Discussion
weight gain, HIV and prediabetes, gestational diabetes, diabetes
GESTATIONAL DIABETES, ADVERSE EVENTS, COMPLICATION, LACTIC ACIDOSIS, TYPE 2 DIABETES, DIABETES
In this Phase II double-blind placebo-controlled trial among people with HIV and prediabetes, there was no significant difference in glucose levels between the metformin and placebo arms at the study end when measured by glucose levels 2 h after a 75 g glucose load or by fasting glucose. However, glucose levels 2 h post glucose load fell in both arms, and fasting blood glucose was lower at study end than at enrolment in the metformin arm but not in the placebo arm, although these declines were not significant when we controlled for baseline values.Whilst assessment of safety was not the primary endpoint of the trial, none of the abnormal laboratory/biochemical results or clinical adverse events that we observed at Grade 3 or higher could be linked to metformin. We observed no cases of lactic acidosis, an extremely rare and serious complication that has been linked to being on ART and metformin [Why did the trial show no differential effect of metformin on blood glucose compared with placebo at the 12 month follow-up? It is possible that, in this population, metformin is either ineffective or that the effect was too small for the study to detect (i.e. the study was underpowered). Our study population was comprised of mostly women who were not pregnant and this distribution was a weakness. Metformin did not confer protection against progression to type 2 diabetes among women who did not have a history of gestational diabetes in a large study in the USA that had a 10 year follow-up [Why glucose levels 2 h post glucose load fell in both arms is not clear. Metformin reduces energy intake, attenuates weight gain and, thus has a beneficial effect on body weight and visceral fat [We had severe disruption from COVID-19 whilst conducting the study. The COVID-19 pandemic started shortly after the trial began and government bodies and media started giving regular advice on the importance of a healthy diet and exercise to protect health from COVID-19, particularly for those living with type 2 diabetes. We also provided participants with basic diet and lifestyle advice at each contact, as planned. However, our contact with participants increased because of the disruption caused to health services by COVID-19 and so the frequency of advice that participants received also increased. We know from studies conducted in high-income settings that intensive structured promotion of diet and exercise is more powerful than metformin in reducing type 2 diabetes risk and that metformin has little added effect if there is substantial behaviour change related to diet and exercise [It is evident from the changes in weight (and also lipid markers [data not shown]), which improved in both arms, that diet and lifestyle behaviour changed. Metformin’s ability to improve lipid makers among individuals without diabetes but with HIV has been shown by others [Pharmacological interventions can be implemented with relative ease in our population, giving them alongside ART. Diet and exercise interventions, as tested in high-income settings, are time intensive and would be costly to implement in SSA. A recent randomised trial from South Africa comprising about 500 participants who were followed for 7–9 months, demonstrated that a behavioural intervention based on video group sessions was feasible and lowered HbAOf note, despite the severe disruption caused by the COVID-19 pandemic, over 70% of participants attended as scheduled throughout the year. This was largely because of the time taken by study researchers to build trust and partnership with participants. We did not titrate the dose of metformin, as is commonly done in the management of type 2 diabetes, primarily for ease of administration and because we felt that the extended-release formulation would be well tolerated. Despite this and the comparatively higher frequency of Grade 1 and Grade 2 side effects in the metformin arm compared with the placebo arm, reported adherence to medication was very high in both arms, and was over 98% among those who attended clinic appointments as scheduled.Our study demonstrates the high frequency of IFG and/or IGT that is present, and which remains largely undetected, in people living with HIV in SSA. It also demonstrates that it is feasible to integrate diabetes services within HIV programmes. These findings support other recent research studies conducted in this setting [In SSA, type 2 diabetes affects people at a younger age than in high-income countries [