Zinc in Preventing the Progression of pre-Diabetes (ZIPPeD Study) – study protocol for a randomised placebo-controlled trial in Australia

The global burden of diabetes (among adults aged 20–79 years) in 2015 was estimated at US 415 million and is expected to rise up to 642 million by 2040 [1‐3]. The global health cost in 2015 was approximately US $673 billion with an expected 25.4% increased cost to US $802 billion in 2040 [2]. The number of deaths attributed to diabetes worldwide in 2015 was 5 million [2]. It is known that 90–95% of diabetes cases are type 2 diabetes mellitus (T2DM), which is a preventable and modifiable disease [1]. Pre-diabetes mellitus (PreDM) is a potentially reversible condition of impaired glucose handling. It is increasingly being diagnosed on the basis of a haemoglobin A1c (HbA1c) measurement, given the low coefficient of variation of this test [4]. The natural history of PreDM is variable; progression to T2DM occurs in ~ 25%; the abnormal glycaemic state remains in 50%; and reversion to normal glycaemic state occurs in 25% over 3–5 years [5]. People with PreDM are 5–15 times more likely to develop T2DM and are at increased risk of cardiovascular disease (CVD) [6]. The progression of disease through the pre-diabetic phase provides an opportunity to intervene to reduce or delay the onset of frank diabetes.

Interventions for PreDM are limited. Improving lifestyle factors, such as nutrition and physical activity, and maintenance of healthy weight have been found to reduce the progression from PreDM to T2DM by ~ 50%, although these changes take time to institute and are often difficult to maintain for the long term [7]. Despite the effectiveness of interventions to reduce such risk factors, the prevalence/incidence of obesity and PreDM continues to increase globally and in Australia [2, 8]. Given this trend, additional and complementary treatment options that will prevent, or at least delay, progression of PreDM are needed. Our intervention will involve the referral of all participants to an existing health promotion programme provided by the NSW State Health Department: the Get Healthy Information and Coaching Service [13]. The free telephone coaching service contacts participants on up to 13 occasions over the first 6 months of the study to encourage lifestyle improvements. In addition, participants will be randomised to receive either a zinc or placebo daily supplement.

This trial sets out to explore whether a new model of care for preventing diabetes in an at-risk Australian population can delay or prevent the onset of diabetes. The scientific literature has supporting evidence, but the sample sizes are small and follow-up duration is short in some instances. Also, the previous studies have been in Asian populations (Bangladesh and Sri Lanka) [1, 24] with differing physical and metabolic characteristics. Their dietary intakes are different, and they are more likely to have an underlying zinc deficiency compared with the overall Australian population. We do not expect a conversion rate from PreDM to diabetes to be as high as 25% over a 12-month period in the control group as observed in the Asian population group [1]. In the Australian population, progression from PreDM to diabetes can take from 7.5 years (females) to 9.5 years (males) or more in a similar age group [25]. However, any differences between treatment groups in the Australian population are important to note. Our study aims to support the current literature by recruiting 410 men and women with PreDM aged between 40 and 70 years who are residing in Australia who would benefit from lifestyle changes with or without zinc supplementation over a 12-month period. If the study proves successful, it will pave the way for a much larger, multi-centre clinical trial with frank diabetes as the endpoint.

This is protocol version 4, dated 25th September 2018 (ANZCTR registration number ACTRN 12618001120268). Recruitment commenced in November 2018 and is expected to be completed by July 2019.