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Glycemic effects of simvastatin: Where do we stand?

ABSTRACT

In clinical practice, simvastatin is usually used in the treatment of dyslipidemia patients and those at risk of or with established cardiovascular disease. However, previous studies have shown that simvastatin has the potential to affect glycemic parameters as it reportedly reduced insulin secretion and sensitivity. The exact mechanism by which simvastatin affects glycemia is still unknown, but previous studies have postulated the involvement of the glucose-insulin secretion mechanism. This review focuses on the effects of simvastatin, either alone or in combination with other lipid lowering agents, antidiabetics and antihypertensives, on glucose homeostasis. Some studies have reported that simvastatin might impair the levels of glucose metabolism markers in the blood while others have reported no effect or improvement in glycemia.

Keywords:
Simvastatin/effects; Glucose; Insulin secretion; Insulin sensitivity; Diabetes; Concurrent medications.

INTRODUCTION

Statins or 3-hydroxyl-3 methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors are used worldwide to treat dyslipidemia and also as part of the management of patients who have high risk of developing or established cardiovascular events resulting from type 2 diabetes mellitus (T2DM) or hypertension (Grover, Luthra, Maroo, 2014Grover HS, Luthra S, Maroo S. Are statins really wonder drugs? J Formos Med Assoc. 2014;113(12):892-898.; Perreault et al., 2009Perreault S, Ellia L, Dragomir A, Cote R, Blais L, Berard A, et al. Effect of statin adherence on cerebrovascular disease in primary prevention. Am J Med. 2009;122(7):647-655.). T2DM patients have a two- to four-fold increase in risk of cardiovascular disease as compared to the general population (Colhoun et al., 2004Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, W Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.). In addition, these patients tend to have high levels of triglyceride, low levels of high-density lipoprotein (HDL) with smaller and denser low-density lipoprotein (LDL) particles that promote atherogenesis (Vijan, Hayward, 2004Vijan S, Hayward RA. Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians. Ann Intern Medic. 2004;140(8):650-658.).

The key action of statins are by inhibition of the HMG-CoA reductase enzyme, hence reducing mevalonate synthesis and subsequently inhibits several other isoprenoid pathways as well as cholesterol synthesis (Gazzerro et al., 2012Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol rev. 2012;64(1):102-146.; Sirtori, 2014Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11.) (Figure 1). Currently, there are several types of statins available in the market, such as simvastatin, atorvastatin, lovastatin, fluvastatin, rosuvastatin and pravastatin. Cerivastatin has been withdrawn from the market after 52 deaths were reported due to kidney failure as a result of rhabdomyolysis (Furberg, Pitt, 2001Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2(5):205-207.).

FIGURE 1
Inhibition of the cholesterol synthesis pathway by statins.

In the United States, data from the National Health and Nutrition Examination Survey 2011-2012 showed that among adults aged 40 years and above who were using lipid-lowering drugs, 83% were using a statin, 10% a combination of a statin and a non-statin and 7% non-statin. Simvastatin was the most commonly used statin (42%), followed by atorvastatin (20.2%), pravastatin (11.2%), rosuvastatin (8.2%) and lovastatin (7.4%) (Gu et al., 2015).

Simvastatin or its brand name Zocor (Al-Foraih, Somerset, 2016Al-Foraih M, Somerset S. Factors affecting adherence to statins in hypercholesterolemic Kuwaiti patients: a cross-sectional study. Med Princ Pract. 2016;26(1):35-40.) is one of the most commonly used statins because of its effectiveness in reducing LDL cholesterol levels, produces fewer adverse effects, and is more affordable compared with other statins. Simvastatin is a semi-synthetic derivative of lovastatin which is obtained from a fermented product of Aspergillus terreus (Manzoni, Rollini, 2002Manzoni M, Rollini M. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol. 2002;58(5):555-564.). Most patients are prescribed simvastatin at dosages of 10, 20, or 40 mg/day. However, the use of simvastatin at 80 mg/day is restricted because of a high risk of muscle injury (FDA, 2011).

The efficacy of simvastatin in reducing the risk, morbidity, and mortality of cardiovascular events has been demonstrated in various studies, such as the Scandinavian Simvastatin Survival Study (Pedersen et al., 1998Pedersen TR, Olsson AG, F rgeman O, Kjekshus J, Wedel H, Berg K, et al. Lipoprotein Changes and Reduction in the Incidence of Major Coronary Heart Disease Events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97(15):1453-1460.), the Heart Protection Study (Heart Protection Study Collaborative Group, 2002), the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) Collaborative Group (Meade et al., 2010Meade T, Sleight P, Collins R, Armitage J, Bowman L, Parish S, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658-1669.) and others (Ceriello, 2002Ceriello A. Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation: Effects of Short- and Long-Term Simvastatin Treatment. Circulation. 2002;106(10):1211-1218.; Dobs et al., 2008Dobs A, Miller M, Delucca PT, Ramsey KE, Tershakovec AM, Horn W. Efficacy of simvastatin therapy in attainment of LDL-C and TG goal levels in patients with type 2 diabetic dyslipidemia. J Clin Lipidol. 2008;2(1):12-18.; Foody et al., 2008Foody JM, Joyce AT, Rudolph AE, Liu LZ, Benner JS. Cardiovascular outcomes among patients newly initiating atorvastatin or simvastatin therapy: a large database analysis of managed care plans in the United States. Clin Ther. 2008;30(1):195-205.). However, some studies have reported association between statins and glycemia, but such effects are controversial and conflicting ranging from adverse, neutral to beneficial. In diabetics, simvastatin has been shown to worsen glycemic control and insulin secretion (Bellia et al., 2012Bellia A, Rizza S, Lombardo MF, Donadel G, Fabiano R, Andreadi K, et al. Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy. Atherosclerosis. 2012;223(1):197-203.), improve insulin resistance (Paolisso et al., 2000Paolisso G, Barbagallo M, Petrella G, Ragno E, Barbieri M, Giordano M, et al. Effects of simvastatin and atorvastatin administration on insulin resistance and respiratory quotient in aged dyslipidemic non-insulin dependent diabetic patients. Atherosclerosis. 2000;150(1):121-127.) or to have no effect on glucose levels (Farrer et al., 1994Farrer M, Winocour PH, Evans K, Neil HAW, Laker MF, Kesteven P, et al. Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures. Diabetes Res & Clin Pract. 1994;23(2):111-119.; Szendroedi et al., 2009Szendroedi J, Anderwald C, Krssak M, Bayerle-Eder M, Esterbauer H, Pfeiler G, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care. 2009;32(2):209-214.).

In terms of solubility, statins can be classified into water-soluble (hydrophilic) and lipid soluble (lipophilic). Atorvastatin, fluvastatin, lovastatin, and simvastatin are lipophilic statins, while rosuvastatin and pravastatin are hydrophilic statins (Igel, Sudhop, Bergmann, 2002Igel M, Sudhop T, Bergmann K. Pharmacology of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins), Including Rosuvastatin and Pitavastatin. J Clin Pharmacol. 2002;42(8):835-845.). For lipophilic statins, it can diffuse through the plasma membranes of extrahepatic cells (for example beta cells, adipocytes and skeletal muscle cells), which can result in a diabetogenic effect (Aiman, Najmi, Khan, 2014Aiman U, Najmi A, Khan RA. Statin induced diabetes and its clinical implications. J Pharmacol Pharmacother. 2014;5(3):181-185.; Schachter, 2005Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-125.). As simvastatin is a lipophilic statin, it has the potential to reduce insulin secretion and sensitivity (Koh et al., 2009Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Park JB, et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis. 2009;204(2):483-490.).

Effect of simvastatin on glucose metabolism: in vitro studies

The exact mechanisms underlying the effect of simvastatin on glycemia are still unknown. However, previous studies have implicated the inhibition of glucose-stimulated insulin secretion. Several experimental studies have indicated how simvastatin affects glucose metabolism (Figure 2).

FIGURE 2
Previous experimental findings on the effect of simvastatin on glucose-insulin secretion.

The effect of statins (simvastatin, simvastatin acids, and pravastatin) on β cell function has been investigated in rat pancreatic β cells. Cytosolic calcium (Ca²+) concentration is an important component in the regulation of pancreatic β cells (De Marchi et al., 2014De Marchi U, Thevenet J, Hermant A, Dioum E, Wiederkehr A. Calcium co-regulates oxidative metabolism and ATP synthase-dependent respiration in pancreatic beta cells. J Biol Chem. 2014;289(13):9182-9194.). A reduction in the cytosolic Ca2+ concentration leads to impairment of insulin secretion. In the study by Yada et al. (1999Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet ß-cells. Br J Pharmacol. 1999;126(5):1205-1213.) has demonstrated that simvastatin inhibited β cell L-type Ca2+channels and reduced insulin secretion but pravastatin did not. After administration of simvastatin for 20 seconds, L-arginine and potassium chloride-induced insulin release were inhibited (Yada et al., 1999).

The mechanisms by which simvastatin impairs insulin secretion have been elucidated using mouse islet β cell lines, MIN6. Compared to normal control cells, simvastatin significantly inhibited insulin secretion in a dose-dependent manner. The inhibition of insulin secretion was indirectly caused by reduced levels of glucose transporter 2 (GLUT2). Simvastatin reduced the adenosine triphosphate (ATP) levels in MIN6 cells, increased the ATP-sensitive potassium channel (KATP) current and reduced the L-type - Ca2+ current. Simvastatin may also reduce insulin secretion by increasing the rectifier potassium channel (Kir6.2) current while simultaneously decreasing the voltage-dependent Ca2+ channel 1.2 (Cav1.2) current, which leads to inhibition of membrane cell depolarization and inhibition of calcium influx (Zhou et al., 2014Zhou J, Li W, Xie Q, Hou Y, Zhan S, Yang X, et al. Effects of simvastatin on glucose metabolism in mouse MIN6 cells. J Diabetes Res. 2014;2014:376570.).

Glycemic effect of simvastatin: human data

Simvastatin has been reported to increase plasma glucose levels and reduce insulin sensitivity. A few studies have measured the effect of simvastatin treatment on glucose homeostasis (Table I). In a study by Koh et al. (2008Koh KK, Quon MJ, Han SH, Lee Y, Ahn JY, Kim SJ, et al. Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes Care. 2008;31(4):776-782.) reported that simvastatin improved flow-mediated dilation, but reduced adiponectin levels and insulin sensitivity in hypercholesterolemia patients (Koh et al., 2008). Patients who were on simvastatin 80 mg/day had a 7% increase in mean plasma glucose levels after 2 months of treatment. Meanwhile, those who were on simvastatin 10, 20, 40, or 80 mg/day had increased insulin secretions relative to the baseline after 2 months of treatment, which is indicative of deterioration in insulin sensitivity. The same study also demonstrated that there was a slight reduction in insulin sensitivity in the simvastatin-treated group, as measured using the quantitative insulin sensitivity check index (QUICKI) (Koh et al., 2008). A separate study by the same authors showed significant reductions in insulin sensitivity and plasma adiponectin levels in hypercholesterolemia patients after taking simvastatin 20 mg/day for 2 months. However, there were no significant differences in insulin or glucose levels compared to baseline (Koh et al., 2015).

TABLE I
The effect of simvastatin on glucose metabolism markers in human data

A study in which patients were selected randomly to receive either simvastatin 20 mg/day or rosuvastatin 20 mg/day showed that there was no effect of simvastatin on insulin sensitivity and glycemic control after 4 weeks of treatment (Bellia et al., 2010Bellia A, Rizza S, Galli A, Fabiano R, Donadel G, Lombardo MF, et al. Early vascular and metabolic effects of rosuvastatin compared with simvastatin in patients with type 2 diabetes. Atherosclerosis. 2010;210(1):199-201.). However, another study by the same authors reported that the simvastatin and rosuvastatin treatments worsen fasting blood glucose (FBG) and A1C levels after 12 months without affecting insulin sensitivity (Bellia et al., 2012). On the same note, a study by Sen et al. (2002Sen K, Misra A, Kumar A, Pandey RM. Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia. Diabetes Res Clin Pract. 2002;56(1):1-11.) found that in simvastatin group, A1C levels were significantly increased at follow-up at 90 and 180 days compared to day 1 (Sen et al., 2002).

Conversely, some studies have reported a lack of association between simvastatin treatment and blood glucose levels. After 90 days of simvastatin treatment, the homeostasis model assessment - insulin resistance (HOMA-IR) values and FBG levels remained unchanged in patients with isolated hypercholesterolemia, even though there were improvements in plasma lipid levels (Krysiak, Okopien, 2013aKrysiak R, Okopien B. Effect of simvastatin on hemostasis in patients with isolated hypertriglyceridemia. Pharmacology. 2013a;92(3-4):187-190.). As for T2DM patients, some studies have reported no significant changes in glucose parameters after simvastatin treatment (Farrer et al.,1994Farrer M, Winocour PH, Evans K, Neil HAW, Laker MF, Kesteven P, et al. Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures. Diabetes Res & Clin Pract. 1994;23(2):111-119.; Hwu et al., 1999Hwu C, Kwok C, Chen H, Shih K, Lee S, Hsiao L, et al. Lack of effect of simvastatin on insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from a double-blind, randomized, placebo-controlled crossover study. Diabet Med. 1999;16(9):749-754.). Szendroedi et al. (2009Szendroedi J, Anderwald C, Krssak M, Bayerle-Eder M, Esterbauer H, Pfeiler G, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care. 2009;32(2):209-214.) reported that there was no effect of simvastatin on insulin sensitivity, fasting insulin levels or HOMA-B levels (Szendroedi et al., 2009). In addition, a study by Hydrie et al. (2007Hydrie MZI, Qasim R, Ahmadani MY, Miyan Z, Fawwad A, Basit A. Effect of simvastatin on insulin sensitivity in type 2 diabetic subjects. Pak J Medical Science. 2007;23(5):755.) found after receiving simvastatin for 3 months, there were no significant differences in HOMA-IR values compared to baseline. However, 20 patients with T2DM who were having insulin resistance with HOMA-IR values of more than 2.8 at the beginning of the study demonstrated improvements in insulin sensitivity after receiving simvastatin (Hydrie et al., 2007).

Simvastatin and new-onset Diabetes

The Heart Protection Study has suggested that there was no association between simvastatin use and new-onset diabetes, although previous studies have reported that statins might induce the new-onset of diabetes. Among 14, 573 subjects without diabetes at study entry, it was noted that there was no significant difference in number of new-onset diabetes between the simvastatin group (4.6%) and the placebo group (4.0%). After follow-up for 4.6 years, among 1087 subjects who had diabetes at study entry, there was no significant difference in increased A1C among treatment groups (Heart Protection Study Collaborative Group, 2003).

However, the Study of Effectiveness of Additional Reductions in Cholesterol, Homocysteine (SEARCH) trial showed that there was a slight increase in new-onset diabetes with high dose simvastatin, 80 mg/day (11.6%) compared to low dose, simvastatin 20 mg/day (10.9%) (Armitage et al., 2010Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658-1669.) (Table II).

TABLE II
Comparison of relative risk of new-onset diabetes with simvastatin use

Effect of simvastatin and concurrent medications on glycemic control

Certain patients, like those with metabolic syndrome and T2DM, require combinations of lipid lowering drugs because the use of simvastatin alone may fail to result in optimal lipid targets. Fenofibrate and niacin are the lipid lowering agents which are most often prescribed together with statins (Cannon, 2008Cannon CP. Combination therapy in the management of mixed dyslipidaemia. J Intern Med. 2008;263(4):353-365.). However, these concomitant drugs may increase the risk of drug-drug interaction with regards to glycemic effects, as shown in Table III.

TABLE III
Summary effects of simvastatin in combination with other lipid lowering medications based on previous studies

Niacin therapy is known to have beneficial effects in patients with dyslipidemia as it increases HDL cholesterol levels and at the same time reduces triglyceride and LDL cholesterol levels. However, niacin has the potential to increase blood glucose levels (Bays, 2008Bays H. Safety of niacin and simvastatin combination therapy. Am J Cardiol. 2008;101(8A):3B-8B.; Sazonov et al., 2013Sazonov V, Maccubbin D, Sisk CM, Canner P. Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with normoglycaemia and impaired fasting glucose. Int J Clin Pract. 2013;67(4):297-302.; Zhao et al., 2004). In a study by Vittone et al. (2007Vittone F, Chait A, Morse JS, Fish B, Brown BG, Zhao XQ. Niacin plus Simvastatin reduces coronary stenosis progression among patients with metabolic syndrome despite a modest increase in insulin resistance: a subgroup analysis of the HDL-Atherosclerosis treatment study (HATS). J Clin Lipidol. 2007;1(3):203-210.), it was found that three years’ usage of niacin in combination with simvastatin had a slight adverse effect on glycemic control, whereby FBG was increased by 3%, fasting insulin was elevated by 19%, and insulin sensitivity was reduced by 10% compared to baseline results (Vittone et al., 2007). As such, even though niacin when used alone or in combination with a statin gives beneficial effects to T2DM patients (in terms of achievement of target lipid levels), glucose levels should be monitored in those who are on long-term treatment (Ding, Li, Wen, 2015Ding Y, Li Y, Wen A. Effect of niacin on lipids and glucose in patients with type 2 diabetes: A meta-analysis of randomized, controlled clinical trials. Clin Nutr. 2015;34(5):838-844.).

In general, fibrates reduce plasma triglyceride levels by 30-50%, reduce LDL cholesterol levels by up to 20% and increase HDL cholesterol levels by 5-15% (Chapman, 2003Chapman MJ. Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives. Atherosclerosis. 2003;171(1):1-13.; National Cholesterol Education Program, 2002). In contrast to niacin, fenofibrate is often used with simvastatin in T2DM patients to achieve target lipid levels because fibrates do not lead to the worsening of blood glucose levels. The simvastatin-fenofibrate combination has been shown to be significantly more effective than simvastatin alone (Grundy et al., 2005Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95(4):462-468.). A study whose objective was to determine the effectiveness of fenofibrate alone, simvastatin alone and both drugs combined recruited 241 patients with T2DM and dyslipidemia who have never been prescribed lipid lowering medications before. The patients were divided into three groups; one received fenofibrate 145 mg/day, another received simvastatin 40 mg/day, and the remaining received a combination of the aforementioned drugs. Glucose and lipid profiles were evaluated at baseline, 6 and 12 months. As expected, total cholesterol, LDL cholesterol, and triglyceride levels decreased while HDL cholesterol increased. In patients treated with simvastatin alone, there was no difference between baseline A1C levels and those at 12 months. However, A1C levels were significantly decreased in the other two groups. After 6 and 12 months of treatment, there were no significant differences in FBG, postprandial glucose and fasting plasma insulin levels in all three groups (Derosa et al., 2009Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, et al. Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients. Curr Med Res Opin. 2009;25(8):1973-1983.).

Ezetimibe is a LDL cholesterol-lowering drug that acts by inhibiting the absorption of dietary cholesterol in the small intestine (Ahmed, Byrne, 2010Ahmed MH, Byrne CD. Potential therapeutic uses for ezetimibe beyond lowering LDL-c to decrease cardiovascular events. Diabetes Obes Metab. 2010;12(11):958-966.). In a randomized double-blinded study, T2DM patients received stable doses of thiazolidinediones (rosiglitazone 2-8 mg/day or pioglitazone 15-45 mg/day) for at least 3 months and simvastatin 20 mg/day for 6 weeks prior to the study. Patients were then randomized to receive either ezetimibe 10 mg/day (n=104) or an increased dose of simvastatin 40 mg/day (n=110) for 24 weeks. The results showed that there were no significant differences between treatment methods with regards to FBG, fasting plasma insulin, and A1C levels. However, LDL cholesterol levels were reduced to a greater extent in patients who received additional ezetimibe 10 mg/day or simvastatin 20 mg/day compared to those who received a doubled simvastatin dose (40 mg/day) (Gaudiani et al., 2005Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y, et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. Diabetes Obes Metab. 2005;7(1):88-97.). Another study found that 2 months after the administration of combined simvastatin 10 mg and ezetimibe 10 mg (Vyto10) to patients with dyslipidemia, fasting insulin was significantly reduced while plasma adiponectin and insulin sensitivity were increased relative to the baseline (Koh et al., 2015Koh KK, Oh PC, Sakuma I, Kim EY, Lee Y, Hayashi T, et al. Vascular and metabolic effects of ezetimibe combined with simvastatin in patients with hypercholesterolemia. Int J Cardiol. 2015;199:126-131.).

Patients with T2DM may have multiple comorbidities that necessitate the concomitant administration of statins with other drugs. Clinical studies have shown that a combination of simvastatin with metformin and pioglitazone results in improved glycemic control (Table IV). In T2DM patients, metformin is the recommended first-line pharmacological treatment after lifestyle interventions fail to result in adequate glycemic control (Rojas, Gomes, 2013Rojas L, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6.). Krysiak et al. (2013bKrysiak R, Okopien B. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metabolism. 2013b;62(1):39-43.) demonstrated that metformin, when administered to simvastatin-treated patients with impaired fasting glucose levels, reduced HOMA-IR values by approximately 55% and A1C levels by 11% (Krysiak et al., 2013b).

Table IV
The effect of concurrent medications in combination with simvastatin (oral antidiabetic agents)

Pioglitazone - a thiazolidinedione that works by enhancing insulin sensitivity -improves A1C levels and is beneficial in reducing free fatty acid and triglyceride levels as well as increasing HDL cholesterol (Herz et al., 2003Herz M, Johns D, Reviriego J, Grossman LD, Godin C, Duran S, et al. A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clinical therapeutics. 2003;25(4):1074-1095.; Kipnes et al., 2001Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med. 2001;111(1):10-17.). In a double-blinded study, pioglitazone alone and the combination of pioglitazone and simvastatin significantly improved glucose levels, insulin levels, and HOMA score. No such changes were seen in the simvastatin treatment group. In addition, it was reported that the pioglitazone-simvastatin combination was better for lowering the risk of cardiovascular events when compared to either of the drugs used alone (Forst et al., 2007Forst T, Pfutzner A, Lubben G, Weber M, Marx N, Karagiannis E, et al. Effect of simvastatin and/or pioglitazone on insulin resistance, insulin secretion, adiponectin, and proinsulin levels in nondiabetic patients at cardiovascular risk--the PIOSTAT Study. Metab Clin Exp. 2007;56(4):491-496.).

Hypertension and hypercholesterolemia are two major health issues that contribute to increased cardiovascular disease risk (Dalal et al., 2012Dalal JJ, Padmanabhan T, Jain P, Patil S, Vasnawala H, Gulati A. LIPITENSION: Interplay between dyslipidemia and hypertension. Indian J Endocrinol Metab. 2012;16(2):240.), and the patients are commonly treated with statins and antihypertensive agents. As shown in Table V, the effect of combined simvastatin and antihypertensive medications has been investigated, and it was found that fasting plasma insulin and FBG levels were not affected by perindopril-simvastatin or barnidipine-simvastatin regimens (Derosa et al., 2015Derosa G, Mugellini A, Pesce RM, D'Angelo A, Maffioli P. Perindopril and barnidipine alone or combined with simvastatin on hepatic steatosis and inflammatory parameters in hypertensive patients. Eur J Pharmacol. 2015;766:31-36.). However, Koh et al. (2004Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Seo Y-H, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation. 2004;110(24):3687-3692.) found that losartan alone or in combination with simvastatin resulted in a significant increase in insulin sensitivity and plasma adiponectin levels relative to the baseline, and that the difference was greater when compared to simvastatin alone (Koh et al., 2004).

TABLE V
The effect of concurrent medications in combination with simvastatin (antihypertensive agents)

CONCLUSIONS

In vitro studies have identified possible mechanisms by which simvastatin affects glucose metabolism. These include the inhibition of insulin secretion, possibly by decreasing GLUT2 activity, reducing ATP production, inhibiting L-type Ca2+ channels and decreasing cytosolic Ca2+ concentrations. Some studies have reported that simvastatin may impair glucose metabolism whereas other studies reported no effect or improvement of glucose metabolism.

Even though statins are beneficial in reducing the risk of cardiovascular events, its glycemic effect on patients should be monitored by periodically evaluating blood glucose levels regardless of whether the patients have diabetes or otherwise. Further studies are required to investigate the possible synergistic effects of statins with concurrent medication on glycemia, especially in patients with multiple comorbidities. Although the benefits of statins have been shown to outweigh its risks, it is important that glycemic control in patients is monitored for potential drug interactions between statins with the concurrent medications used. Besides that, further studies are recommended to determine whether or not the dose and duration of statin use could affect the glycemic control.

ACKNOWLEDGEMENTS

The authors would like to thank the University of Malaya for financial and technical support (Research Grant RP024C-14HTM).

REFERENCES

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Publication Dates

  • Publication in this collection
    2018

History

  • Received
    03 Apr 2017
  • Accepted
    30 Aug 2017
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br