Carolina Ortiz-Lopez

Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial

Nonalcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide (1) and is the most common chronic liver condition in obese patients with prediabetes or type 2 diabetes mellitus (T2DM). Histologic findings range from isolated steatosis (with no or minimal inflammation) to severe nonalcoholic steatohepatitis (NASH) and variable perisinusoidal or perivenular fibrosis (2). Patients with T2DM and NASH have the highest risk for cirrhosis and hepatocellular carcinoma (3, 4), and the presence of NAFLD seems to worsen microvascular and macrovascular complications of diabetes (57). Given that most patients with T2DM have NAFLD (812) and many are at risk for NASH even if they have normal liver aminotransferase levels (6, 9, 13, 14), it is surprising that few trials have focused on this population. This distinction (patients with NASH with vs. without T2DM) is relevant because additional metabolic factors, such as hyperglycemia (15, 16), lower adiponectin levels (17, 18), worse dyslipidemia (19, 20), and more severe insulin resistance and hepatic steatosis (10, 16, 1821), may account for the higher rates of severe liver disease observed in patients with T2DM (22). Although the cause of NASH is multifactorial and treatment remains challenging (23), a major factor is the increase in liver triglyceride content caused by chronic release of free fatty acids (FFAs) from insulin-resistant dysfunctional adipose tissue (7, 2427). Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic lipotoxicity in NASH (7, 22, 28) (which is also a prominent feature of T2DM [15]), they may be more helpful for treating steatohepatitis in this population. In predominantly nondiabetic patients with NASH, several studies have reported variable degrees of histologic benefit with thiazolidinediones (2933). In the largest study to date in patients without T2DM (34), pioglitazone was no better than placebo for the primary outcome but was beneficial for secondary outcomes, such as resolution of NASH. However, in patients with prediabetes or T2DM, the only available randomized, controlled trial is a relatively small proof-of-concept study (35). This is disappointing given that there are 29.1 million adults with diabetes (>90% with T2DM) and 86 million with prediabetes (36) in the United States, many of whom are at risk for cirrhosis from NASH. Moreover, because pioglitazone may also halt the progression of prediabetes to T2DM (37), defining its role in patients with prediabetes and NASH is critical. Finally, safety concerns about the long-term use of thiazolidinediones remain (38, 39); therefore, studies with extended thiazolidinedione exposure are needed before a pioglitazone-based approach can be embraced in this population. The aim of our study was to assess the efficacy and safety of long-term pioglitazone treatment in improving liver histologic outcomes in patients with NASH and prediabetes or T2DM. Methods Design Overview This was a single-center, parallel-group, randomized (1:1 allocation), placebo-controlled study, conducted between December 2008 (first patient enrolled) and December 2014 (final data collection). Participants, investigators, and health care providers were blinded to treatment assignment throughout the study. The Institutional Review Board at the University of Texas Health Science Center at San Antonio (UTHSCSA) approved the study, and all participants provided written informed consent before enrollment. In October 2009, while updating registry data for another study, investigators discovered that this trial, which they thought had been registered by other study personnel, was not registered. At the time of registration (ClinicalTrials.gov: NCT00994682), 29 patients (of 97 anticipated) were enrolled in the study. None of these patients had had the follow-up metabolic measurements or liver biopsies (primary outcome) that were to be performed at 18 months, and no interim analyses were done before the trial was registered. A recent review of ClinicalTrials.gov (November 2015) revealed that the initial trial registration data erroneously stated that patients with normal glucose tolerance would be randomly assigned to treatment or placebo. Given that the trials eligibility criteria required patients to have an abnormal oral glucose tolerance test (OGTT) result (that is, prediabetes or T2DM), the investigators never planned to enroll patients with normal glucose tolerance. This error in trial registration was corrected by the principal investigator. The trial registry states that the primary end point is liver histologic outcomes (Kleiner criteria [40]) at 18 months, and these data are presented in Appendix Table 1. In this article, the primary end point is defined as a reduction of at least 2 points in 2 categories of the NAFLD activity score (NAS) without worsening of fibrosis, an outcome that was not specified in the original registration. This end point has been accepted by investigators in this field as representing significant change in liver histologic outcomes in clinical trials involving patients with NASH (34, 4143). Some secondary outcomes that were assessed, such as insulin secretion, prevention of the onset of T2DM or reversal of glucose intolerance, measurement of visceral fat by magnetic resonance imaging, bone density measurement via dual-energy x-ray absorptiometry (DXA), plasma measurements of bone metabolism, and molecular metabolic pathways, are not reported in this article. Appendix Table 1. Liver Histologic Variables at Baseline and After 18 mo, Based on Observed Data* Setting and Participants Participants were recruited from the general population of San Antonio, Texas, via newspaper advertisements and from the endocrinology and hepatology clinics at UTHSCSA and the Veterans Affairs Medical Center. Persons were eligible for the trial if they had histologically confirmed NASH and either prediabetes or T2DM. All patients had a screening 2-hour OGTT to diagnose or confirm a diagnosis of prediabetes or T2DM. Prediabetes was defined as impaired fasting glucose (5.6 to 6.9 mmol/L [100 to 125 mg/dL]), impaired glucose tolerance (7.8 to 11.1 mmol/L [140 to 199 mg/dL] on an OGTT), or a hemoglobin A1c level of 5.7% to 6.4%. Exclusion criteria included use of thiazolidinediones or vitamin E; other causes of liver disease (22) or abnormal laboratory results (such as an aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level 3 times the upper limit of normal [ULN]); type 1 diabetes mellitus; or severe heart, hepatic, or renal disease. Detailed inclusion and exclusion criteria are provided in the Appendix. Randomization and Interventions After initial screening (medical history, physical examination, laboratory tests, and 75-g OGTT), patients began receiving placebo and were instructed by the research dietician (C.D.) to keep physical activity and diet constant during the run-in phase (mean duration, 1 month). After completion of baseline metabolic measurements, participants were prescribed a hypocaloric diet (500kcal/d deficit from the calculated weight-maintaining diet) and were randomly assigned in a 1:1 ratio to either pioglitazone (Actos [Takeda Pharmaceuticals]), 30 mg/d (titrated after 2 months to 45 mg/d), or placebo. Randomization (computer-generated) and patient allocation were performed by the research pharmacist without stratification and using a block factor of 4, which was unknown to investigators. Takeda Pharmaceuticals provided pioglitazone and placebo pills with identical physical characteristics, which were stored at the research pharmacy and dispensed in identical bottles. Outcomes and Follow-up The primary outcome was a reduction of at least 2 points in 2 histologic categories of the NAS without worsening of fibrosis after 18 months of therapy. Secondary liver histologic outcomes included resolution of NASH; improvement in individual histologic scores; or improvement in a combined histologic outcome, defined as a reduction in ballooning with at least a 2-point improvement in the NAS or an absolute NAS of 3 or lower (with improvement in steatosis or inflammation) without worsening of fibrosis. Baseline liver biopsy specimens were read by a team of experienced clinical pathologists to establish or rule out the presence of NASH and thus determine whether patients were included or excluded. At the end of the study, all biopsy specimens were reread by an experienced research pathologist (F.T.), who was blinded to patient identity, intervention assignment, and pretreatment or posttreatment sequence (0, 18, or 36 months). Biopsy specimens were read by the research pathologist 2 times, with good to excellent intraobserver variability (agreement >75% for all histologic parameters). Diagnosis of definite NASH was defined as zone 3 accentuation of macrovesicular steatosis (any grade), hepatocellular ballooning (any degree), and lobular inflammatory infiltrates (any amount). The NAS was calculated as the sum of the steatosis, inflammation, and ballooning grades from the liver biopsy, and histopathologic changes were determined by using standard criteria (44). Additional secondary outcomes included the following: 1) fasting plasma glucose, fasting plasma insulin, FFA, hemoglobin A1c, fasting plasma lipid profile, adiponectin, and cytokeratin-18 concentrations; 2) total body fat percentage, measured by DXA; 3) hepatic triglyceride content, measured by magnetic resonance and proton spectroscopy (1H-MRS) as previously described (14, 16, 35, 45) (baseline and 18 months only); 4) glucose tolerance and insulin secretion on an OGTT; 5) endogenous glucose production (EGP), rate of glucose disappearance (R d), and insulin-induced suppression of EGP and plasma FFA concentration, all measured during a euglycemic insulin clamp with tritiated glucose and indirect calorimetry (baseline and 18 months only) as previously reported (16

Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients.

Liver ultrasound (US) is usually used in the clinical setting for the diagnosis and follow‐up of patients with nonalcoholic fatty liver disease (NAFLD). However, no large study has carefully assessed its performance using a semiquantitative ultrasonographic scoring system in overweight/obese patients, in comparison to magnetic resonance spectroscopy (1H‐MRS) and histology.

Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes

OBJECTIVE Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown. RESEARCH DESIGN AND METHODS We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS (1H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements. RESULTS No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH (P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis (r = –0.62; P < 0.001) and severity of steatohepatitis (rs = −0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups. CONCLUSIONS In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on.

Acute kidney injury following peripheral angiography and endovascular therapy: A systematic review of the literature.

Radiographic contrast administration is a major cause of acute kidney injury (AKI), worldwide. Currently, contrast induced acute kidney injury (CI‐AKI) is the third leading cause of hospital acquired renal failure in the United States. Over 50% of these cases are the result of contrast exposure during cardiac catheterization. The predictive risk factors for and clinical impact of AKI following coronary procedures have been extensively studied and documented in the literature. Similar data, however, are lacking for AKI following angiography or endovascular interventions for lower extremity peripheral artery disease (PAD).

The use of the AVERT system to limit contrast volume administration during peripheral angiography and intervention

The AVERTTM Contrast Modulation System (AVERT) (Osprey Medical, MN) is designed to reduce contrast volume administration during angiography. The AVERT provides an adjustable resistance circuit which decreases the pressure head delivering contrast towards the patient. The AVERT has not been previously studied in patients undergoing peripheral digital subtraction angiography (DSA). The purpose of this study was (1) to evaluate contrast savings with the AVERT and (2) to evaluate the ability to generate clinically acceptable DSA images in the process. To better define the mechanism of action in the peripheral circulation, we also developed a bench model to study the effects of the AVERT on the hydrodynamics of contrast delivery.

Reducing contrast administration during coronary angiography—time to revisit the manifold

The basic goals of a good coronary angiogram are well known to all of us: opacify the entire vessel without streaming and reflux the ostium. These are skills taught to every first year fellow—and soon enough are taken for granted. Injecting contrast into a patient, however, is not a trivial act as the development of acute kidney injury (AKI) following coronary angiography reminds us. In general, pharmacological approaches for preventing or treating AKI in this context have been disappointing. We know that, in addition to inadequate periprocedural hydration, contrast volume is related to the propensity to develop AKI. Perhaps it is time to take another look at our manifolds and revisit the mechanics of our injections. Do we administer more contrast than is needed to satisfy the aforementioned goals of a “good angiogram?” It seems the answer may be “yes.” The hydrodynamics behind adequate contrast injection into the coronary circulation seem simple but begin to become more complex as individual components are examined. In general, variables which must be accounted for, include: the cannulated vessel size, vessel bed resistance/pressure, viscosity of contrast media, resistance of the catheter (determined by length and size), resistance of the tubing between the syringe and the catheter and within the syringe itself—as well as the force and volume of injection. One might theorize that if one or more of these components could be altered such that the pressure head of contrast delivered to the coronary vessel was reduced postinjection—yet still was adequate to fill the vessel then contrast volume could be saved. The AVERT (Osprey Medical, Minnetonka, MN) system is a device that aims to reduce contrast delivery and in the process avoid excessive reflux by altering the pressure delivery of contrast to the target vessel. The design and theory behind the device are elegant in their simplicity and should remind all of us that no component of catheterization is immune from potential improvement. The AVERT uses a separate tubing line which attaches to the standard manifold system and is connected to an adjustable resistance system. The resistance in this additional line “competes” with the catheter resistance and therefore the net delivered contrast to the patient is determined by the ratio of these two resistances. By increasing the resistance in the AVERT line, more contrast is delivered to the patient and the converse is true when resistance is decreased. As it follows, larger diameter catheters have less resistance than smaller diameter catheters therefore the resistance in the AVERT system must be reduced for larger catheters to allow for contrast savings—and vice versa for smaller catheters. Essentially, we can summarize this process by looking back at Ohm’s Law (V1⁄4 I R) — in this case V1⁄4 injection pressure, I1⁄4 volume of contrast/time, and R1⁄4 resistance. By providing an alternative resistance pathway for contrast flow following injection, injection pressure is reduced (I1⁄4V/R) thus resulting in less volume of contrast delivered/unit time. This reduction in contrast ideally should still opacify the vessel but minimize the amount of reflux into the aorta. In this issue of Catheterization and Cardiovascular Interventions, Kaye et al. [1] evaluate the first in human use of the AVERT technology in patients undergoing coronary angiography. Their study demonstrates the feasibility of obtaining adequate quality angiograms with concomitant contrast savings. On an average, there was a 40% savings in total injected contrast amount. Image quality was not compromised

Iso-osmolar contrast (iodixanol) reduces patient and operator pain during peripheral angiography

Lest we forget, pain is in fact the fifth vital sign. Regardless of the skill we might display in completing a complex endovascular case, it is the discomfort that some patients may take away from their procedure. Fortunately, with careful attention to conscious sedation, a patient’s perception of pain during peripheral angiography is rarely a major problem. There is, however, “operator pain” to consider. This “operator pain” is familiar to anyone who performs peripheral digital subtraction angiography (DSA). Despite adequate analgesics, injection of contrast media into a limb can induce pain (often described as cramping, burning or cold sensations) in the patient. This discomfort results in a twitching or near-involuntary movement of the limb—essentially destroying the quality of the DSA image relative to the mask. This movement often requires the need to repeat the image and produces “operator pain.” Over time, many endovascular operators have gravitated toward iso-osmolar contrast for peripheral angiography—that is, iodixanol (Visipaque 270, GE Healthcare, Little Chalfont, UK). Empirically, the use of iodixanol appears better tolerated by patients. In our experience, warmth but not pain (or burning) is reported by patients receiving lower extremity iodixanol. Small studies and a meta-analysis to date have supported the use of iodixanol as compared to other agents in the context of peripheral angiography [1]. In this issue of CCI, Palena et al. report the results of a randomized controlled trial comparing iodixanol to the low-osmolar, nonionic contrast agent ioversol (Optiray 320, Covidien, Dublin, Ireland) on patient discomfort and image quality in diabetic patients undergoing lower extremity DSA [2]. As compared to the ioversol group, patients receiving iodixanol had less reported pain and better image quality. However, the total contrast volume and number of injections was not different between the two groups. There are numerous limitations to this small study. Specifically, assessment of pain can be challenging—particularly in patients with diabetes who may have peripheral neuropathy. Unfortunately, no assessment of diabetic neuropathy or medications for its treatment was reported. Furthermore, the analgesia and sedation management used in the study may not be consistent with the practices at many centers, as premedication with analgesics/anxiolytics was not allowed. Moreover, intraprocedural pain management is not reported in the trial which would obviously impact nociceptive response. Despite these limitations, the findings of Palena et al. confirm our prior experience with iodixanol as the preferred agent for peripheral angiography. What is the mechanism underlying the relative benefit of iodixanol in this context? To understand this we need a brief primer on the chemistry behind contrast media. All forms of iodinated contrast agents have an iodine molecule on a single benzene ring or a dimer of such rings. Variables which influence the clinical properties of the various agents revolve around the electrical charge, viscosity, osmolarity, and concentration of iodine. Iodixanol is an isotonic, iso-osmolar, nonionic, and dimer. As described by McCullough and Capasso, iodixanol results in less stress on the vascular endothelium resulting in less histamine and nitric oxide release [1]. This sequence of events attenuates endothelium dependent vasodilation while the iso-osmolarity results in less subsequent vasoconstriction. The net result of these effects is a more uniform and stable arteriolar tone feeding into the skeletal muscles which limits the activation of pain receptors. Given that the greatest difference between iodixanol and isoversol is osmolarity and not iodine content or viscosity—this study appears