The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial.

AIMS/HYPOTHESIS: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. METHODS: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30-70 years of age, and prediabetes (HbA1c 39-47 mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). RESULTS: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). CONCLUSIONS/INTERPRETATION: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. TRIAL REGISTRATION: ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

Validation of cardiovascular diagnoses in the Greenlandic Hospital Discharge Register for epidemiological use.

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. In Greenland, valid estimates of prevalence and incidence of CVD do not exist and can only be calculated if diagnoses of CVD in the Greenlandic Hospital Discharge Register (GHDR) are correct. Diagnoses of CVD in GHDR have not previously been validated specifically. The objective of the study was to validate diagnoses of CVD in GHDR. The study was conducted as a validation study with primary investigator comparing information in GHDR with information in medical records. Diagnoses in GHDR were considered correct and thus valid if they matched the diagnoses or the medical information in the medical records. A total of 432 online accessible medical records with a cardiovascular diagnosis according to GHDR from Queen Ingrid's Hospital from 2001 to 2013 (n=291) and from local health care centres from 2007 to 2013 (n=141) were reviewed. Ninety-nine and ninety-two percent of discharge diagnosis in GHDR from Queen Ingrid's Hospital and local health care centres were correct in comparison with diagnoses in the medical record indicating valid registration practice. The correctness of cardiovascular diagnoses in GHDR was considered high in terms of acceptable agreement between medical records and diagnoses in GHDR. Cardiovascular diagnoses are valid for epidemiological use.

The obesity-associated risk of cardiovascular disease and all-cause mortality is not lower in Inuit compared to Europeans: A cohort study of Greenlandic Inuit, Nunavik Inuit and Danes.

BACKGROUND AND AIMS: Inuit populations have lower levels of cardiometabolic risk factors for the same level of body mass index (BMI) or waist circumference (WC) compared to Europeans in cross-sectional studies. We aimed to compare the longitudinal associations of anthropometric measures with cardiovascular disease (CVD) and all-cause mortality in Inuit and Europeans. METHODS: Using pooled data from three population-based studies in Canada, Greenland and Denmark, we conducted a cohort study of 10,033 adult participants (765 Nunavik Inuit, 2960 Greenlandic Inuit and 6308 Europeans). Anthropometric measures collected at baseline included: BMI, WC, waist-to-hip-ratio (WHR), waist-to-height-ratio (WHtR) and a body shape index (ABSI). Information on CVD and death was retrieved from national registers or medical files. Poisson regression analyses were used to calculate incidence rates for CVD and all-cause mortality. RESULTS: During a median follow-up of 10.5 years, there were 642 CVD events and 594 deaths. Slightly higher absolute incidence rates of CVD for a given anthropometric measure were found in Nunavik Inuit compared with Greenlandic Inuit and the Europeans; however, no cohort interactions were observed. For all-cause mortality, all anthropometric measures were positively associated in the Europeans, but only ABSI in the two Inuit populations. In contrast, BMI and WC were inversely associated with mortality in the two Inuit populations. CONCLUSIONS: Inuit and Europeans have different absolute incidences of CVD and all-cause mortality, but the trends in the associations with the anthropometric measures only differ for all-cause mortality. Previous findings of a lower obesity-associated cardiometabolic risk among Inuit were not confirmed.

Cardiovascular Disease Susceptibility and Resistance in Circumpolar Inuit Populations.

Cardiovascular disease (CVD) is a major public health issue in indigenous populations in the Arctic. These diseases have emerged concomitantly with profound social changes over the past 60 years. The aim of this study was to summarize the literature on CVD risk among Arctic Inuit. Literature on prevalence, incidence, and time trends for CVD and its risk factors in Arctic Inuit populations was reviewed. Most evidence supports a similar incidence of coronary heart disease and a higher incidence of cerebrovascular disease among Arctic Inuit than seen in western populations. Factors that may increase CVD risk include aging of the population, genetic susceptibility, and a rapid increase in obesity, diabetes, and hypertension in parallel with decreasing physical activity and deterioration of the lipid profile. In contrast, and of great importance, there has been a decrease in smoking and alcohol intake (at least documented in Greenland), and contaminant levels are declining. Although there have been marked socioeconomic and dietary changes, it remains unsolved and to some extent controversial how this may have influenced cardiovascular risk among Arctic Inuit. The increase in life expectancy, in combination with improved prognosis for patients with manifest CVD, will inevitably lead to a large increase in absolute numbers of individuals affected by CVD in Arctic Inuit populations, exacerbated by the rise in most CVD risk factors over the past decades. For preventive purposes and for health care planning, it is crucial to carefully monitor disease incidence and trends in risk factors in these vulnerable Arctic populations.