Today, I review, link to, and excerpt from Cell Metabolism‘s Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Cell Metab. 2024 Feb 6;36(2):408-421.e5. doi: 10.1016/j.cmet.2023.12.027.
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Abstract
Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.
Keywords: Clostridium; GLP-1; UDCA; glucose intolerance; statin.
Copyright © 2024 Elsevier Inc. All rights reserved.
Summary
Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) [from StatPearls] could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.Keywords
Introduction
Statin is the cornerstone of primary and secondary prevention for atherosclerotic disease by contemporary guidelines. According to statistics, 1 in 4 people over 40 years old on average takes statin as secondary prevention of cardiovascular disease.1 However, the adverse effects caused by statin utilization have also attracted extensive attention. In addition to severe or common complications such as rhabdomyolysis and liver function injury, the new-onset diabetes mellitus (DM) or glucose intolerance has been reported more and more frequently as a concomitant symptom after statin therapy. According to previous clinical trials, statin treatment was associated with a significant increase in new-onset diabetes. In addition, participants with one or more major diabetes risk factors were at higher risk of developing diabetes than those without.2,3,4 Epidemiological studies also suggest that the hazard ratio for developing type 2 diabetes ranges from 1.3 to 3.3 over the follow-up point among patients utilizing statin.5,6,7,8 Statin-caused new-onset diabetes appears to be more pronounced among Asian populations.7,9 Despite growing concerns about dysregulated glucose homeostasis related to statin therapy, few mechanistic investigations have been conducted.The concept of “gut dysbiosis” and its association with cardiometabolic diseases have attracted growing attention. An increasing number of studies have shown that changes in the structure and function of gut microbiome can promote the occurrence of obesity and insulin resistance, which is an important pathogenesis for type 2 diabetes and cardiovascular disease. Intestinal bacteria can also ferment dietary fiber, increasing the secretion of intestinal peptides and insulin-like growth factors.10,11 The gut microbiota modulates host metabolism via regulating various circulating metabolites, including bile acids and indoles. Previous studies have analyzed the remodeling effect of metformin on gut microbiota and its metabolites and revealed that glycoursodeoxycholic acid (GUDCA) and intestinal farnesoid X receptor (FXR) are new targets for treating metabolic diseases associated with obesity.10,12,13 A recent study has further proposed that microbial host isoenzymes are widely present in the intestine. Specifically, bacterial dipeptidyl peptidase-4 (mDPP4) isoenzymes have been identified as capable of degrading the host active glucagon-like peptide-1 (GLP-1), which leads to the disruption of the integrity of the intestinal barrier and the impaired glucose metabolism in mice.14In addition, more and more evidence shows that the therapeutic effects of various drugs are related to the different functions of gut microbiota.15 Besides the influence of gut microbes on drug metabolism and toxicity, the complex relationship between the gut microbiota and host also interferes with the therapeutic effect of drugs.15 A recent population-based cross-sectional gut microbiota analysis has shown that statin therapy is associated with lower gut microbiota dysbiosis, with the predominant difference in the distribution of Bacteroides, Ruminococcaceae, Prevotella, etc.16 Meanwhile, prior work has demonstrated that individual responses to statins, both in terms of on-target low-density lipoprotein (LDL) lowering and in terms of off-target insulin resistance, can be explained by baseline variation in the microbiome.17 Our previous investigation has pointed out that the alteration of fecal bacteria also affects the individual response to statin therapy.18 However, it remains to be elucidated whether the gut microbiome exerts an influence on glucose homeostasis after statin therapy.Given the vital role of the gut microbiome in glucose homeostasis, we hypothesize that statin utilization may contribute to the gut microbiome dysbiosis, which potentially affects circulating metabolites and host glucose homeostasis. In this study, by performing metabolomic and metagenomic analyses in a cohort of atherosclerotic patients receiving atorvastatin, the Clostridium species were identified to be closely associated with bile acid synthesis and excretion in a time-dependent manner. Through a series of animal and cell culture experiments, we also clarified that the Clostridium-rich microbiota could influence bile acid excretion, which regulated glucose intolerance via targeting GLP-1 secretion. At last, by supplementing ursodeoxycholic acid (UDCA) to individual patients receiving chronic statin therapy who also exhibited elevated hemoglobin A1c (HbA1c), we observed that the combination therapy of statin and UDCA could ameliorate the glucose homeostasis without affecting its lipid-lowering effects.Results
Statin induced glucose intolerance and decreased serum GLP-1 level in hyperlipidemia patients
To investigate how statin affects glucose levels in patients, we established a cohort of 30 patients with atorvastatin and 10 control subjects without atorvastatin at baseline and followed up for 16 weeks (Figure 1A). The baseline information for the patients enrolled was listed in Tables S1-1 and S1-2. As compared with the control, patients with atorvastatin exhibited a significant decrease in total cholesterol (TC) and LDL levels 1 week after statin initiation (Figures 1B and 1C). In addition, although the fasting glucose levels showed no difference, the HbA1c increased significantly at 4 weeks and prolonged to 16 weeks (Figure 1D), together with increased insulin, C-peptide, and homeostatic model assessment for insulin resistance (HOMA-ir) (Figures 1E–1G). Previous studies identified that GLP-1 can promote insulin secretion and inhibit glucagon secretion.19,20 We then tested the effect of atorvastatin on serum level of GLP-1 and found that the active GLP-1 concentration decreased significantly 4 weeks after atorvastatin initiation (Figure 1H), suggesting that atorvastatin could inhibit GLP-1 secretion to affect glucose homeostasis.Figure 1 Statin induced glucose intolerance and decreased serum GLP-1 level in hyperlipidemia patients(A) Clinical study flow chart of patients taking atorvastatin (n = 30) or healthy control (n = 10).(B and C) Total cholesterol (B) and LDL (C) levels at week 0, 1, 4, and 16.(D–G) HbA1c (D), insulin (E), C-peptide (F), and HOMA-ir (G) levels at week 0, 1, 4, and 16.(H) GLP-1 at week 0, 1, 4, and 16. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, as determined by one-way ANOVA. Data are shown as means ± SEM.See also Methods S1.
