^^The liver, when everyone’s talking about the kidneys. (Image)

Steph’s Note: Remember our series a couple of years back on cirrhosis? Remember how we said the poor liver is often forgotten in favor of discussing the “cooler” organs - the kidneys and the heart? Guess what, people, we’re here with a post to remind you just how cool the liver can be (well, really we just want to emphasize how NOT cool it is when the liver malfunctions…). That being said, the liver is pretty redunk.

Here to shed light on a topic that everyone should be talking about (but probably isn’t…yet…because it’s the poor liver) is Carley Moses, PharmD. She most recently graced us with a post about RSV prevention, but she’s written a number of fantastically informative articles for us (adult vaccines, pediatric vaccines, GLP-1 agonists, and chronic care management). And gosh, we love her panache! So, without further ado, take it away, Carley!

Yeah. This cat can’t believe that stat either. (Image)

Hello again, my sweet pharmacy phamily! A quick fact to kick us off - did you know that up to 70% of our patients with Type 2 Diabetes Mellitus (T2DM) are also grappling with Non-Alcoholic Fatty Liver Disease (NAFLD) or Non-Alcoholic Steatohepatitis (NASH)?

That's a staggering statistic, and here at tl;dr, we're all about keeping you up-to-speed with the evolving world of healthcare. Today, we're zeroing in on a hot topic in comprehensive diabetes care. This will be a journey right to the center of liver health, exploring NAFLD and NASH in our diabetic patients.

I can hear it now. All the voices saying, “But, CARLEEEYYYY…I’m not a hepatologist!”

No worries! You may not be a hepatologist, but as a pharmacist, you are THE most accessible healthcare provider. That means you play a crucial role in identifying, managing, and educating patients at risk for, or living with, NAFLD or NASH.

And guess what? We’re right here to guide you through it, boosting your confidence every step of the way. Let’s dive in!

How is Non-Alcoholic Fatty Liver Disease (NAFLD) Different from Non-Alcoholic Steatohepatitis (NASH)?

Imagine this: a patient hits a snag – a little thing called insulin resistance, throwing their body's rhythm offbeat. It’s like a glitch in their metabolic software, messing up how the liver deals with fats and sugars. Normally, insulin is the head-honcho that keeps the metabolic show going. But when it’s not working as efficiently as we need, the liver starts stockpiling fats, particularly triglycerides, like a squirrel preparing for winter. What we end up with is a fatty liver, AKA our first culprit – NAFLD.

Let’s be clear here, folks, this isn’t just about an indulgent diet. It’s the liver trying its best to adapt to the chaotic metabolic state of diabetes.

But the plot thickens…

Where NAFLD and NASH fall on the spectrum of liver disease. Oh, you too noticed the far right end with CANCER?!?! Yeah, that’s why this IS a big deal. (Image)

For some patients, this isn’t the end of the story. That excess fat in the liver? It’s not just sitting there; it's more like a spark ready to ignite. Cue NASH, the dramatic sequel. It ramps the situation up a notch, bringing in inflammation and liver cell damage. Imagine a series of tiny battles happening right in the liver – immune cells and inflammatory signals clashing, causing damage and scarring. We’ve moved from a quietly accumulating fat scenario in NAFLD to an all-out brawl where the liver is not just fatty but also fighting an internal war – that's NASH for you.

How Does Diabetes Affect the Liver?

Now, let's tie it all back to diabetes. High blood sugar and insulin resistance in diabetes don’t ride solo; they often bring along buddies like obesity and abnormal lipids. We know this and typically account for it within our mitigation plan for macro/microvascular complications. We all know to use statins to reduce cardiovascular disease risk and ACE inhibitors to help the kidneys.

BUT WE FORGOT OUR TRUSTY LIVER. (So neglected, always neglected…sigh.)

The increased lipids in diabetes crash the liver’s party, contributing to the fat buildup that is characteristic of NAFLD. Diabetes then throws in some extra fuel with ongoing metabolic stress and inflammation. This relentless metabolic chaos acts as a catalyst, fast-tracking the liver from NAFLD to the more treacherous terrain of NASH. Each piece of it – insulin resistance, high sugar levels, wonky lipids – compounds the liver damage, increasing the importance that we include our lovely liver in the conversation surrounding diabetes complications.

The complex interplay between diabetes and liver damage. (Image)

Now, when talking numbers, the prevalence of NAFLD and NASH amongst our diabetic population can be pretty jarring. Like I said before, up to 70% of folks with T2DM have NAFLD. That's not just a statistic; it's a major health alert. Those with diabetes developing NAFLD are on a slippery slope towards NASH, with even more serious foes like cirrhosis and hepatocellular carcinoma lurking in the shadows.

Pretty important that we can spot these people out, right? You guessed it - we’re getting there.

How to Identify Patients at Risk for NAFLD and NASH

Now, shifting gears from understanding to action, let's talk about how we, as pharmacists, can spot potential NAFLD/NASH cases in our daily interactions, especially in our patients with diabetes. It’s all about sharpening our detective skills and being on high alert for those tell-tale signs.

It starts with being aware of the risk factors. T2DM, obesity, high cholesterol, and hypertension are big red flags. A casual conversation about general health, or even a quick medication review, might reveal these risk factors for you.

What signs and symptoms should you look out for?

Upper right quadrant abdominal pain, increased fatigue, and in more serious cases, jaundice or ascites should all be flashing neon warning signs to have the patient contact their doctor and get that trusty liver checked out…just to be safe.

Using FLI and FIB-4 as Specific Screening Tools for NAFLD and NASH

Next, we have our screening tools: the Fatty Liver Index (FLI) and the Fibrosis-4 (FIB-4) Index. The FLI involves a mix of measurements like BMI, waist circumference, triglycerides, and (Gamma-glutamyl transferase) GGT levels. Alls of these contribute to a composite picture indicating potential fatty liver.

With that being said, it's the FIB-4 that often is our go-to tool. It’s simpler (always a win!), requiring just age, AST, ALT, and platelet count, making it more accessible in a pharmacy setting. It helps us estimate the level of liver fibrosis, a key step in identifying more advanced liver conditions.

Just like any detective tool, these indices aren't foolproof. They're more about raising a flag for potential issues rather than giving a definitive diagnosis. FLI points us towards liver fat accumulation, while FIB-4 gives us an idea of the severity of liver scarring. For the full picture, further assessments, like imaging studies or even a liver biopsy, might be required – but we will leave that stuff to our physician friends.

Which Patients Require Further Workup for NAFLD or NASH?

Now, after we've done our initial detective work, let's talk about the next critical step: knowing when to refer to a physician. This is where our role shifts from detection to action.

Results from FLI and FIB-4:

FLI: A score less than 30 generally rules out steatosis, while a score above 60 suggests its presence.
FIB-4: A score below 1.30 is considered low risk for liver fibrosis, while a score above 2.67 indicates a higher risk and necessitates further evaluation.

Elevated Liver Enzymes: Keep an eye out for persistently high AST or ALT levels.
High-Risk Patients: Those with diabetes, particularly with obesity or metabolic syndrome, might need further evaluation.
Signs of Advanced Disease: Symptoms like jaundice or severe fatigue are red flags for immediate referral.

Timely and spot-on referrals are our superpower here. They can make all the difference. Early intervention can significantly alter the course of liver disease, potentially reversing early-stage NAFLD and preventing serious complications in more advanced cases like NASH. Our role as pharmacists is crucial in this process. We're not just identifying potential issues but also ensuring that patients receive the specialized care they need as soon as possible.

Treatment of NAFLD and NASH

Diving into the AASLD’s NAFLD guidelines, it's all about the trio – specialists, primary care pros, and lifestyle changes all joining forces for top-notch management. Lucky for us, we're in the sweet spot between primary care and lifestyle changes, making us key players in the NAFLD and NASH management game. On top of that, while the specialists primarily drive the ship when it comes to prescribing for these patients, it doesn’t hurt for us to be aware of what treatments these patients may be on - and how they could affect their other medications or disease states!

Alright, let's kick things off small – cue the lifesavers of lifestyle interventions. These are the first-line, go-to gurus for NAFLD/NASH.

The NAFLD populations should aim for a weight loss of at least 3-5%, but a weight loss of more than 10% will typically be needed to help repair the dirty damages of NASH.

How should they achieve this weight loss?

First, diet. The guidelines suggest to us that many types of dietary switches could help! Whether it be lowering carbs, lowering saturated fats, or using intermittent fasting, the ultimate goal is to decrease the metabolic load on these patients. One diet, the Mediterranean diet, is already known for its benefit on both cardiovascular health as well as liver fat.

Second, alongside our dietary changes, as always, should be exercise. NAFLD patients should aim for the usual recommendation of 150 minutes of exercise per week, or 30 minutes of moderate intensity 5 days a week.

Third, our final tool for weight loss is bariatric surgery. Although our physician colleagues handle this one, be sure to keep your pharmacist hats on as these surgeries typically come with lots of changes in drug absorption.

Pharmacotherapy for NAFLD and NASH

Now to pharmacotherapy. There are currently no FDA-approved drugs for the treatment of NAFLD or NASH; however, we have lots of drugs that have proven their benefit off-label. Given the increasing prevalence of NAFLD/NASH, specifically in our diabetic and obese populations, we can expect to see approved treatments emerge soon. But for now, we patiently wait and prepare.

Now let’s dive into the literature, where the majority of our trials have focused on NASH, the more troublesome child…

Pioglitazone for Treatment of NAFLD and NASH

When it comes to tackling NAFLD/NASH in our diabetic patients, pioglitazone seems to be stepping up to the plate. Let’s unpack the evidence from three key trials that put pioglitazone under the microscope.

Trial #1: A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis

54% drop in hepatic fat content compared to control? Yessss. (Image)

This study published in 2006 enrolled 70 individuals with NASH and impaired glucose tolerance or T2DM. It rigorously excluded heavy drinkers and those on conflicting medications and included 10 healthy controls for comparison. Participants were divided into two groups: one received pioglitazone, initially dosed at 30 mg and later increased to 45 mg, while the control group received a placebo. Both groups were advised to follow a diet reduced by 500 calories daily.

In a striking turn of events, after 6 months of treatment, the pioglitazone crew saw a whopping 54% plummet in hepatic fat content compared to the control group as assessed by magnetic resonance spectroscopy, highlighting the medication’s potential to reverse fatty liver changes in NASH. Furthermore, improvements in insulin sensitivity were observed, with reductions in fasting plasma glucose and insulin levels, indicating better metabolic control.

Check out that impressive drop in liver fat content (box C) with pioglitazone, especially compared to the placebo groups flat before and after. TZDs often get a bad rap, but phew, maybe, just maybe there’s a happy ending for this class after all! (Image)

More impressive and positive results with pioglitazone… definitely food for thought, but let’s remember the size and duration of this study… (Image)

Of course, this was a relatively small and short-term proof of concept study, so although it was positive, it’s certainly not enough to stand on alone. Cue the next trial.

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

In a larger cohort of 101 participants, this 2016 study further explored pioglitazone's effects on NASH in the context of prediabetes or T2DM. This one switched methods up a little bit. Everyone was assigned a 500 calorie deficit, just like the first trial, and then they were randomized to either pioglitazone 45 mg daily or placebo for 18 months. Those 18 months were followed by another 18-month open-label phase with pioglitazone treatment, just to really emphasize those results.

It showed out once again. The pioglitazone team showed a remarkable 51% resolution in NASH, leaving the 19% resolution in the placebo group in the dust. The pioglitazone group also experienced a significant normalization of liver enzymes, a key indicator of liver health. Additionally, increased adiponectin levels were noted, suggesting improved metabolic health and adipose tissue function. These findings underscore pioglitazone's multifaceted benefits beyond just glucose control.

These figures are a little tricky to follow, but heads up that box A is the only one for which lower data points are better. For all the others, higher data points are better. Essentially, pioglitazone was better for all of these insulin sensitivity endpoints as well as for lowering hepatic triglycerides. (Image)

Sooo, the placebo patients’ LFTs really didn’t budge much UNTIL they hit the open label phase at 18 months and they started taking pioglitazone… Plus pioglitazone’s positive effects were durable for the entire 36 months. (Image)

Ok, the jury’s starting to come around towards pioglitazone now. What other pieces of evidence could they use to hammer the verdict home?

Trial #3: Concentration-dependent Response to Pioglitazone in Nonalcoholic Steatohepatitis

In the last trial for our friend pioglitazone, 54 participants underwent 18 months of pioglitazone treatment at the same dosing of 45 mg each day as in previous trials, alongside a 500-calorie reduced diet. Because some - but not all - NASH patients experienced improvement with pioglitazone in previous studies, this 2017 study sought to specifically examine the relationship between pioglitazone concentrations in the blood and improvements in liver histology.

Aka WHY does it work for some but not all patients?!? WHY CAN’T IT JUST BE A FIX ALL??

Sorry. Pharmacokinetics and individual patient responses can be stressful.

So what did this study find? When in doubt - go high! (You know, we pharmacists always like to emphasize lowest dose, shortest time to be effective, etc. But lookee here, whaddaya know. Sometimes more actually is better!)

Higher levels of pioglitazone were strongly correlated with better therapeutic outcomes, including significant improvements in NAS scores, which measure the severity of liver disease in NASH. Participants achieving the primary outcome (≥2-point reduction in NAS score with at least one-point improvement in more than one liver histology category and without worsening of fibrosis) had much higher pioglitazone concentrations, suggesting a dose-dependent relationship. Notably, improvements in steatosis and inflammation were also observed with higher pioglitazone levels.

The tl;dr of Using Pioglitazone for NAFLD and NASH

These 3 trials collectively illustrate pioglitazone's promising role in managing NAFLD/NASH, especially in patients with diabetes. Its impact on reducing liver fat, improving insulin sensitivity, and normalizing liver enzymes positions it as a valuable therapeutic option. The dose-dependent effects observed highlight the importance of precision when dosing for those silver-lined outcomes.

Liraglutide for Treatment of NAFLD and NASH

As we continue exploring effective treatments for NAFLD/NASH for our friends with diabetes, liraglutide comes into focus. The LEAN trial provides valuable early insights into its star-studded role.

The LEAN Trial: Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled phase 2 study

This trial recruited 52 patients with confirmed NASH. Notably, many participants also had diabetes, making this study particularly relevant to the homies we’re trying to help out today. The patients were divided into two groups, with one receiving liraglutide at a daily dose of 1.8 mg and the other a placebo.

Here’s a snapshot of this trial’s key observations:

Guess what? In addition to all the above endpoints, a cool 39% of patients in the liraglutide group hit the jackpot with resolution of NASH, which was significantly more than the 9% in the placebo group. The trial also showed less progression of fibrosis in patients treated with liraglutide, suggesting a protective effect on the liver, crucial for patients with diabetes. Finally, the liraglutide group saw greater improvements in steatosis and hepatocyte ballooning, indicating its potential to mitigate liver damage.

The tl;dr of Using Liraglutide for NAFLD and NASH

The LEAN trial fills us in on liraglutide's potential as an effective treatment for NAFLD/NASH, particularly in our center-stage population of patients with diabetes. It mirrors the success seen with pioglitazone, demonstrating its ability to improve those key histological features of NASH. Liraglutide thus emerged as a significant treatment option, enhancing our arsenal in treating NAFLD/NASH for patients with diabetes.

Semaglutide for Treatment of NAFLD and NASH

Following our exploration of liraglutide, semaglutide enters the stage as a promising candidate for NAFLD/NASH, particularly for patients across the diabetes spectrum. Let's explore a pivotal trial that evaluated semaglutide's efficacy in another comprehensive patient cohort.

The Semaglutide Trial: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis

Echoing the diversity of the LEAN trial with liraglutide, this 2021 semaglutide study broadened its scope. The trial enrolled 320 patients, with a varied demographic including those with and without T2DM, and with a BMI over 25. Participants were randomized to receive once-daily semaglutide at doses of 0.1, 0.2, or 0.4 mg, or a corresponding placebo.

Diving into the findings…

Take note… dose (again) matters. (Image)

Wegovy —> Ozempic —> Semaglutide. Couldn’t resist this meme (even though we’re specifically talking about its liver effects today rather than general weight loss). (Image)

Here’s a headline grabber: an impressive 59% of the gang in the 0.4 mg semaglutide group scored a NASH resolution without fibrosis worsening, surpassing the 17% in the placebo group. This outcome is particularly relevant given the inclusion of both diabetic and non-diabetic patients (we really value inclusivity around here, and semaglutide doesn’t discriminate). Although significant differences in fibrosis stage improvement weren’t observed, the data suggest a potential beneficial impact of semaglutide on overall liver health, ultimately preventing things from worsening.

The tl;dr of Using Semaglutide for NAFLD and NASH

Semaglutide, following in the footsteps of pioglitazone and liraglutide, emerged as a shining light in the realm of NAFLD/NASH treatments. Its effectiveness in achieving NASH resolution is remarkable, especially considering the broad range of patients involved in the trial (we love to see it).

Tirzepatide for Treatment of NAFLD and NASH

As we delve deeper into effective treatments for NAFLD/NASH, tirzepatide emerges as a promising candidate, once again, especially for patients with T2DM. Let’s examine two critical trials that spotlight tirzepatide's shining glory.

Trial #1: Tirzepatide Once Weekly for the Treatment of Obesity

In this diverse 2022 study, adults with obesity were assessed for tirzepatide's efficacy in weight management, a key factor in NAFLD/NASH progression. While NAFLD/NASH wasn’t directly on the table, this study gave us insights into mitigating one of those known nasty risk factors - obesity. Participants were assigned to tirzepatide doses of 5 mg, 10 mg, or 15 mg, or a placebo, alongside lifestyle interventions.

Some key observations:

Tirzepatide, droppin’ it like it’s hot. (Image)

Did you catch the big reveal there? Tirzepatide showed some serious muscle in the weight loss department, crucial in managing NAFLD/NASH. The 15 mg dose showed an average weight reduction of 20.9% from baseline, significantly higher than the placebo group's 3.1% reduction.

Trial #2: Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial

Tirzepatide didn’t stop at just weight loss. Focusing on 296 participants with T2DM (our beautiful target population), this 2022 substudy concentrated on tirzepatide’s effect on liver fat content. The groups ultimately received tirzepatide (5 mg, 10 mg, 15 mg) or insulin degludec.

Key observations:

Check out tirzepatide’s effects on liver fat content, complete with pretty, colorful pictures. (Image)

Notably, the pooled groups receiving 10 mg and 15 mg tirzepatide showed a significant reduction in liver fat content, with an absolute decrease of 8.09% at week 52, compared to a 3.38% reduction in the insulin degludec group. The decrease in liver fat observed with tirzepatide was significantly linked to the initial liver fat levels. Plus tirzepatide induced reductions in visceral adipose tissue (VAT), aspartate aminotransferase (ASAT) levels, and overall body weight, bringing to the limelight tirzepatide's extensive impact on metabolic health.

The tl;dr of Using Tirzepatide for NAFLD and NASH

These early trials collectively position tirzepatide as an effective treatment for NAFLD/NASH, particularly in patients with T2DM. Its dual action in facilitating significant weight loss and directly reducing liver fat content makes it a promising therapeutic option in NAFLD/NASH management, especially considering the multifactorial nature of the disease.

SGLT-2 Inhibitors for Treatment of NAFLD and NASH

You guys are doing great!! As we dig further into pharmacotherapy for NAFLD/NASH, particularly in T2DM, SGLT-2 inhibitors have started to stand out for their notable benefits on liver health (in addition to all the other crazy good things they already do). These drugs, initially aimed at glycemic control, have shown promising effects on hepatic steatosis. Let’s examine the outcomes of three critical trials (you know the routine by now).

Trial #1: Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)

The E-LIFT trial, a 2018 randomized clinical study, assessed empagliflozin 10 mg/day in patients with T2DM and NAFLD. This trial utilized MRI-Proton Density Fat Fraction (MRI-PDFF) to measure hepatic steatosis in 50 participants after a treatment duration of 20 weeks.

Some key findings…

Yep, you guessed it (or we wouldn’t be talking about it!). Empagliflozin did serious work on liver fat content. (Image)

Empagliflozin came through like a champ, slashing liver fat content significantly, with the mean difference in liver fat change between the groups being a significant 4.0%. Serum ALT levels decreased notably, suggesting potential generalized liver health benefits.

Trial #2: The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients

This study used a different SGLT-2 inhibitor, focusing instead on dapagliflozin's impact on tissue glucose uptake in patients with T2DM. Initially, 55 volunteers were recruited, leading to the inclusion of 32 eligible subjects who were then divided 1:1 to either dapagliflozin 10 mg daily for 8 weeks as an add-on to their previous diabetes medications, or a placebo.

The key takeaway:

Sorry for the meh image quality here, but essentially, dapagliflozin is on the left for each endpoint, and placebo is on the right. And remember that PDFF is proton density fat fraction, aka a way to quantify liver fat content. (Image)

Time for our favorite part…results! The dapagliflozin group experienced a significant reduction in liver fat (absolute reduction of 3.7%) and liver volume. There was a substantial decrease in HbA1c from 7.0% to 6.6%, and fasting plasma glucose levels dropped too! Another win in the books for both the liver and the pancreas.

Trial #3: Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

I promise we’re almost done here. You’ve been troopers!

This was a 2020 phase 4 trial that investigated empagliflozin in well-controlled patients with T2DM. This double-blind study randomized 84 patients to receive either empagliflozin 25 mg daily or a placebo for 24 weeks.

Notable results:

If you haven’t guessed it by now, LFC = liver fat content and BW = body weight. Notice again how the SGLT2-inhibitor just plain compared to placebo. (Image)

A significant reduction in liver fat content was observed in the empagliflozin group, with a placebo-corrected absolute decrease of 1.8% and a relative decrease of 22%. Additional benefits included a 2.5 kg weight loss, a notable decrease in serum uric acid levels, and an increase in high-molecular-weight adiponectin, again pointing us to signs of improving metabolic health.

The tl;dr of Using SGLT-2 Inhibitors for NAFLD and NASH

These trials collectively shined a spotlight on the efficacy of SGLT-2 inhibitors in managing liver fat content in NAFLD and NASH, especially for patients with T2DM. Their ability to significantly reduce liver fat, improve liver enzymes, and facilitate weight loss positions them as an integral part of the therapeutic arsenal for NAFLD/NASH management.

Vitamin E for Treatment of NAFLD and NASH

Our last option crosses into the world of supplements, and it potentially serves as an option for patients who do not have access to the therapies listed above. Vitamin E has garnered attention in the realm of NAFLD/NASH treatment, particularly for non-diabetic individuals. Let’s explore two significant trials to better understand its impact.

Trial #1: PIVENS (Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis)

This 2010 trial involved 247 non-diabetic adults with NASH, who were randomized to receive either vitamin E 800 IU daily, pioglitazone 30 mg daily, or a placebo.

Some key findings:

In a vitamin E victory lap, 43% of patients witnessed noteworthy histological improvements, compared to 19% in the placebo group. Improvement in scores for steatosis and lobular inflammation were also significant with vitamin E; however, no significant changes in fibrosis scores were observed. Adverse events, including weight changes, were comparable across the groups, except for weight gain in the pioglitazone group, which was increased.

Trial #2: Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial

This 2019 study enrolled 105 patients with T2DM and NASH. Participants were randomized to receive either 800 IU of vitamin E daily, a combination of vitamin E and 30-45 mg/day pioglitazone, or a placebo.

A few key observations…

The combination therapy group showed a 54% improvement in NASH compared to 19% in the placebo group. However, vitamin E alone did not significantly differ from placebo in improving NASH. Reductions in plasma ALT and AST concentrations were noted in both treatment arms, and significant weight gain and improved glycemic control were observed in the combination therapy group (thanks a lot, pioglitazone). This mixed bag of results should raise your eyebrow before jumping to vitamin E monotherapy in our patients with diabetes.

The tl;dr of Using Vitamin E for NAFLD and NASH

The PIVENS trial and the second study with T2DM patients collectively highlight the potential role of vitamin E in NAFLD/NASH management. Its ability to improve liver histology in non-diabetic patients and the mixed results in the diabetic population underline its utility as a selective therapeutic option; however, it is critical to consider individual patient profiles and patient access when choosing vitamin E as an option.

Tailoring Diabetes Management: A Patient-First Approach Considering Liver Health

After exploring the potential role of vitamin E in our last section, it's time to turn our focus to personalizing diabetes medications, keeping our friend, the liver, in mind. Remember, every patient's story is unique, and our approach should be as tailored as a custom suit.

Pioglitazone - The Balancing Act: For patients where NAFLD/NASH and diabetes coexist, pioglitazone often emerges as a solid choice; however, it's not just about managing liver fat and blood sugar. We need to consider its adverse effects, like potential heart failure exacerbation and weight gain. If a patient has any cardiac red flags or concerns about weight, we might need to explore other avenues.
Liraglutide and Semaglutide – GLP-1 RA Siblings: These guys are like the Swiss Army knives for patients grappling with diabetes, obesity, or atherosclerotic cardiovascular disease, all while keeping an eye on NAFLD/NASH. With this being said, we can’t forget the possible gastrointestinal side effects and the risk of gallstones, particularly due to their weight loss effects. They are great choices, but we need to make sure our patients are fully informed and prepared for these potential issues.
Tirzepatide – The New Kid on the Block: If obesity and diabetes are in the picture with NAFLD, tirzepatide can be a game-changer. It's a newer player, so while its full cardiac impact is still under the microscope, its benefits for weight management and liver health are promising. Again, we need to educate our patients about possible gastrointestinal side effects.
SGLT-2 Inhibitors – For the Heart and Kidneys: When kidney disease or cardiovascular issues accompany diabetes and NAFLD, SGLT-2 inhibitors like empagliflozin and dapagliflozin become our go-tos. They do a fantastic job but come with risks like urinary infections and dehydration. Our role includes ensuring patients understand how to mitigate these risks.
Vitamin E – The Non-Diabetic Path: Since the data regarding vitamin E use in NAFLD/NASH alongside diabetes is lacking at best, vitamin E should probably be saved for just our peeps without diabetes for now. If it is the only option available, we must weigh the benefits against potential risks, like hemorrhagic stroke or prostate cancer.

In the end, our mission is to put the patient at the center of this complex medication puzzle. It's about more than just treating numbers on a lab report. It's about treating individuals with their own unique set of challenges and concerns.

Tackling Hepatic Toxicity Amidst Polypharmacy

Alright, team, let’s pivot to a critical aspect of our pharmaceutical finesse: dodging the hepatotoxic bullets. When managing NAFLD/NASH, especially in our diabetic patients, it's not just about what we give, but also about what we DON’T give. Here’s a rundown of some usual suspects we should sidestep, if and when possible:

Amiodarone: This antiarrhythmic can be a liver's nightmare, potentially leading to steatosis, steatohepatitis, and even cirrhosis. It can disrupt the liver’s fat processing, making it a less-than-ideal choice for our NAFLD/NASH patients.
5-Fluorouracil (5-FU): Used in chemotherapy, this drug can accumulate catabolites that hinder the liver's lipid metabolism, leading to steatosis. It’s a case where we need to weigh the benefits against the liver risks.
Irinotecan: This one’s a bit of a double-edged sword in oncology, potentially triggering mitochondrial dysfunction and impaired autophagy, leading to steatohepatitis.
Tamoxifen: While it's a game-changer in hormone receptor-positive breast cancer, tamoxifen can promote fat buildup in the liver, leading to steatosis and steatohepatitis. It’s a tricky one, especially in patients with existing liver issues.
Methotrexate: Known for its role in managing autoimmune diseases, methotrexate can harm liver mitochondria and the canals of Hering, potentially causing steatosis, steatohepatitis, and even cirrhosis.
Corticosteroids: A double-edged sword in managing inflammation, corticosteroids can exacerbate metabolic issues and impair the liver's fat processing, making them a cautious choice in patients with fatty liver disease.

Remember, as pharmacists, we're the gatekeepers of medication safety. Spotting these risks and navigating our patients to safer waters? That’s where we shine. Let's not forget the broader spectrum of hepatotoxic agents either – from painkillers and antibiotics to antifungals. Be vigilant with drugs like NSAIDs, some statins, and even over-the-counter meds like acetaminophen, particularly in those with compromised livers. It’s about keeping a keen eye on the whole medication list, ensuring every medication we recommend aligns with a healthy liver in mind.

Emerging Therapies for NAFLD and NASH

Okay, so we've navigated the current landscape of NAFLD/NASH management, especially concerning our diabetic patients. Given we have some frontrunners potentially inching toward FDA approval for NAFLD/NASH, let's peek at the horizon to glimpse at some emerging therapies you might encounter soon.

FXR Agonists (like obeticholic acid): Think of the farnesoid X receptor (FXR) as a liver's guardian angel. These FXR agonists step up to protect and manage bile acid processes, inflammation, and overall liver metabolism. The REGENERATE trial demonstrated that obeticholic acid could notably improve liver fibrosis without worsening NASH, making it a potential game-changer.
GLP-1 Agonists and SGLT2 Inhibitors: There's an intriguing approach being explored - combining GLP-1 agonists, known for reducing liver fat and inflammation, with SGLT2 inhibitors, celebrated for their metabolic benefits. This combination aims to enhance both glycemic control and liver health synergistically.
Vitamin E and Pioglitazone: Remember the PIVENS trial? It put this duo in the spotlight for patients with NASH. Vitamin E brings its antioxidant A-game, while pioglitazone works on insulin sensitivity. Together, they're like a dynamic duo for the liver, though we've got to keep an eye on the side effects.
FXR Agonists and Statins: Research is cooking up something new here - combining FXR agonists, focusing on liver fibrosis, with statins, famous for lowering lipids and possibly taming liver inflammation. This could be a fresh, holistic approach to liver care.

As we watch these therapies progress from experimental stages to potential treatment options, they represent a beacon of hope and innovation in the ongoing fight against NAFLD/NASH. Stay tuned, as these advancements could become a norm in the very near future!

The Importance of NAFLD and NASH Awareness

So here's the kicker. The biggest battle in managing NAFLD/NASH is often simply awareness…or the lack thereof. And I mean lack of awareness both amongst patients and within the healthcare system.

As pharmacists, we're positioned to bridge this gap by educating not just our patients but also our peers in healthcare about the intricacies of these monsters. Alongside education is advocacy - that is, advocating for all of our patients at risk to have access to EARLY screening and ultimately to comprehensive care (aka stop leaving the liver out of the conversation).

Given the asymptomatic nature of early-stage NAFLD/NASH, early detection can be challenging. Regular LFTs and risk factor screenings can be key tools in our arsenal for early identification and escalation of care. These screenings don’t have to wait for a specialist. Maximize your scope to help identify these patients and get them into the right hands like they deserve. Again, our goal here is early intervention and education so that the sneaky silent NAFLD doesn’t slip by before it’s too late.

The tl;dr on NAFLD, NASH, and Diabetes

In a nutshell, our dive into diabetes, NAFLD, and NASH reveals a complex relationship demanding our keen attention for the foreseeable future. We’ve discussed the importance of identifying the patients at risk and how to screen those patients that may be more silent.

Armed with tools like lifestyle interventions and pharmacotherapy recommendations, this pharmacy gang is ready to assist in the management of NAFLD and NASH at any turn. Remember, early intervention, personalized treatment, and collaboration with our physician colleagues will be the focal points for ensuring all of our patients receive thorough, equitable care.

So the next time someone brings up diabetes with you and discusses the heart, the kidney, or the pancreas, be sure to tell them all about the new dude in the picture..the liver!

What Every Pharmacist Needs to Know about Non-Alcoholic Fatty Liver Disease (NAFLD)