To the best of our knowledge, our study is the first to demonstrate the usefulness of telmisartan in reducing the risk of statin-induced DM in ASCVD hypertensive patients requiring high-intensity statin. The main findings of this study were 1) for participants with IFG who had hypertension and ASCVD requiring high-intensity statin, both 24-week treatment of amlodipine and telmisartan did not significantly improve HOMA-IR. However, HOMA-B, an indicator of insulin secretion, was maintained in the telmisartan-statin group but significantly reduced in the amlodipine-statin group, suggesting the protective effect of telmisartan on beta-cell function; 2) fasting glucose tended to increase slightly at week 24 than at the baseline in the amlodipine-statin group, but it decreased significantly during the study period in the telmisartan-statin group, with a significantly lower value at week 24 in the telmisartan-statin group than in the amlodipine-statin group; and 3) the telmisartan-statin group showed a lower proportion of fasting plasma glucose of ≥100 mg/dL or HbA1c of ≥6.5% and a lower rate of new-onset DM at 24 weeks than the amlodipine-statin group. In the multivariate analysis, the use of telmisartan was a significant protective factor for preventing new-onset DM at 24 weeks, demonstrating the beneficial role of telmisartan for ASCVD and IFG patients at-risk of DM and requiring high-intensity statin.
In several studies, statin has been shown to increase the risk of DM through various mechanisms: statin can affect beta-cell function, which is one of the possible mechanism of new-onset DM . In statin-treated beta cells, intracellular Ca2+ peaks induced by the uptake of glucose in beta cells are reduced, so a higher concentration of glucose is required for stimulating insulin secretion [13, 14]. In addition, statin treatment affecting pancreatic islet beta cells reduces insulin secretion rate dose-dependently . Another mechanism is that insulin resistance is increased by statins. Statin increases the expression of fatty acid synthesis gene, which leads to a higher amount of fatty acid content in the muscle . The accumulation of fatty acid causes detrimental effect on insulin signaling in muscle cells . Consistent with these results, HOMA-IR, an indicator of insulin resistance, showed a significant dose-dependent increase with rosuvastatin 10, 20, and 40 mg in hyperlipidemia patients with IFG . Thus, the risk of developing DM could be increased by statins, but DM does not develop in all patients receiving statin. Patients with an increased insulin resistance have a higher risk of developing DM with statin medication [3, 6]. It is strongly recommended not to discontinue statins in patients at a high risk of developing ASCVD because the protective effects of statins on cardiovascular disease outweigh the risk of diabetes . However, considering the decrease in quality of life and the increase in medical expenses owing to DM, it is necessary to reduce the development of new-onset DM .
In ASCVD patients with hypertension and dyslipidemia, the choice of antihypertensive drugs would be a good way to lower the side effects of statin, especially the risks of new-onset DM. Among antihypertensive drugs, which are classified as first-line, beta-blocker, and thiazide-like diuretics are known to increase insulin resistance . In contrast, renin-angiotensin-aldosterone system (RAAS) blockades, including ARB, can reduce the risk of new-onset DM through an important role in glucose homeostasis; angiotensin II negatively affects glucose uptake by inhibiting Glucose Transporter Type 4 translocation in the muscle and adipocytes, activates the inflammatory cytokine, and promotes the sympathetic nervous system, thereby increasing blood catecholamine levels, resulting in insulin resistance [21, 22]. Whereas calcium channel blockers, one of most common antihypertensive drug, have been reported to be associated with a higher incidence of DM than RAAS blockers in hypertensive patients .
Of the many ARBs, telmisartan has been reported to be more effective in lowering the risk of diabetes and differs from other ARBs in that it has a structural similarity to pioglitazone and can activate PPARγ even at low concentrations . A previous study showed that the combination of rosuvastatin with telmisartan decreased HOMA-IR in patients with IFG than irbesartan or olmesartan . Telmisartan may be superior in preventing cardiovascular disease independently of the BP-lowering effect than amlodipine, a calcium channel blocker. Telmisartan attenuates MCP-1 gene expression in peripheral blood monocytes and increases PPAR-r gene expression than amlodipine and has a positive influence on glycemic control and insulin resistance .
Although there was no significant difference in HOMA-IR reduction between the treatments, 24-week telmisartan treatment preserved the level of HOMA-B, significantly reduced the level of fasting plasma glucose and the proportion of participants with fasting plasma glucose of ≥100 mg/dL or HbA1c of ≥6.5%, and increased the change in euglycemic status from IFG, which effectively lowered the incidence of new-onset DM in patients receiving high-intensity statin than the 24-week amlodipine treatment. Prior studies had examined the effects of telmisartan in patients with insulin resistance regardless of the use of statin and evaluated the changes in metabolic parameters using a combination of telmisartan and a moderate dose of rosuvastatin without comparing with amlodipine [10, 25, 26]. Thus, our study was the first to investigate the effects of telmisartan versus amlodipine on glucose homeostasis in hypertensive ASCVD patients with high-dose and high-intensity statin treatment.
Telmisartan showed a tendency to improve insulin resistance and beta-cell function in patients with insulin resistance compared to a placebo . In contrast, the numerical improvement in HOMA-IR was not shown in our study. This is probably because the average baseline HOMA-IR was 3.8 in the previous study, but the baseline HOMA-IR was lower in our study. Therefore, the reduction effect by telmisartan might not be well observed. Generally, telmisartan has a favorable effect on glucose metabolism, but there are also reports indicating that telmisartan show a neutral effect on HOMA-IR . One of the novelties of our study was that telmisartan showed no changes in HOMA-B compared to amlodipine. Low HOMA-B is associated with a high risk of diabetes , and this is the first human study to confirm that telmisartan can prevent the statin-induced deterioration of beta-cell function.
There are some limitations of this study. First, this study was not double-blinded and not placebo-controlled. Second, because this study targeted patients with clinical ASCVD, most of these patients had hypertension, and the antihypertensive drug previously administered could have affected the metabolic parameters. Hence, a wash-out period should be considered after discontinuation of the antihypertensive drugs. However, the setting of wash-out period was impossible for patients with clinical ASCVD. Third, this study did not target statin-naïve patients. Therefore, it is possible that HOMA-IR was not significantly changed by rosuvastatin at the end of the study compared to the baseline. Finally, the weight changes or lifestyle modification might affect glucose metabolism even with short-term observation, but these were not analyzed.