Study finds fewer T2 patients on exenatide once-weekly reported gastrointestinal adverse events, compared with those on exenatide twice-daily or liraglutide once-daily.

According to findings published in Diabetes, Obesity and Metabolism, patients with type 2 diabetes experienced gastrointestinal events less frequently when treated with a once-weekly dose of the glucagon-like peptide-1 receptor agonist exenatide than a twice-daily dose of exenatide or liraglutide.

“The purpose of the study was to characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs). Gastrointestinal symptoms occur frequently in patients with T2D and represent a substantial cause of morbidity, so it is important to understand the potential effects of medications on these symptoms. GLP-1RAs have been shown to reduce HbA1c and body weight, with low intrinsic risk of hypoglycemia. One potential AE associated with these agents is an increase in gastrointestinal events that is transient in most cases. As such, understanding the specific gastrointestinal AE profile and how it varies across the GLP-1RA class is of interest to patients and physicians, and may be useful in guiding therapy.

Both pooled patient-level data and a single trial were studied in the present analysis, so that data for three separate GLP-1RAs were available. The most common gastrointestinal AEs reported were nausea, vomiting, and diarrhea. Other diagnoses, including dyspepsia and gastroesophageal reflux disease, were also associated with the GLP-1RAs studied, but differed between individual GLP-1RAs and were reported less frequently. The results also suggest that some patients experience both upper and lower gastrointestinal AEs, most commonly nausea followed within 10 days by diarrhea—an observation not previously reported.

Incidences of gastrointestinal AEs differed between the GLP-1RAs investigated. Upper gastrointestinal AEs were less common for exenatide once-weekly, compared with exenatide twice-daily and liraglutide. In contrast, the frequency of lower gastrointestinal AEs was similar across treatment groups, although diarrhea occurred more frequently with liraglutide than with exenatide once-weekly. In head-to-head studies, albiglutide was associated with lower rates of nausea and vomiting compared with liraglutide, while gastrointestinal AE rates were similar for dulaglutide 1.5 mg vs exenatide twice-daily or liraglutide and lower for dulaglutide 0.75 mg vs exenatide twice-daily.

Several studies have suggested a possible relationship between gastrointestinal symptoms and HbA1c in patients with T2D, with symptoms occurring more frequently in patients with poor glycemic control and higher HbA1c levels, possibly because of the impact of long-term poor glycemic control on diabetic complications, such as autonomic neuropathy; however, this association was not observed in the present analyses. Additionally, the presence of gastrointestinal AEs as a whole did not influence changes in HbA1c in response to therapy; however, in the pooled analysis, patients who reported gastrointestinal AEs had significantly greater weight loss than those who did not in both the exenatide once-weekly and exenatide twice-daily groups, although absolute differences in mean weight loss were <1 kg. This is consistent with the outcome of a recent analysis of 12 studies that found that weight loss among exenatide once-weekly-treated patients was greater for those with nausea/vomiting at 24 weeks than those without (−3.1 kg vs −2.2 kg; P < .05).

Although it is commonly perceived that GLP-1RAs cause gastrointestinal AEs by slowing gastric emptying, there is, in general, a weak relationship of symptoms with delayed gastric emptying. Moreover, symptoms occur in the fasted state; therefore, it is likely that centrally mediated effects are important.

Possible reasons for differences in gastrointestinal AEs between GLP-1RAs include differences in drug concentration profiles; the half-life and time to minimal effective and steady-state concentrations are much longer for exenatide once-weekly than for exenatide twice-daily or liraglutide. GLP-1RAs also differ in their ability to cross the blood–brain barrier, with small-molecule GLP-1RAs such as exenatide, liraglutide and lixisenatide being able to enter the brain, whereas larger GLP-1RAs such as albiglutide cannot; it is possible that these differences impact centrally mediated AEs. It was recently established that tachyphylaxis occurs for the effects of exogenous glucagon-like peptide-1 on the slowing of gastric emptying with prolonged exposure. Thus, while short-acting GLP-1RAs such as exenatide twice-daily are likely to have a sustained effect to slow gastric emptying substantially, this effect is likely to be markedly diminished with longer-acting formulations such as exenatide once-weekly or liraglutide. It is unknown whether a similar phenomenon applies to the effects of GLP-1RAs on other gut regions (e.g., the small or large intestine), or for the central effects of these agents.

In conclusion, the present study provides detailed information on the gastrointestinal tolerability of three GLP-1RAs based on patient-level data from the exenatide once-weekly clinical trial program. Gastrointestinal AEs were usually mild and transient and particularly affected the upper gastrointestinal tract, and occurred more frequently with exenatide twice-daily and liraglutide than with exenatide once-weekly. These insights inform physician and patient expectations of potential experiences when initiating GLP-1RA therapy.

Practice Pearls:

• The most common gastrointestinal AEs reported were nausea, vomiting, and diarrhea.
• Gastrointestinal events occur less frequently when treated with a once-weekly dose of the glucagon-like peptide-1 receptor agonist exenatide.
• Albiglutide was associated with lower rates of nausea and vomiting compared with liraglutide.
• Gastrointestinal AE rates were similar for dulaglutide 1.5 mg vs exenatide twice-daily or liraglutide and lower for dulaglutide 0.75 mg vs exenatide twice-daily.

Reference:

Diabetes, Obesity and Metabolism.

Initiation of glucagon like peptide-1 agonists may increase risk of gallbladder or bile duct disease and cholecystectomy.

Glucagon like peptide-1 agonists (GLP-1RA) are effective glucose-lowering agents that can often aid in weight reduction, an important benefit for obese patients with type 2 diabetes (T2D). While substantial or rapid weight loss is associated with an increased risk of cholelithiasis, the registration trials for high-dose liraglutide (Saxenda) demonstrated a greater incidence of acute gallbladder disease in patients receiving the study drug compared with placebo, even after accounting for the degree of weight loss.1  The current study by  J.L. Faille, et-al, is a population-based cohort study designed to investigate the association between incretin-based therapy and acute gallbladder disease.2

The United Kingdom Clinical Practice Research Datalink and the Hospital Episodes Database were used to evaluate the occurrence of gallbladder and bile duct disease resulting in hospitalization in patients prescribed either a GLP-1RA, dipeptidyl peptidase-4 inhibitor (DPP4-I), or at least two non-incretin glucose-lowering agents. Secondary outcomes were cholecystectomy associated with incretin therapy, and the association of gallbladder or bile duct disease and duration of T2D or of uninterrupted incretin therapy.

Data was collected from January 1, 2007, when incretin therapy was first made available in the UK, to December 31, 2013. Patients included were 18 years or older and had at least 1 year of medical records in the database prior to initiation of hypoglycemic therapy. Newly diagnosed patients with T2D initiating therapy with insulin were excluded due to severity of their baseline diabetes. Patients with a history of polycystic ovarian syndrome, gestational diabetes, gallbladder and bile duct disease, biliary cancer or cirrhosis, HIV or AIDS, hemolytic disease, or taking ursodiol or ursodeoxycholic acid were excluded from the cohort.

Of the 71,369 patients included in the cohort, 693 were prescribed a GLP-1RA, 3,270 were prescribed a DPP4-I, and 67,406 were on non-incretin dual therapy. Baseline characteristics were similar amongst groups with the exception of increased prevalence of obesity, younger mean age, longer duration of diabetes and higher baseline A1c in the GLP-1RA arm compared with the other arms.

After adjusting for confounders (age, sex, BMI, smoking status, year of cohort entry, diabetic vascular complications, number of physician visits, history of gastric bypass, and the use of morphine or fibrate derivatives), there was a significant increase in the risk of hospitalization for gallbladder or bile duct disease in those patients in the GLP-1RA arm compared with the non-incretin dual-therapy arm (crude HR 1.89, adjusted HR 1.79; 95% CI, 1.21-2.67).  The risk of hospitalization was not statistically significantly different in the DPP4-I arm compared with the non-incretin dual-therapy arm. Significant secondary outcomes included: increased risk of hospitalization for gallbladder or bile duct disease in patients with duration of GLP-1RA therapy less than 180 days (adjusted HR, 2.01; 95% CI, 1.23-3.29), as well as a hospitalization resulting in a cholecystectomy in the GLP-1RA arm (adjusted HR, 2.08; 95% CI, 1.08-4.02). Duration of diabetes was not significant in either arm, and all secondary outcomes were insignificant in the DPP4-I arm.

This retrospective cohort study supports the association between GLP-1RA therapy and increased risk of hospitalization for gallbladder or bile duct disease and cholecystectomy in accord with results from randomized, controlled trials. However, the small number of patients identified for inclusion in the GLP-1RA group over the study period of 6 years may be an indicator of selection bias that minimized use of GLP-1RAs in the population studied, except for patients who had more significant duration of diabetes or higher baseline A1c. Additionally, this study was not designed to evaluate the effect of the rate of weight loss on the risk of development of acute gallbladder disease. Until further randomized, controlled trials are available to elucidate the mechanism of these outcomes, it is advised by the manufacturer of high-dose liraglutide to limit weight loss to no more than 1.5 kg per week and to pursue gallbladder studies and appropriate clinical follow up if cholelithiasis is suspected.

Practice Pearls:

• GLP-1 receptor agonists were associated with a 79% increased risk of developing gallbladder or bile duct disease and an a 2-fold increased risk of cholecystectomy in a large, population-based cohort in the UK.
• Therapy with DPP-4 inhibitors was not associated with an increased risk of acute gallbladder or bile duct disease.
• Providers should closely monitor patients initiating GLP-1 agonist therapy especially in the first 6 months for rate of weight loss and signs of gallbladder or bile duct disease.GLP-1 receptor agonists were associated with a 79%

References:

Saxenda (liraglutide)[package insert]. Novo Nordisk; Plainsboro (NJ): 2010.

Faillie JL, Yu OH, Yin H, Hillaire-Buys D, Barkun A, Azoulay L. Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus. JAMA Intern Med. 2016 Aug 1. doi: 10.1001/jamainternmed.2016.1531.

Researched and prepared by Iman Aberra, URI College of Pharmacy Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D, BCPS, BCACP, CDOE, CVDOE.

Diabetes Solution
Richard K. Bernstein, MD, FACE, FACN, FACCWS
Part 1 Chapter 22
Gastroparesis

Anumber of times throughout this book, you’ve come across the terms “delayed stomach-emptying” and “gastroparesis.” As I explained in Chapter 2, elevated blood sugars for prolonged periods can impair the ability of nerves to function properly.  It’s very common that the nerves that stimulate the muscular activity,  enzyme secretion, and acid production essential to digestion function poorly in long-standing diabetes. These changes affect the stomach, the gut, or both. Dr. Richard McCullum, a noted authority on digestion, has said that if a diabetic has any other form of neuropathy (dry feet, reduced feeling in the toes, diminished reflexes, et cetera), he or she will also experience delayed or erratic digestion.

Slowed digestion can be fraught with unpleasant symptoms (rarely), or it may only be detectable when we review blood sugar profiles (commonly) or perform certain diagnostic tests. The picture is different for each of us. For more than twenty-five years, I suffered from many unpleasant symptoms myself. I eventually saw them taper off and vanish after thirteen years of essentially normal blood sugars.  Some of the physical complaints possible (usually after meals) include burning along the midline of the chest (“heartburn”), belching, feeling full after a small meal (early satiety), bloating, nausea, vomiting, constipation, constipation alternating with diarrhea, cramps a few inches above the belly button, and an acid taste in the mouth.

GASTROPARESIS: CAUSES AND EFFECTS

Most of these symptoms, as well as effects upon blood sugar, relate to delayed stomach-emptying. This condition is called gastroparesis diabeticorum, which translates from the Latin as “weak stomach of diabetics.”  It is believed that the major cause of this condition is neuropathy (nerve impairment) of the vagus nerve. This nerve mediates many of the autonomic or regulatory functions of the body, including heart rate and digestion. In men, neuropathy of the vagus nerve can also lead to difficulty in achieving penile erections. To understand the effects of gastroparesis, refer to Figure 22-1.

On the left is a representation of a normal stomach after a meal. The contents are emptying into the intestines, through the pylorus. The pyloric valve is wide open (relaxed). The lower esophageal sphincter (LES) is tightly closed, to prevent regurgitation of stomach contents. Not shown is the grinding and churning activity of the muscular walls of the normal stomach.

On the right is pictured a stomach with gastroparesis. The normal rhythmic motions of the stomach walls are absent. The pyloric valve is tightly closed, preventing the unloading of stomach contents. A tiny opening about the size of a pencil point may permit a small amount of fluid to dribble out. When the pyloric valve is in tight spasm, some of us can sometimes feel a sharp cramp above the belly button. Since the lower esophageal sphincter (LES in Figure 22-1) is relaxed or open, acidic stomach contents can back up into the esophagus (the tube that connects the throat to the stomach). This can cause a burning sensation along the midline of the chest, especially while the person is lying down. I have seen patients whose teeth were actually eroded over time by regurgitated stomach acid.

Because the stomach does not empty readily, one may feel full even after a small meal. In extreme cases, several meals accumulate and cause severe bloating. More commonly, however, you may have gastroparesis and not be aware of it. In mild cases, emptying may be slowed somewhat, but not enough to make you feel any different. Nevertheless, this can cause problems with blood sugar control. Consuming certain substances, such as tricyclic antidepressants, caffeine, fat, and alcohol, can further slow stomach-emptying and other digestive processes.

Some years ago, I received a letter from my friend Bob Anderson.  His diabetic wife, Trish, who has since passed away, had been experiencing frequent loss of consciousness from severe hypoglycemia, caused by delayed digestion. His description of an endoscopic exam, when he was allowed to look through a flexible tube into Trish’s stomach and
gut, paints a graphic picture.

All this brings me to today’s endoscopy exam. I watched through the scope and for the first time, I now understand what you have been saying about diabetic gastroparesis. Not until I viewed the inside of the duodenum did I understand the catastrophic effect of 33 years of diabetes upon the internal organs. There was almost no muscle action apparent to move food out of the stomach.  It appeared as a very relaxed smooth-sided tube instead of having muscular ridges ringing the passage. I suppose a picture is worth a thousand words. Diabetic neuropathy is more than a manifestation of a tilting gait, blindness, and other easily observable presentations; it wrecks the whole system. This you well know. I am learning.

Copyright © 2005 by Richard K. Bernstein, M.D. All rights reserved. No part of this book may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review.

Author’s Note:
This book is not intended as a substitute for professional medical care. The reader should regularly consult a physician for all health-related problems and routine care.

For more information on Dr. Bernstein’s and to purchase his books, CD’s or get access to his free monthly webinars, visit his website at DiabetesBook.com.

Diabetes Solution
Richard K. Bernstein, MD, FACE, FACN, FACCWS
Part 2 Chapter 22
Gastroparesis

How Does Gastroparesis Affect Blood Sugar Control? – Part 2Consider the individual who has very little phase I insulin release and must take fast-acting insulin or one of the older-type (sulfonylurea) or newer pancreas-provoking OHAs before each meal. If he were to take his medication and then skip the meal, his blood sugar would plummet.

When the stomach empties too slowly, it can have almost the same effect as skipping a meal. If we knew when the stomach would empty, we could delay the insulin shot or add some NPH insulin to the regular to slow down its action. The big problem with gastroparesis, however, is its unpredictability. We never know when, or how fast, the stomach will empty. If the pyloric valve is not in spasm, the stomach contents may
empty partially within minutes and totally within 3 hours. On another occasion, when the valve is tightly closed, the stomach may remain loaded for days. Thus, blood sugar may plummet 1–2 hours after eating, and then rise very high, say 12 hours later, after emptying eventually occurs. It is this unpredictability that can make blood sugar control impossible if significant gastroparesis is ignored in people who take insulin (or the type of OHAs I don’t recommend) before meals.

For most type 2 diabetics, fortunately, even symptomatic gastroparesis may not grossly impede blood sugar control, because they may still produce some phase I and phase II insulin. They therefore may not require significant amounts of injected insulin to cover their lowcarbohydrate meals. Much of their insulin is produced in response to blood sugar elevation. Thus, if the stomach does not empty, only the low basal (fasting) levels of insulin are released, and hypoglycemia does not occur. Of course, the sulfonylurea and similar OHAs (which I don’t recommend) can cause hypoglycemia under such circumstances.

If the stomach empties continually but very slowly, the beta cells of most type 2s will produce insulin concurrently. Sometimes the stomach may empty suddenly, as the pyloric valve relaxes. This will produce a rapid blood sugar rise, caused by the sudden absorption of carbohydrate following the entrance of stomach contents into the small intestine. Most beta cells of type 2 patients then cannot counter rapidly enough. Eventually, however, insulin release catches up and blood sugar drops to normal, if a reasonable regimen is followed. If your supper doesn’t fully leave your stomach before you sleep, you may awaken with a high morning blood sugar due to emptying overnight,
even though your bedtime blood sugar was low or normal.

In any event, if you do not require insulin or use a sulfonylurea type OHA before meals, there is no hazard of hypoglycemia due to delayed stomach-emptying. This assumes that any long-acting insulin or sulfonylurea is administered in doses that cover only the fasting state, as discussed in prior chapters. The traditional use of large doses of
these medications, meant to cover both the fasting and fed states, brings with it the hazard of postprandial hypoglycemia when gastroparesis is present.

Copyright © 2005 by Richard K. Bernstein, M.D. All rights reserved. No part of this book may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review.

Author’s Note:
This book is not intended as a substitute for professional medical care. The reader should regularly consult a physician for all health-related problems and routine care.

For more information on Dr. Bernstein’s and to purchase his books, CD’s or get access to his free monthly webinars, visit his website at DiabetesBook.com.

Diabetes Solution
Richard K. Bernstein, MD, FACE, FACN, FACCWS
Part 3 Chapter 22
Gastroparesis

Efforts at diagnosis are usually unnecessary if there is no reason to suspect the presence of gastroparesis. So first we must have an index of suspicion. If, at the initial history-taking interview with your physician, you mention symptoms like those described earlier in this chapter, he should have a high index of suspicion. If your R-R interval study (Chapter 2) at the initial physical exam is grossly abnormal, he can be quite certain of gastroparesis. Remember that this study checks the ability of the vagus nerve to regulate heart rate. If the nerve fibers going to the heart are impaired, the branches that activate the stomach are probably also impaired. In my experience, the correlation of grossly abnormal R-R studies with demonstrable gastroparesis is very real.*

Diagnostic Tests
Given the physical symptoms or the abnormal R-R study, your physician may want to consider further tests to evaluate your condition.  The most sophisticated of these studies is the gamma-ray technetium scan. This test is performed at many medical centers, and is quite costly. It works this way: You eat some scrambled eggs to which a minute amount of radioactive technetium has been added. A gammaray camera trained on your abdomen measures (from outside your body) the low levels of radiation the

Delayed Stomach-Emptying: Gastroparesis 361
* If, during an R-R study, your heart rate varies only 28 percent between inhaling and exhaling, then you will likely have mild gastroparesis. If the variation is about 20 percent, gastroparesis will probably be what I call moderate, and if less than 15 percent, I would call it severe.technetium emits as the eggs pass from your stomach into your small intestine. If the gamma radiation drops off rapidly, the study is considered normal.

A less precise study can be performed at much lower cost by any radiologist. This is called the barium hamburger test. In this test, you eat a ½ pound hamburger and then drink a liquid that contains the heavy element barium. Every half hour or so, an X-ray photo is taken of your stomach. Since the barium shows up in these photos, the radiologist can estimate what percent of the barium remains in your stomach at the end of each time period. Total emptying within 3 hours or less is usually considered normal.

Despite their theoretical usefulness, neither of these studies is anywhere near 100 percent sensitive, because of the unpredictable nature of the paretic stomach. One day it may empty normally, another day it may be a bit slow, and on yet another day its emptying may be severely delayed. Because of this unpredictability factor, the study may have to be repeated a number of times before a diagnosis can be made. The possibility exists that you could have several normal studies but still have abnormal stomach-emptying. I therefore advise my patients against using either of these two tests. The R-R study is my gold standard.

Telltale Blood Sugar Patterns
Having medical tests is bad enough, but having to repeat them with conflicting results naturally proved quite annoying to my patients many years ago when I actually repeated them. Worse than annoyance, the studies are not cheap, and most insurance companies will not pay for repeats of the same study unless they’re separated by many months. If you’re regularly measuring your blood sugar levels and trying to keep them in the normal range, it’s really not difficult to spot gastroparesis that’s severe enough to affect blood sugars. For practical purposes, this is just the degree of gastroparesis that should concern us.

Below are some of the typical blood sugar patterns that I look for. To call these patterns, though, is slightly misleading. The hallmark of gastroparesis is randomness, unpredictability from one day to the next. These “patterns” come and go in such a fashion that blood sugar profiles are rarely similar on 2 or 3 successive days. The first two patterns together are highly indicative of gastroparesis, while the third by itself is usually adequate for diagnosis.

• Low blood sugar occurring 1–3 hours after meals.
• Elevated blood sugar occurring 5 or more hours after meals with no other apparent explanation.
• Significantly higher fasting blood sugars in the morning than at bedtime, especially if supper was finished at least 5 hours before retiring. If bedtime long-acting insulin or ISA is gradually increased in an effort to lower the fasting blood sugars, we may find that the bedtime dose is much higher than the morning dose. On some days fasting blood sugar may still be high, but on other days it may be normal or even too low. We’re thus giving extra bedtime medications to accommodate overnight stomach emptying— but sometimes the stomach doesn’t empty overnight and fasting blood sugars drop too low.

Having seen such patterns of blood sugar, we can then perform a simple experiment to confirm that they really are caused by delayed emptying.

Skip supper and its premeal insulin or ISA one night. When you go to bed, be sure to take your basal (bedtime) insulin or ISA, measure your blood sugar, and then measure your fasting blood sugar the next morning on arising. If, without supper, your blood sugar has dropped or remained unchanged overnight, gastroparesis is the most likely cause of the roller-coaster morning blood sugars.

Repeat this experiment several days later, and again a third time, after another few days. If each experiment results in the same effect, delayed stomach-emptying is virtually certain on one or more of the nights when you had eaten. When you had previously been eating suppers, at least some of the following mornings had shown an overnight rise in blood sugars. Since such rises occurred on nights when you had eaten supper, but not on the nights when you did not eat, the rise must have been caused by food that did not leave your stomach until after you went to bed. Be very cautious when performing this experiment, as you may experience severe hypoglycemia upon arising or during the night. To play it safe, check your blood sugar midway through the night and correct it if it’s below your target.

“False Gastroparesis”
I’ve seen a number of patients whose blood sugar profile or physical symptoms could have been diagnostic of gastroparesis, yet their R-R interval studies were normal or only slightly impaired. These people had delayed stomach-emptying but well-functioning vagus nerves. The conflicting data obliged me to order upper gastrointestinal endoscopic studies for these people. Endoscopy uses a thin, flexible, lighted fiber-optic cable to look directly into the stomach and duodenum.

The endoscopic tests demonstrated that they all had abnormalities unrelated to their diabetes. Such findings have included gastric or duodenal ulcers, erosive gastritis, irritable gastrointestinal tract, hiatal hernia, and other gastrointestinal disorders such as tonic or spastic stomach. Each of these conditions required treatment distinct from treatment for diabetes. Only with hiatal hernias were we unable to at least partially alleviate the digestive problem. In such cases, however, surgical correction of the hiatal hernia is possible, but it may or may not normalize emptying. Blood tests for parietal cell antibodies and
serum vitamin B-12 might be performed to rule out autoimmune gastropathy as a cause of gastritis.

The following suggestions for treating gastroparesis may or may not facilitate stomach-emptying for the above conditions but should certainly be tried. The loud and clear message from this is that the R-R interval study should be performed on every diabetic patient whose blood sugar profiles resemble those outlined above.

Copyright © 2005 by Richard K. Bernstein, M.D. All rights reserved. No part of this book may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review.

Author’s Note:
This book is not intended as a substitute for professional medical care. The reader should regularly consult a physician for all health-related problems and routine care.

For more information on Dr. Bernstein’s and to purchase his books, CD’s or get access to his free monthly webinars, visit his website at DiabetesBook.com.