bims-mitost 2019-03-31 papers

Issue of 2019‒03‒31
five papers selected by
Yvonne Will
Scientia-Consultants LLC

Polim Med. 2018 Jul-Dec;48(2):48(2): 77-82

The polymorphism of statins and its effect on their physicochemical properties.

Karaźniewicz-Łada M, Bąba K, Dolatowski F, Dobrowolska A, Rakicka M.

Polymorphism of pharmaceutical substances has a significant impact on their physicochemical properties, durability, bioavailability and consequently on their pharmacological activity. Solid dosage forms may exist in both crystalline and amorphous forms. Amorphous varieties are characterized by higher solubility and dissolution rates, while crystalline forms show greater purity and storage stability. The choice between the crystalline or amorphous form of a drug is extremely important to ensure effective and safe pharmacotherapy. Statins - the most commonly used group of drugs in the treatment of lipid disorders - are an example of drugs that occur in many crystalline and amorphous forms. Statins belong to class II in the biopharmaceutical classification system (BCS), which means that they are poorly soluble, but permeate biological membranes well. The bioavailability of statins shows considerable variation, which is associated with the first-pass effect in the liver and the accumulation of the drug in the hepatocytes. The improvement of bioavailability after oral administration of poorly soluble medicinal substances remains one of the most challenging aspects of the drug development process. A specific polymorphic form is obtained by applying appropriate conditions during the process of its preparation under industrial conditions, including the use of a suitable solvent, a specific temperature or rate of crystallization. The article provides a comprehensive update on the current knowledge of the influence of polymorphic form on statin solubility and bioavailability. Research is still being carried out to obtain new polymorphic varieties of statins that are characterized by better physicochemical and pharmacokinetic parameters.

Keywords: amorphic substances; bioavailability; crystalline forms; solubility; statins

DOI: https://doi.org/10.17219/pim/102978

Maturitas. 2019 Mar 19. pii: S0378-5122(19)30135-5. [Epub ahead of print]

Management of dyslipidaemias in the elderly population-A narrative review.

Anagnostis P, Vaitsi K, Veneti S, Georgiou T, Paschou SA, Lambrinoudaki I, Goulis DG.

The impact of dyslipidaemias on the risk of cardiovascular disease (CVD) is well documented. However, it is often under-estimated and, sometimes, suboptimally managed in the elderly population. The prevalence of dyslipidaemias seems to decline from the 7th decade of life in both genders. The association of dyslipidaemias with CVD weakens after the 7th decade, perhaps due to other age-related comorbidities. Low-density lipoprotein cholesterol remains the main target in the management of CVD risk. Although the evidence is not robust for the elderly, statins are the cornerstone of the management of CVD. Statins do have a potentially beneficial role in elderly individuals with established CVD and/or a history of type 2 diabetes mellitus. Data on their use in other elderly populations are inconsistent. There is no clear evidence for a beneficial effect of other hypolipidaemic drug categories in the elderly, such as ezetimibe, fibrates, niacin, omega-3 fatty acids and the new proprotein convertase subtilisin/kexin type 9 inhibitors. Their use should be balanced against possible adverse effects, such as the increased risk of myopathy with fibrates. Potential drug-drug interactions should be also taken into account. In conclusion, there is a need to establish the most effective lipid-lowering strategy in the elderly population with respect to CVD risk reduction, in future well-designed trials.

Keywords: Cardiovascular disease; Dyslipidaemia; Elderly; Hypercholesterolaemia; Hypertriglyceridaemia; Statins

DOI: https://doi.org/10.1016/j.maturitas.2019.03.011

J Am Heart Assoc. 2019 Apr 02. 8(7): e011662

Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance.

Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S, Stroes ESG.

Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.

Keywords: hypercholesterolemia; lipids; low‐density lipoprotein cholesterol; muscle; statin

DOI: https://doi.org/10.1161/JAHA.118.011662

Semin Liver Dis. 2019 Mar 25.

Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms.

Kim G, Kang ES.

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used to treat hypercholesterolemia for primary and secondary prevention of cardiovascular disease. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and modulate the downstream signaling of the mevalonate pathway. In addition to the primary effect, the antitumor effect of statins can be associated with mevalonate pathway-mediated and nonmevalonate pathway-mediated mechanisms, which improve endothelial function and lead to proapoptotic, antiproliferative, antiinflammatory, and antifibrotic properties. Statins are implicated in the improvement of metabolic status. Statins are orally available and safely and widely used for long-term treatment; they represent a novel approach for the prevention and treatment for hepatocellular carcinoma (HCC). Although several observational studies and experimental studies have revealed the preventive and therapeutic potential of statins for HCC treatment, further prospective interventional studies and randomized control trials are warranted to confirm these observations.

DOI: https://doi.org/10.1055/s-0039-1679956

Sci Rep. 2019 Mar 29. 9(1): 5389

Efficacy and Safety of Pioglitazone Monotherapy in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Alam F, Islam MA, Mohamed M, Ahmad I, Kamal MA, Donnelly R, Idris I, Gan SH.

Pioglitazone, the only thiazolidinedione drug in clinical practice is under scrutiny due to reported adverse effects, it's unique insulin sensitising action provides rationale to remain as a therapeutic option for managing type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis comparing pioglitazone monotherapy with monotherapies of other oral antidiabetic drugs for assessing its efficacy and safety in T2DM patients. Mean changes in glycated haemoglobin (HbA1c), and mean changes in fasting blood sugar (FBS) level, body weight (BW) and homeostasis model assessment-insulin resistance (HOMA-IR) were primary and secondary outcomes, respectively. Safety outcomes were changes in lipid parameters, blood pressure and incidences of adverse events. Metafor package of R software and RevMan software based on random-effects model were used for analyses. We included 16 randomised controlled trials. Pioglitazone monotherapy showed equivalent efficacy as comparators in reducing HbA1c by 0.05% (95% CI: -0.21 to 0.11) and greater efficacy in reducing FBS level by 0.24 mmol/l (95% CI: -0.48 to -0.01). Pioglitazone showed similar efficacy as comparators in reducing HOMA-IR (WMD: 0.05, 95% CI: -0.49 to 0.59) and increasing high-density lipoprotein level (WMD: 0.02 mmol/l, 95% CI: -0.06 to 0.10). Improved blood pressure (WMD: -1.05 mmHg, 95% CI: -4.29 to 2.19) and triglycerides level (WMD: -0.71 mmol/l, 95% CI: -1.70 to 0.28) were also observed with pioglitazone monotherapy. There was a significant association of pioglitazone with increased BW (WMD: 2.06 kg, 95% CI: 1.11 to 3.01) and risk of oedema (RR: 2.21, 95% CI: 1.48 to 3.31), though the risk of hypoglycaemia was absolutely lower (RR: 0.51, 95% CI: 0.33 to 0.80). Meta-analysis supported pioglitazone as an effective treatment option for T2DM patients to ameliorate hyperglycaemia, adverse lipid metabolism and blood pressure. Pioglitazone is suggested to prescribe following individual patient's needs. It can be a choice of drug for insulin resistant T2DM patients having dyslipidaemia, hypertension or history of cardiovascular disease.

DOI: https://doi.org/10.1038/s41598-019-41854-2