Combination therapy is key to successfully controlling a condition as broad Type 2 diabetes. There are several hormones involved in the regulation of glucose control within the body, and therefore many points of action for drug therapy to take place. One combination that is of interest is Repaglinide and Metformin, a currently unlicensed combination for second intensification of drug treatment in type 2 diabetes management, however trials such as this one have been demonstrating effective Hb1ac control with this particular dual therapy (NICE 2017).
In order to find this particular trial, I made a search in the Wiley online library. This is a well known database that contains thousands of publications and journal articles. I searched the term ‘metformin combination therapy’ which gave me 8679 results. I then went into the advanced search option, and chose articles from 2013 onwards and changed the search such that the term ‘metformin combination therapy’ was in the article title, which then gave me 18 hits. I then carefully reviewed the searches until I arrived to the chosen trial.
This study has positive qualities that make it a good paper to review the combination in question, including the fact that it was a multicenter, randomised, double blind, parallel group trial, with patients being transferred into an extended 52 week trial to measure titrating dose effects, allowing for a greater length of time to measure efficacy/adverse events (phase 3 initial study lasted 16 weeks). The participants in the study were all on metformin mono-therapy and then either randomly assigned into a group where they were given a placebo or repaglinide. Moreover, the outcomes to be measured were clearly defined as the efficacy and adverse effects of the use of repaglinide (through measurement of HbA1c for efficacy and listing all adverse effects). The study was also funded by Dainippon Sumitomo Pharma Co., Ltd. and therefore should have ample access to funds through the course of the trial. Each test group was evidently treated equally, with a range of BMIs for both sexes, with all participants being tested on a wide range of metformin doses with a large range of fasting plasma glucose levels and postprandial blood glucose (Kawamori et al., 2013).
One area that this study failed to investigate was the effect of this combination in younger patients and newly diagnosed type 2 diabetics, mainly investigating an age group between 40 – 65 years old. However, Wang et al., (2011) who investigated a wider range of ages (18-75 year olds) and amongst newly diagnosed diabetics also reached the same conclusion that the combination of the two drugs achieved greater glycaemic control than either alone. This study could have been further improved by creating a triple blind system, providing further quality to the trial.
Kawamori et al., (2013) concluded that combination therapy provides a stable reduction in HbA1c and postprandial blood glucose, and also can prevent the onset and progression of micro and macrovascular complications. These findings have been demonstrated in numerous other studies, and Raskin (2008) also concludes that Repaglinide may be a better alternative to sulfonylureas due to the reduced propensity for hypo-glycaemia (Raskin, 2008).
The study by Kawamori et al., (2013) was sponsored by a pharmaceutical company and employees of the company wrote apart of the study and statistical analysis adds a potential conflict of interest to the trial. There is also the fact that the study just took place in Japan, and so does not encompass all physiology of different ethnicities, however this was acknowledged in the study.
Considering the number of original participants enrolled onto the study (n=133), there was a fairly large fallout (17.29%) by the end of the trial, with 23 leaving the study (albeit 8 left from adverse medication events), which is a large percentage to have left this size of a trial.
Statistical analysis of the results from the shorter term part of the study (16 weeks) demonstrated that repaglinide in combination with metformin had a significant reduction (P<0.001) in Hb1ac compared to the metformin and placebo group. In the long term study (52 week trial), there was also a significant reduction in Hb1ac from the dual drug combination compared to placebo and metformin, although the results were not as significant as compared to the shorter term study (P<0.05). Yin et al., (2014) conducted a meta-analysis of randomised control trials and also concluded that there was a significant statistical reduction in Hbl1ac with repaglinide compared to using a placebo. NICE (2017) state that of repaglinide is a 'cost effective drug', costing 588 pence for 90 tablets of Repaglinide 2mg tablets. Converserly the 1mg version of the drug is much more expensive at 1038 pence. This costing is related to the fact that 16mg is the maximum dose for Repaglinide daily, and so the higher strength of the drug is more often used (NHSBSA, 2018). CONCLUSION Having reviewed many studies that have investigated the effect of Repaglinide in combination with Metformin, it is evident that there is potential for this use of drug for second intensification of drug treatment in Type 2 diabetes, due to its successful decrease of Hb1ac levels and low level of adverse effects (mainly gastrointestinal disturbance). There does, however, need to be more research conducted in the area of the use of Repaglinide efficacy compared to other second line drug treatments for diabetes i.e. DPP-4 inhibitors, SGLT2 inhibitors, sulfonylureas and thiazolidinediones to gain a true understanding of its beneficial and detrimental effects. The cost effectiveness of Repaglinide is a factor that needs to be considered, given the fact that the NHS is under financial pressure, and in comparison to drug classes that are still under patent (DPP-4 inhibitors and SGLT2 inhibitors) it is a cost effective alternative, that does not compromise patient safety. The current NICE guidance on the treatment pathway is