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PRE-D Trial: Effect of Metformin, Dapagliflozin, or Exercise on Prediabetes Outcomes

Nov 24, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences

Multiple treatments were compared to improve outcomes in patients with prediabetes (Pre-DM). 

Patients with prediabetes (Pre-DM) have a higher risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD). Some methods are recommended to reduce this risk, including weight loss and lifestyle changes. Also, metformin is used to reduce glucose tolerance, and thus decrease the risk of developing T2DM. Although there is a known correlation between blood glucose control and T2DM prognosis, not much is known regarding the effect of those interventions and glucagon levels in patients with Pre-DM. Previous studies have shown that there is an association between insulin resistance and fasting glucagon levels. Similarly, patients with DM had higher fasting glucagon compared to patients who have normal glucose tolerance.  

However, there have been conflicting reports regarding the effect of exercise and weight loss on glucagon levels in patients with overweight or obesity. Some studies showed an impact of those lifestyle medications on glucagon levels, while other studies did not show a change in patients’ fasting glucagon levels after weight loss. Also, the effect of pharmacological treatments on fasting glucagon levels has been conflicting.  Some studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors use increases glucagon levels and insulin-glucagon ratio when used in patients with T2DM. However, whether SGLT2 inhibitors can benefit patients with pre-DM has not been determined. Also, some studies looked at metformin’s effect on glucagon level when compared to placebo. The results showed an increase in glucagon levels in patients who were healthy or had DM or Pre-DM. In contrast, other studies showed a decrease in glucagon levels with metformin.  

This study aimed to compare the effect of metformin, SGLT2 inhibitor (dapagliflozin), and exercise on the fasting glucagon levels in patients with Pre-DM and overweight or obesity. The study was designed as a randomized, controlled, open-label trial carried out over 13 weeks, followed by a 13-week follow-up. There were four intervention groups divided at a 1:1:1:1 ratio. The groups included dapagliflozin 10mg daily, metformin 850mg two times daily, exercise 30min daily five days per week, and control group.  

The study defined the primary outcome to be a change in glycemic variability. The study included patients aged 30-70 years with a BMI ≥25 kg/m2 and with Pre-DM (A1C 39–47 mmol/mol) as per the American Diabetes Association’s (ADA) definition. It excluded patients with DM, pregnancy or breastfeeding, bariatric surgery in the past two years, deranged kidney function, neurogenic bladder, allergy to any study’s treatments, or inability to exercise. Also, it excluded patients who are taking medications like β-blockers, steroids, diuretics (thiazide and loop), and drugs that alter glucose metabolism. Patients had the oral glucose tolerance test (OGTT) done at baseline, weeks 13 and 26.  

Around 120 (30 per group) patients were included in the trial. Some patients did not complete the study periods, and the remaining were 28, 29, 27, and 28 in the dapagliflozin, metformin, exercise, and control groups, respectively. There was a nonsignificant reduction in A1C between the treatment groups compared to the control (1.1 to 1.3mmol/mol). Dapagliflozin and metformin decreased fasting insulin by around 20%. Also, metformin use leads to an increase in OGTT. On the other hand, exercise did not show any significant difference in OGTT or insulin levels. There was no significant difference between the groups and the control group in fasting glucagon levels from baseline to week 26 or at any point during the study. 

The study showed that metformin and dapagliflozin use were associated with changes to insulin and glucose levels, but did not change fasting glucagon levels. One study has reported that dapagliflozin use is associated with a 20% increase in fasting glucagon levels in patients with T2DM. Similarly, other studies have shown that metformin use was associated with increased glucagon levels. On the other hand, other studies reported that exercise was associated with reduced glucagon levels, which was also not seen in this study. It was attributed to a low exercise potency. Additionally, these differences in findings were linked to the small number of study participants leading to a reduced power to detect significant outcomes. Future studies may be required with bigger sample sizes to identify potential consequences appropriately.  

Practice Pearls: 

  • Dapagliflozin, metformin, and exercise each had a small impact on A1C, insulin, and glucose concentrations in 12 weeks.  
  • The treatment groups did not show any significant change in the fasting glucagon levels. 
  • Other studies showed that metformin, SGLT2 inhibitors, and exercise had an impact on fasting glucagon levels.  


Clemmensen, Kim K.B. et al. “No Effects Of Dapagliflozin, Metformin Or Exercise On Plasma Glucagon Concentrations In Individuals With Prediabetes: A PostHoc Analysis From The Randomized Controlled PRED Trial.” Diabetes, Obesity, And Metabolism, 2020. Wiley, doi:10.1111/dom.14246. Accessed November 17, 2020. Available from: https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14246 

Færch, Kristine et al. “Insulin Resistance Is Accompanied By Increased Fasting Glucagon And Delayed Glucagon Suppression In Individuals With Normal And Impaired Glucose Regulation.” Diabetes, vol 65, no. 11, 2016, pp., 3473-3481. American Diabetes Association, doi:10.2337/db16-0240. Accessed November 17, 2020. Available from: https://diabetes.diabetesjournals.org/content/65/11/3473 


Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences