CARDIOVASCULAR JOURNAL OF AFRICA • Volume 34, No 5, November/December 2023 266 AFRICA The data were collected at the three time points on case report forms with specified fields captured to determine the outcome of the study. Among the fields assessed were total cholesterol, HDL-C, LDL-C (mmol/l, fasting) and TG (mmol/l, fasting). The total cholesterol, HDL-C, LDL-C and TG levels are reflected in Table 2. The mean changes in these levels from visit 1 to visit 2 (the reference period) and from visit 2 to visit 3 (the maintenance period) are also shown. The results show that from visit 2 to visit 3 there was no significant change in total cholesterol levels and that Simvotin® tablets maintained lipid control in these patients, after the switch was made from Zocor® tablets. The switch between brands occurred between visit 2 and visit 3 and we allowed six months between these visits on the same drug dose to assess therapeutic similarity. Discussion In this study, the generic simvastatin (Simvotin®) has been shown to be clinically equivalent in maintaining the lowered lipid levels at the same level as the originator simvastatin, Zocor®, in this real-world study. Adequate risk-factor control in patients at high risk for cardiovascular disease is essential to improve long-term prognosis. The significant benefit of good risk-factor control has been well established in patients with hypercholesterolaemia. Statins or HMG-CoA (3-hydroxy-3-methylglutaryl co-enzyme A) reductase inhibitors still remain the backbone of the treatment of patients with hypercholesterolaemia and have been well proven to reduce mortality and morbidity rates.10 As the statin drugs, such as simvastatin, have come off-patent, multiple multisource products or so-called generic drugs have been introduced into the current market. Since clinical or therapeutic comparative studies have never been a prerequisite for registration of small-molecule oral generic drugs where the active product ingredient is identical and where bioequivalence alone is considered sufficient proof of equivalence by the relevant regulatory authorities, many clinicians have had doubts as to the clinical equivalence of these multisource generic medicines. In this study the multisource simvastatin (Simvotin®) has been shown to be therapeutically equivalent in maintaining the lowered lipid levels at the same level as the originator simvastatin (Zocor®). A multisource product is described as having the same active product ingredient at the same dose strength, the same route of administration and same manufacturing quality and rigour, with a presumed similar therapeutic outcome. This then constitutes a bioequivalent product, according to the USA Food and Drug Administration (FDA).11 This real-world study aimed to demonstrate that a multisource product retained the therapeutic effect achieved by the originator. Statins are reversible inhibitors of the HMG-CoA enzyme, which leads to improved cholesterol clearance due to upregulation of receptors on the hepatocytes (LDL-C receptors).12-14 The bioavailability of simvastatin is very low due to its extensive pre-systemic elimination (approximately 7%), which gives relevance to doing a therapeutic equivalence study ensuring real-world similarity, since a typical bioequivalence study may be impaired by low and variable bioavailability of simvastatin.15 With the appropriate evidence of clinical equivalence, this generic drug can be prescribed with confidence by the practitioner. A generic drug is referred to as a drug that is a copy of a brand-name drug that has equivalent dosage, intended use, effectivity, side-effect profile, route of administration, risks, safety, as well as strength as the original drug and would, after dosing, reach the receptor site in equivalent concentrations and time exposure. Therefore, the pharmacological action is identical to that of the brand-name counterpart.16 Clinicians often express concern regarding therapeutic equivalence of multisource products. However, the fact that these products are more affordable and therapeutically equivalent may save the funder significantly and may enhance access.17 Pharmaceutical regulators around the world, such as the South African Health Products Regulatory Agency (SAHPRA) and the USA FDA requirements of a generic drug is that it is as safe and effective as the brand-name innovator.16,18 The efficacy and source of any medicine, in this case simvastatin, must be reliable to produce the desired clinical surrogate outcome, lowering of cholesterol, to be able to assume the same clinical risk-reduction outcome. Lipid lowering and reduced progression to significant coronary artery disease are the markers for successful treatment of hypercholesterolaemia and coronary artery disease. Lifestyle changes may affect outcomes, which is often seen as a weakness of real-world studies. However, in this study no significant changes inmeanweight were seen for the study subjects over the three data-collection time points, implying no major lifestyle impacts on the observed results. Other weaknesses of the study include the paucity of long-term outcomes, especially as these patients also suffered from other co-morbidities. However, the aim of the study was simply to assess therapeutic equivalence related to reduction and maintenance of reduction of lipid levels on different brands of simvastatin over a short period of time. Table 2. Cholesterol values (mmol/l): patients were on a constant strength of simvastatin between the time points Visit Number Mean SD Mean change p-value Total cholesterol Visit 1 117 6.28 4.35 Visit 2 118 5.43 1.65 Visit 3 118 5.53 1.65 ∆V1→V2 117 –0.84 4.16 –0.84 0.030* ∆V2→V3 118 0.10 1.00 0.10 0.283 HDL-C Visit 1 117 1.16 0.37 Visit 2 118 1.18 0.41 Visit 3 117 1.15 0.44 ∆V1→V2 117 0.02 0.28 0.02 0.515 ∆V2→V3 117 –0.02 0.28 –0.02 0.426 LDL-C Visit 1 113 3.90 1.85 Visit 2 115 3.55 1.74 Visit 3 114 3.67 1.68 ∆V1→V2 111 –0.39 1.04 –0.39 < 0.001* ∆V2→V3 112 0.10 0.86 0.10 0.202 Triglycerides Visit 1 41 1.81 1.05 Visit 2 118 1.66 1.17 Visit 3 118 1.63 0.94 ∆V1→V2 41 –0.26 1.08 –0.26 0.127 ∆V2→V3 118 –0.03 1.05 –0.03 0.753 * Statistically significant. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ∆V1→V2, difference between visit 1 and visit 2.
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