The International Diabetes Federation (IDF) has reported that about 537 million adults (aged 20–79 years) had diabetes in 2021, which accounts for 10.5% of the adult population in this age group(1, 2, 3). Diabetes represents a significant global health problem, and its prevalence rates are expected to accelerate (1, 4). Drug repositioning (commonly known as repurposing) is the use of a drug in an indication other than that for which it was originally formulated (15). There is no treatment to prevent or cure type 2 diabetes (T2DM). Extending the indications of drugs with established efficacy to other new indications is a powerful approach for new drugs and clinical treatments for T2DM.
The complexity of diabetes prevention and control is exacerbated in low-income countries, including those in Africa, due to genetic factors and logistical, social, and financial burdens(12, 13, 14, 15, 14). The prevalence of diabetes is higher in low- and middle-income countries, and despite available therapeutic options, many patients fail to achieve optimal control (5, 6,. Access to anti-diabetic drugs can be more challenging in low-income countries (12). Therefore, repurposing drugs for type 2 diabetes in African populations could be a promising strategy to improve treatment outcomes, however this could elicit some adverse effect.
Diabetes is one of the main risk causes for kidney disease. Approximately one in three adult diabetics suffer from chronic kidney disease (CKD), and every 24 hours, 170 diabetics start taking kidney failure medication (16, 17).
The kidneys are a key organ in regulating bodily liquid volume, maintaining electrolyte equilibrium, and the elimination/ re-uptake of internal and external compounds (15). Within these renal functions, the ability to excrete/reabsorb both endogenous and exogenous chemicals is vital for ensuring physiological homeostasis in the organism (16). The estimated glomerular filtration rate (eGFR) measures healthy kidney function (the amount of blood the kidneys filter per minute, based on body size). The eGFR test is an essential diagnostic tool for detecting kidney disease at an early stage, monitoring kidney function, identifying risk factors, assessing drug dosages, and developing personalized treatment plans (17). Diabetes and kidney disease are very closely linked, with several classes of drugs that target both disorders.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs for the treatment of type 2 diabetes that block the renal reabsorption of blood glucose, thereby improving the excretion of sugar in the urine(18, 21). SGLT2 inhibitors have been revealed to have protecting effects on the kidneys of patients with type 2 diabetes and diabetic nephropathy, reducing the risk of renal failure and cardiovascular events(19).
Platinum-based drugs, like cisplatin and oxaliplatin, are largely explored in the organ cation transporter arena, including SLC22A1 and SLC22A2(20). Organic anion transporters (OAT or SLC22A) play an extremely vital role in renal dysfunction and are widely recognized as drug transporters. Several distinct isoforms belong to the SLC22A family (21). These isoforms present different transport substance profiles and renal localization. Previous studies have shown that genetic variations in the SLC22A1, SLC22A2, and SLC22A3 genes have been found to affect glycemic control and response to metformin in patients with type 2 diabetes (25, 26, 27, 28).
Mendelian randomization (MR) applies genetic variants to judge the causal relationship between a risk factor and an outcome based on observational data. In one phase at a time (26). MR studies are less subject to confounding, bias, and reverse causation than observational designs, as genetic variants are attributed to the chance of conception and are not mediated by environmental or lifestyle factors (29, 30). MR can provide a feasible alternative approach to assessing a drug's effect (31, 32). In short, MR applies genetic variations, generally single nucleotide polymorphisms (SNPs), as exposure tools to give the ideal, unfounded influence of exposure on outcome. Genetic alternatives found at the genetic locus of the gene encoding the medication's affect protein occur thought to impact the effect of exposure on outcome. The drug's target protein is believed to impact protein expression or function(30). Exploiting these variations as genetic tools can imitate in what manner the medication controls its target protein, helping us predict the effect of exposure on outcome. In this way, we can evaluate the effect of a genetic variation in the drug's target on a new indication, as in a RCT. (31)
This study sought to assess the effect of renal dysfunction drugs in type 2 diabetes mellitus using MR approaches with genetic variants in positions of genes coding targets of different renal drug targets in African populations.