Journal Watch: Non-Alcoholic Fatty Liver Disease, CVD, EXAMINE Trial and More

This column highlights recent diabetes clinical trial data and landmark trials to provide relevant information and links for obtaining trial data and articles to facilitate discussion with patients and other providers. Each trial will be identified by its acronym, its ClinicalTrials.gov Identifier (NCT Number) and its journal reference. 

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease

This is a joint guideline from:
European Association for the Study of the Liver (EASL);
European Association for the Study of Diabetes (EASD); and
European Association for the Study of Obesity (EASO).

This CPG had simultaneous publication in:
J Hepatol. 2016 Jun;64(6):1388-402. PMID: 27062661;
Obes Facts. 2016;9(2):65-90. PMID: 27055256; and
Diabetologia. 2016 Jun;59(6):1121-40. PMID: 27053230.

Introduction/Description from the EASL
(http://www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/the-management-of-non-alcoholic-fatty-liver-disease-easl-easd-easo-clinical-practice-guidelines)

The Clinical Practice Guidelines propose recommendations for the diagnosis, treatment and follow up of non-alcoholic fatty liver disease (NAFLD) patients and are the product of a joint effort by the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). They update a position statement based on the 2009 EASL Special Conference. The data have been retrieved by an extensive PubMed search up to April 2015. The final statements are graded according to the level of evidence and strength of recommendation, which are adjustable to local regulations and/or team capacities.

In particular, screening for NAFLD in the population at risk should be in the context of the available resources, considering the burden for the national health-care systems and the currently limited effective treatments. The document is intended both for practical use and for advancing the research and knowledge of NAFLD in adults, with specific reference to pediatric NAFLD whenever necessary. The final purpose is to improve patient care and awareness of the importance of NAFLD and to assist stakeholders in the decision-making process by providing evidence-based data, which also takes into consideration the burden of clinical management for the health-care system.

Summary: This guideline presents the most up-to-date recommendation for identifying people at risk for NAFLD, algorithm for evaluation and management and review of evidence-based treatments.


Prediction of First Cardiovascular Disease Event in Type 1 Diabetes Mellitus: The Steno Type 1 Risk Engine

References: Vistisen D, Andersen GS, Hansen CS, Hulman A, Henriksen JE, Bech-Nielsen H, Jørgensen ME. Circulation. 2016 Mar 15;133(11):1058-66. PMID: 26888765

Summary: This article describes the development of a clinical decision-making model for predicting risk in Type 1 diabetes of the composite CVD outcome: ischemic heart disease, ischemic stroke, heart failure and peripheral artery disease.
Current risk models for CVD have been developed either for the general population or for Type 2 diabetes mellitus and have been shown to underestimate CVD risk in T1D. This model uses parameters we are already measuring to provide a five-year and 10-year estimated risk.

There is an interactive Web-based calculator at: www.steno.dk/T1RiskEngine.


A Long-term, Randomized, Double-blind, Placebo-controlled, Multinational, Multi-centre Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN™ 6—Long-term Outcomes)

ClinicalTrials.gov Identifier: NCT01720446

References (related): 1. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, Madsen K, Knudsen LB, McGuire J, Steensgaard DB, Strauss HM, Gram DX, Knudsen SM, Nielsen FS, Thygesen P, Reedtz-Runge S, Kruse T. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015 Sep 24;58(18):7370-80. doi: 10.1021/acs.jmedchem.5b00726. PMID: 26308095
2. Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges JP, Lindegaard ML, Jensen CB, Atkin SL; Study 1821 Investigators. A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes. Diabetes Care. 2016 Feb;39(2):231-41. doi: 10.2337/dc15-0165. PMID: 26358288

Sponsor: Novo Nordisk A/S

Study Design: Examine the long-term cardiovascular and other safety outcomes of 0.5-mg and 1.0-mg semaglutide, which was administered subcutaneously once weekly and compared with placebo, both in addition to standard of care, in approximately 3,300 people with Type 2 diabetes treated for 104 weeks. The trial was conducted in Canada, Italy, Japan, Mexico, Russia, South Africa, U.K. and the U.S.

Purpose: This trial was conducted globally in 20 countries. Its aim was to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with Type 2 diabetes. The trial was event-driven, i.e., the maximum trial duration (up to maximum 148 weeks) depended on the accrual of major adverse cardiovascular events (MACE) in this trial and the remaining research program. The incidence of MACE was monitored throughout the trial, which will be terminated according to plan when pre-specified stopping criteria are met.

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Investigator)

Primary Purpose: Treatment

Time Frame: Time from randomization to end of follow up (up to maximum 148 weeks)

Primary Outcome Measure: Time from randomization to first occurrence of a MACE, defined as cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

Results: Note: Results from the SUSTAIN 6 trial were presented at the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD) 2016 in Munich, Germany.

The trial achieved its primary endpoint of showing non-inferiority of major cardiovascular events (MACE) with semaglutide compared with placebo, as well as a statistically significant reduction in cardiovascular risk. In the trial, about 250 MACE were accrued. The primary endpoint of the study was defined as the composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

Summary: These data show that once weekly semaglutide does not increase MACE. However, unlike liraglutide, it did not decrease MACE. This has created a debate as to whether CV benefit is a class effect or specific to liraglutide, which is dosed daily rather than weekly.


Phase II Safety and Efficacy Study of Oral ORMD-0801 in Patients With Type 2 Diabetes Mellitus

ClinicalTrials.gov Identifier: NCT02496000

References (related): Eldor R, Arbit E, Corcos A, Kidron M. Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled Type 1 diabetes: a pilot study. PLoS One. 2013 Apr 9;8(4):e59524. doi: 10.1371/journal.pone.0059524. PMID: 23593142

Sponsor: Oramed, Ltd. With Collaborator: Integrium

Study Design: This is a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group study. After appropriate screening, approximately 180 male and female patients from up to 33 study centers were treated in this study. Patients with Type 2 diabetes mellitus who are being treated by diet, exercise, untreated with antidiabetic medications or treated with metformin monotherapy or in combination with one other antidiabetic drug (excluding insulin) were eligible for enrollment.

Primary Outcome Measure: The effect of ORMD-0801 (Doses 1 & 2, pooled) on weighted mean night time glucose levels based on two nights of Continuous Glucose Monitor (CGM) data by comparison of the mean percent change between baseline and week 4 of ORMD-0801 treatment and placebo groups. [Time Frame: Study day -7 (± 1 day) through Study day 1 (± 1 day), and Study day 22 (± 1 day) through Study day 29 (± 1 day)]

Results: http://www.oramed.com

Summary: Although this trial is not yet published, it is something patients are asking about. Even with once weekly GLP-1s, patients still want to know if there is any way they can “just take pills.” The introduction of oral insulin may change the way we treat diabetes. However, it still needs to complete the required safety and efficacy trials so we can tell patients there are such compounds in development and they should keep asking us about the progress of these trials.


EXAMINE Study

Cardiovascular Mortality in Patients With Type 2 Diabetes and Recent Acute Coronary Syndromes From the EXAMINE Trial

Authors: White WB, Kupfer S, Zannad F, Mehta CR, Wilson CA, Lei L, Bakris GL, Nissen SE, Cushman WC, Heller SR, Bergenstal RM, Fleck PR, Cannon CP; EXAMINE Investigators.

References: Diabetes Care. 2016 Jul;39(7):1267-73. doi: 10.2337/dc16-0303. Epub 2016 Jun 11. PMID: 27289121. This publication reports on a Secondary Outcome Measure of the previously reported EXAMINE trial (N Engl J Med. 2013 Oct 3;369(14):1327-35.).

Results: EXAMINE randomly assigned 5,380 patients with Type 2 to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF] and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011) and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo.

Summary: This is the first of many reports of secondary outcomes from this trial. Fortunately, the Steering Committee planned the trial with a goal of analyzing this population and saving samples for future analyses as indicated by new information related to Type 2 and/or CVD. This report not only shows there is no increase in mortality after ACS when treated with alogliptin, but also gives us useful data about CVD in people with Type 2. Specifically, we see that risk of death is significantly increased after one of these nonfatal events, suggesting we really need aggressive medical therapy and close monitoring of these patients after a nonfatal event.

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About our expert: Kathleen Wyne, MD, PhD, FACE, FNLA, Associate Professor, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH

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