PPAR-α activator pemafibrate lowered plasma insulin-like growth factor-1 level in a patient with acromegaly

Abstract

Summary

This is a report of a patient with acromegaly that was ameliorated by pemafibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) activator. Baseline acromegaly medication for this patient was lanreotide (90 mg/month). A marked reduction in insulin-like growth factor-1 levels was observed after initiating pemafibrate and remained during 12 months of follow-up. PPAR-α agonists might prove useful in pharmacotherapy for acromegaly.

Learning points

• Pemafibrate was effective for regulating dyslipidemia in the present case.

• A concomitant decrease in plasma IGF-1 levels was observed following initiation of pemafibrate treatment.

• Some in vitro studies have described beneficial effects of pemafibrate.

• Pemafibrate warrants investigation as a new treatment for acromegaly.

Background

Acromegaly is a rare, intractable endocrine disease, with an annual prevalence in Japan recently estimated as 92 cases per million (1). Clinical manifestations of acromegaly range from subtle signs of acral overgrowth, soft tissue swelling, arthralgia, jaw prognathism, hyperglycemia, and hyperhidrosis to florid osteoarthritis, diabetes mellitus, hypertension, and respiratory and cardiac failure (2, 3). Pemafibrate is the first clinically available selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) and has been used to improve dyslipidemia and reduce both macro- and microvascular complications (4, 5, 6). A patient in whom acromegaly was ameliorated by SPPARMα is reported here. After initiating treatment with the PPAR-α activator pemafibrate, improvements were seen in blood concentrations of both triglyceride (TG) and insulin-like growth factor (IGF)-1.

Case presentation

The patient was a 63-year-old woman who visited a local clinic in 2017 after she could no longer wear her wedding ring. The doctor recognized a positive heel pad sign and macroglossia. At this time, the concentration of IGF-1 was 736 ng/mL (normal: 66–194 ng/mL) and growth hormone (GH) was >5 ng/mL following 75 g oral glucose tolerance testing. Acromegaly was therefore diagnosed. Somatostatin receptor scintigraphy showed radioisotope accumulation in the pituitary gland. Her doctor initiated monthly subcutaneous infusion of lanreotide at 60 mg/month (Fig. 1). Neither radiation therapy nor surgery was performed. The patient started visiting our department in 2019, at which time she was receiving oral administration of rosuvastatin and ezetimibe. However, this prescription was causing adverse effects of general pain, so administration was suspended. Her medical history on first presentation to the department included surgery for ovarian cyst, chronic thyroiditis, carpal tunnel syndrome, and lipidemia. Since 2017, she had been diagnosed with signet ring cell gastric cancer, colon polyp, and gallbladder stone. Other medications being administered at this time were alendronic acid, levothyroxine sodium hydrate, and a proton pump inhibitor.

Figure 1.

Clinical time course.

Investigation

The patient was 158.0 cm tall and weighed 55.2 kg (body mass index: 22.1 kg/m²). Blood pressure was 142/95 mmHg, and heart rate was 74 beats/min. Palpebral conjunctivae were not anemic, and bulbar conjunctivae were not icteric. No struma was evident, and breath sounds were clear. Auscultation revealed no cardiac murmurs. The abdomen was soft and flat on palpation. Bowel sounds were normal. No edema was observed in the lower legs. No visual field disturbances, protrusion of the lower jaw, or bulging of the brow arch was recognized. The patient complained of headache and joint pain. TG was 208 mg/dL and low-density lipoprotein cholesterol (LDL-C) was 173 mg/dL (Table 1), so dyslipidemia was diagnosed.

Table 1.

Laboratory data after initiation of pemafibrate treatment.

Parameters	Values
Urine test
SG	1.006
pH	7.0
Protein	-
Sugar	-
Ketones	+
Bilirubin	-
Urobilinogen	0.1
Blood analysis
WBC	4,300/μL
Neutrophils	45.9%
Lymphocytes	45.7%
Monocytes	4.6%
Eosinophils	1.3%
Basophils	0.7%
RBC	392 × 104/μL
Hb	11.6 g/dL
Ht	35.7%
MCV	90.9 fL
MCH	29.6 pg
MCHC	32.5 g/dL
Platelets	206 × 103/μL
AST	30 IU/L
ALT	30 IU/L
γGTP	18 IU/L
Triglycerides	208 mEq/L
LDL-C	173 mEq/L
Na	142 mEq/L
K	4.5 mEq/L
Cl	104 mEq/L
Urea nitrogen	10.5 mg/dL
Creatinine	0.72 mg/dL
eGFR	62.5 mL/min/1.73 m2
Glu	78 mg/dL
HbA1c	6.2%

Treatment

Pemafibrate (0.2 mg/day) was prescribed in April 2024 (Fig. 1). The patient did not complain of any pain or discomfort at this time. Six months later, TG was 93 mg/dL and LDL-C was 116 mg/dL (Fig. 2). Subcutaneous lanreotide was continued at 90 mg/month. After starting pemafibrate, a marked reduction in IGF-1 levels was observed, compared to levels under lanreotide monotherapy (Fig. 3). IGF-1 levels decreased from 113 mg/dL at the initiation of pemafibrate to 74 mg/dL at 24 weeks, representing a 35% reduction, and were maintained within a stable range between 24 and 48 weeks. In contrast, GH levels remained relatively stable during the same period from 0 to 48 weeks after starting pemafibrate, remaining within the range of 0.1–9.88 ng/mL. An area of early enhancement of the right side of the anterior pituitary gland on magnetic resonance imaging (MRI) did not change between before and after pemafibrate initiation (Fig. 4).

Figure 2.

Decreases in levels of triglyceride (TG) (A) and LDL-C (B) in the patient with acromegaly during 6 months of treatment with pemafibrate and lanreotide.

Figure 3.

Plasma levels of GH (A) and insulin-like growth factor-1 (IGF-I) (B) secretion in the patient with acromegaly during 48 weeks of lanreotide treatment. The baseline means the time at initiation of pemafibrate.

Figure 4.

MRI. No change in early enhancement of the right anterior pituitary gland (arrow) is evident between before (A) and after (B) pemafibrate initiation.

Outcome and follow-up

Both GH and IGF-1 levels remained within the normal range. The baseline acromegaly medication was lanreotide at 90 mg/month. Pemafibrate was initiated for lipidemia treatment.

Discussion

Pemafibrate was effective for regulating dyslipidemia in the present case, but a concomitant decrease in plasma IGF-1 levels was also observed following initiation of pemafibrate. This decrease in IGF-1 should not be attributed solely to the pemafibrate, and delayed or cumulative effects of lanreotide therapy were also raised as possible contributors. However, the dose of lanreotide had been escalated from 60 mg/month to 90 mg/month in May 2021, approximately 3 years prior to the initiation of pemafibrate in April 2024. The decrease in IGF-1 observed immediately after pemafibrate administration was thus considered unlikely to have been a delayed effect of the prior lanreotide dose adjustment.

One report described basic experiments on the effects of fenofibrate on acromegaly (7). Rotondi et al. reported a relationship between PPAR-α and somatotropinomas, finding that dual effects of fenofibrate were observed in GH3 cells, consisting of cell growth inhibition and an increase in GH secretion that was in turn inhibited by octreotide. Their conclusion was that PPAR-α represents a potential new player for the treatment of somatotropinoma. Potential interactions between PPAR-α agonists and somatostatin analogs may thus warrant further investigation (7). While no reports describing a relationship between IGF-1 and PPAR-α were found, Polidoro et al. reported that PPAR-α was expressed in a majority of pituitary adenomas and fenofibrate significantly reduced the growth of these tumor cells (8).

In the case of PPAR-γ, the effects seen in the present case might not be expected, as Bastemir et al. reported that the PPAR-γ activator rosiglitazone failed to lower plasma levels of GH and IGF-1 levels in patients with acromegaly (9). Morcos et al. reported on PPAR-γ agonists in pituitary diseases (10), discussing unusual effects in 14 patients followed up for 48 weeks. Kim et al. reported that short-term treatment with conventional doses of pioglitazone did not improve biochemical measures of disease activity in acromegaly (11).

No reports describing the relationship between pemafibrate and acromegaly or on the use of saroglitazar (ZYH1) in acromegaly were found. This might represent the first clinical report of potential effects from pemafibrate in patients with acromegaly. As this was a case report and thus was limited in the generalization of the findings, accumulation of more cases and verification of the data are warranted.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Ethical approval was not required for this study in accordance with local and national guidelines. Written informed consent was obtained from the patient for publication of the details of this medical case and the accompanying images.

Author contribution statement

GY was the principal clinician for the patient and prepared the manuscript.