction is a lot like BS reduction:“…it depends where you start.” Across studies to date with the first of this class, Cana-gliflozin, in patients with controlled hyper-tension, systolic BP drops were in the order of 3-6mm, vs placebo.

Addressing renal function specifically, Dr. Weinstein pointed out the Canagliflozin phase 3 research program, and the SGLT2 development programs in general, are the largest ever performed for a new therapy and they indicate that these therapies are entirely neutral in their effect on renal func

conclusions. Lipase levels may be higher on average in incretin users, potentially due to low-level pancreatic inflammation.

However, simply having type 2 diabetes in itself carries a significant risk of pancre-atitis. Dr. Rabasa-Lhoret outlined a recent meta-analysis of seven observational studies which suggested a pancreatitis risk that is 84% higher in diabetes patients compared to those without diabetes. Although regis-try studies have reported increased incidenc-es of pancreatitis in incretin users, many were not adequately controlled and did not correct for important other contributors such as alcohol use, cystic fibrosis, gallstone disease, and others. Large controlled tri-als like the recently published SAVOR and EXAMINE trials, have shown no increase in pancreatitis nor pancreatic cancer, in users of saxagliptin or alogliptin.

To rule out even a 25% increased risk of pancreatitis, one would need a randomized controlled trial with 89 000 patients-years follow up per group. Given the natural his-tory of pancreatic carcinoma, a controlled surveillance would need at least a 12-year duration.

QUESTION 2 - Are SGLT2 inhibitors safe for the kidney?

Dr. Cheng introduced this new class of blood sugar (BS) lowering therapies with the confession that the mechanism – clear-ance of glucose through intentional glycos-uria – took her by surprise. The extensive evidence to date shows them to be effective in BS lowering – what is their impact on GFR and albuminuria in diabetes patients? And in diabetes patients with CKD?

Dr. Jordan Weinstein reviewed their mecha-nism – we naturally filter 180 mg/day of glucose through the proximal kidney (glom-eruli). We then undergo an attempt at con-serving that “lost” glucose by reabsorbing it in the distal kidney (tubules) via the work of the SGLT2 glucose-sodium cotransport-ers. If we inhibit the SGLT2 transporters, we prevent the re-absorption of the filtered

Renal handling of glucose in non-diabetic individuals

Glomerulus

Loop of Henle

Distal tubule

Collecting duct

Proximal tubule

S3 segment of proximal tubule -  ~10% glucose reabsorbed -  Facilitated by SGLT1

S1 segment of proximal tubule -  ~90% glucose reabsorbed -  Facilitated by SGLT2

Glucose reabsorption

S3 ~10%

S1

~90% Glucose filtration

(180 L/day) (1000 mg/L)=180 g/day#

Adapted from: 1.  Bailey CJ. Trends in Pharmacol Sci 2011;32:63-71.

2.  Chao EC. Core Evidence 2012;7:21-28.

No/minimal glucose

excretion

SGLT = Sodium-dependent glucose transporter

1

Renal handling of glucose in non-diabetic individuals

Systolic BP reductions !Canagliflozin phase 3 program Systolic BP Reductions

Canagliflozin phase 3 program

Systolic BP reductions !Canagliflozin phase 3 program

Baseline SBP

(mm Hg)

tion and on albuminuria. Overall, in regards to renal safety, he felt there was not much “signal for concern”.

Dr. Ron Goldenberg, again in his role as Devil’s Advocate, did point out that a small minority of patients might experience a more significant GFR decline (> 30%) – in-cluding the elderly, RAAS therapy users, and those already using loop diuretics, especially in patients with pre-existing moderate CKD. Dr. Goldenberg mused that when SGLT2 in-hibitors do become available in Canada, the Clinical Practice Guidelines scientific com-mittee would have to consider adding them to the list of “sick day” medications – thera-pies to be withheld during an acute illness.

A provocative audience question emerged: as we begin using this class of medications, should we be holding or discontinuing ACEi/ARB therapies and/or diuretics? Dr. Wein-stein used the opportunity to remind the Endocrinologist audience that there is no proven cardioprotection with diuretics and went on to suggest that the SGLT2 class could conceivably replace current thiazide diuretic use. If a diuretic-user is showing very well-controlled BP as their baseline, then addition of an SGLT2i might suggest withholding the prior diuretic to avoid the risk of hypotension.

Dr. Goldenberg pointed out recent studies with empagliflozin, another SGLT2i, which showed that BP drops were dependent on the patient’s own baseline – if they were al-ready in the lower end of the normal range, they did not experience any further drop in BP. In contrast, recent posters have indicat-ed that BP lowering was greater in antihy-pertensive users (with a history of hyperten-sion) than in non-users – possibly related to loss of the adaptive response to BP changes. The general consensus was that our clinical experience would guide us as we begin us-ing this important new class of therapies.

Dr. Cheng wrapped up the SGLT2i discussion by asking whether we know the implica-tions of long-term exposure of the renal

tubules to higher glucose levels. In the proximal kidney, the nephrons, the known pathophysiology of glomerular nephropathy is related to high blood levels of glucose, not to filtered tubular levels of glucose. In the distal kidney, the tubular portion, glu-cose is consistently accommodated as part of our natural physiology. The marginal in-crease in the amount of glucose in the distal kidney that would be produced by SGLT2i is unlikely to contribute to any known renal disease. Dr. Goldenberg further pointed out that, in fact, an existing rare genetic disease called “Familial Renal Glycosuria”, with an autosomal dominant inheritance, produces a natural model of the SGLT2 effect and that these people live perfectly normal lives with no sign of chronic kidney damage.

QUESTION 3 - Intensification beyond basal insulin – prandial insulin or an incretin?

Dr. Cheng posed the question of the DM2 patient, optimized on basal insulin therapy with well-controlled fasting glucose levels, BUT with a persistent uncontrolled A1C.

Drs. Rabasa-Lhoret and Goldenberg dis-cussed the evidence to date. Three trials have taken uncontrolled basal insulin-treat-ed patients and randomly assigned them to addition of prandial insulin vs. an incretin agent. While full publications are still not available, the trials have been presented in abstract form at the ADA meeting over the past 2 years. The 4B study compared exena-tide BID with prandial insulin TID and found them to be equal – exenatide was non-inferior and was actually associated with less hypoglycemia and with weight loss. Liraglutide similarly showed weight loss and less hypoglycemia, and was also significantly more effective than OD prandial insulin. Finally, the once-weekly GLP-1R agonist, albiglutide was non-inferior to TID prandial insulin, again with weight loss and a trend towards less hypoglycemia.

Supported by educational grants from members of the pharmaceutical industry.

TORONTO • OAKVILLE • ETOBICOKE • THORNHILL • BARRIE • MARKHAM • BRAMPTON • MONTREAL • CALGARY

Basal Insulin Intensification: GLP-1 RA vs Prandial Insulin

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B.H.R. Wolffenbuttel1, M.A. Nauck, et al, EASD 2013. . Mathieu C et al. ADA Annual Meeting 2013.

Rosenstock J et al. ADA Annual Meeting 2012. Abstract 55-OR.

0

0.4

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Liraglutide OD

-0.74*

Liraglutide vs Aspart

Δ Weight (kg): -2.5* 2.1 -2.8* 0.9 -0.7* 0.8 Hypos: 2.1 5.2 1.0 * 8.2 1.0 2.1 (/10000 patient-years)

Mea

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Although very promising, in each of these studies, the prandial insulin was not titrated aggressively enough to provide a perfect comparison and each was an open label study, with some potential impact of bias. The Endocrinologist audience generally con-curred with the important caveat that thera-py choice be individualized for each patient.

QUESTION 4 - statins and fibrates and the kidney - what is their impact on GFR and albuminuria in patients with or without CKD?

Dr. Weinstein addressed this key question, clarifying a recent misconception regarding fibrates and renal function. Initial interpre-tations of the serum creatinine levels in the course of the FIELD study had suggested a significant rise in serum creatinine and a de-cline in GFR, with fibrate use. However, we now understand that fibrates do not impair GFR (glomerular filtration as estimated by creatinine) but they actually reduce creati-nine secretion, the other mechanism of cre-atinine clearance. The result is an artefactual increase in serum creatinine levels in pa-tients assigned to fibrates. Inulin-based mea-sures of GFR have since confirmed that there is no change in GFR when patients begin a fibrate. Fibrates are similar to cimetidine or trimethoprim in this phenomenon of creati-

nine rise but it is a non-pathological rise.

In fact, follow-up analyses of the FIELD data showed a remarkable stability in patients on fibrates, with a slower loss of renal func-tion over time, than patients not treated with a fibrate. Dr. Goldenberg highlighted that this point was further reinforced in the FIELD and ACCORD washout studies suggest-ing that fenofibrate may be a nephroprotec-tive agent. In fact, fenofibrate definitively slows progression of the albuminuria, much as it does in other microvascular diseases like retinopathy.

Statins and proteinuria have recently come under scrutiny again. Dr. Weinstein refer-enced two prior posters related to the rosuv-astatin studies, PLANET 1 & 2, which showed increased proteinuria with statin therapy, found to be entirely related to tubular protein (2-microgolbulin) and therefore not suggestive of renal pathology.

Finally, in the area of statins and renal func-tion – although a recent patient registry study suggested worsened renal function in patients using high-dose statins, meta-analy-sis of all the atorvastatin and all the rosuvas-tatin trials looking at renal function shows a minor improvement in GFR in patients ran-domized to statins versus placebo.

FIELD: Fenofibrate reduced albuminuria

Keech A et al. Lancet. 2005;366:1849-1861.

11.0

8.2

9.5 9.4

0

2

4

6

8

10

12

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Progression 14% Reduction

Regression 15% Increase

Placebo Fenofibrate Placebo Fenofibrate

Basal Insulin Intensification:GLP-1 RA vs Prandial Insulin

FIELD:Fenofibrate reduced albuminuria