Objective Polypharmacy is common in people with diabetes and associated with the use of potentially inappropriate medication (PIM). This study aimed to assess trends in prevalence of polypharmacy and PIM in older and middle-aged people with diabetes. Methods A repeated cross-sectional study using the University Groningen IADB.nl prescription database was conducted. All people ≥45 years treated for diabetes registered in the period 2012-2016 were included. PIMs were assessed using Beers criteria for people ≥65 years old, and PRescribing Optimally in Middle-aged People’s Treatments (PROMPT) criteria for 45-64 years old. Chi-square tests and regression analysis were applied. Results The prevalence of polypharmacy increased from 56.5% to 58.2% during the study period. In 2016, the prevalence of polypharmacy was 36.9% in the group of 45-54 years old, 50.3% in 55-64 years old, and 66.2% in ≥65 years old. All age-groups showed significant increases. The prevalence of older people with at least one PIM decreased around 3%, while in the middle-aged group this prevalence increased around 1% with a highest level in 2015. The most common PIMs in both age groups were the use of long-term high-dose proton-pump-inhibitors, benzodiazepines, and strong opioids without laxatives. Of those, only benzodiazepines showed a decreasing trend. Conclusions Polypharmacy increased in older and middle-aged people with diabetes. While the prevalence of PIM decreased over time in older age, this trend was not observed in middle-aged people with diabetes. Efforts are needed to decrease the use of PIMs in populations already burdened with many drugs, notably at middle age