Thiozolidineiones (Mech of their adverse effects)

[codebluewinniethepooh]

Hey everyone,

I have these three questions:

1- Does anybody know the mech. of edema and hepatotoxicity resulting from glitazones (let's call them glit.)?
2- for the fractures, I think it has to do with glit. increasing the level of adiponectin and increase lipid catabolism. Correct me if I am wrong?
3- In regard to the heart failure side effects, I know It can be the result of edema and fluid retention, but it does not make any sense when you think of the increased b-oxidation resulting from the glit.. literally, glit. prepare the heart favorite meal (the increased b-oxidation leading to increase ketones)

Thank you in advance,

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[cellsaver]

Hey everyone,

I have these three questions:

1- Does anybody know the mech. of edema and hepatotoxicity resulting from glitazones (let's call them glit.)?
2- for the fractures, I think it has to do with glit. increasing the level of adiponectin and increase lipid catabolism. Correct me if I am wrong?
3- In regard to the heart failure side effects, I know It can be the result of edema and fluid retention, but it does not make any sense when you think of the increased b-oxidation resulting from the glit.. literally, glit. prepare the heart favorite meal (the increased b-oxidation leading to increase ketones)

Thank you in advance,

These are excellent questions and they deserve answers. Here's what I know from my experience in the industry (Rezulin/Troglitazone in the late 1990s) and some links I found. T2D is a fascinating disease to study hence my response.

1. Fluid Retention / Hepatoxicity

TZDs (thiazolidinediones) increase Na+ intake in the kidneys (i.e. renal collecting tubules). By doing so they promote fluid retention. There are already other physiological processes in the body promoting Na+ reabsorption so when TZD’s do likewise they contribute to increase plasma volume, which leads to peripheral edema. CHF follows.

PPAR-γ was expressed exclusively in the medullary collecting duct. Because the collecting duct plays a critical role in the regulation of sodium balance, this finding was highly suggestive of a PPAR-γ-mediated contribution to distal sodium reabsorption.

Thiazolidinediones and fluid retention​

Hepatoxicity was a concern with the first TZD brought to market called Rezulin (Troglitazone). Parke Davis brought it to the USA but it was removed precisely because of liver toxicities and deaths. I believe the UK also removed it from their markets. Hepatoxicity has been a lesser concern with the other 2 TZDs (rosiglitazone and pioglitazone) on the US market. They have been available for many years with none of the effects or dangers of Troglitazone. I believe liver enzymes monitoring is encouraged though.

2. Bone Fxs

TZDs have been shown in some studies that they decrease osteoblast activity and hence inhibit bone formation. However, other studies have shown otherwise so it is not definitive.

"Nevertheless, the results of currently available reports have still been inconclusive"
Thiazolidinediones and bone fractures​

We should bear in mind that T2D in itself is associated with higher incidence of bone fractures despite the tx used.

"The increased frequency of bone fractures in diabetics treated with insulin lies more in the fact that these patients suffer from diabetes longer, have more diabetic complications and are at a higher risk of hypoglycemia, which is associated with a higher frequency of falls."​

The effect of antidiabetic treatment on the bone of patients with type 2 diabetes​

3. With regard to Heart Failure, you can't ignore the fluid retention as you noted, but the data is very conflicted. Some studies implicate the class as resulting in HF while also state the opposite. It is important to keep in mind that by the time a patient is placed on TZDs, they have already had T2D for a while and have been treated with other classes of drugs.

There are clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination. Overall, use of gliptins or glitazones was associated with decreased risks of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs

Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care
BMJ 2016; 354 doi: Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care | The BMJ (Published 13 July 2016)​

It's a mixed bag when it comes to TZDs and CHF.


I found weight gain to be a reoccurring theme in the class. TZDs also impact Adiponectin which we know are affiliated with ADIPOcytes, hence the name. Adiponectin is a cytokine synthesized by fat tissue which regulate insulin sensitivity and fatty acid oxidation. TZDs increase levels of Adiponectin and thereby truly increase insulin sensitivity, unlike sulfonylureas and biguanides (Metformin). In regulating FA oxidation they augment the conversion of pre-adiopocytes into mature adipocytes. These collect in subcutaenous tissues instead of visceral hence weight gain. Then again, most patients with T2D all overweight or obese, so there is that to consider.

 

[codebluewinniethepooh]

Thank you for the very informative and detailed answer Cellsaver

 

[cellsaver]

Two recent studies have been published that provide new information on TZDs with regard to your very good questions on liver and heart failure. The first study showed that Pioglitazone improved histological markers in patients with nonalcoholic steatohepatitis (NASH). The second study uncovered researcher bias when implicating TZDs in cardiac events

In summary, as I wrote previously, the data is contradictory when it comes to TZDs deleterious effects on liver and cardiac parameters. Follow the data.

Medicine is in the minutiae.

First study:

"Results This study analyzed 8 (Randomized Clinical Trials) RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven ( nonalcoholic steatohepatitis) NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%)"

"Conclusions and Relevance Pioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study."

Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic SteatohepatitisA Meta-analysis. JAMA Intern Med. 2017;177(5):633-640. doi:10.1001/jamainternmed.2016.9607​

Second study:

RESULTS:

"The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2)  = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) ≥ 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons."

CONCLUSION/INTERPRETATION:

"Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity."

Pladevall, M., Riera-Guardia, N., Margulis, A. V., Varas-Lorenzo, C., Calingaert, B., & Perez-Gutthann, S. (2016). Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovascular Disorders, 16, 14. Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies​

Side note: nonalcoholic steatohepatitis (NASH) is on the rise globally. Risk factors for NASH include obesity, dyslipidemia, and glucose intolerance. As I referenced in passing earlier, cardiomyopathy (which leads to HF) is an outcome of chronic T2D patients regardless of treatment choices. T2D is a chronic illness that is injurious to the CV profile over the long term...