Prevalence of postprandial hyperglycaemia in basal insulin-treated patients with type 2 diabetes mellitus with controlled fasting glycaemia and elevated glycosylated haemoglobin

Diabetes is one of the most important public health challenges worldwide. Its related clinical complications have doubled the prevalence over the past three decades [1] and it is estimated that 10.1% of worldwide adult population will suffer diabetes by 2035 [2].

The glycosylated haemoglobin (HbA1c), is the most accepted measure of chronic glycaemic levels and the most accepted target of diabetic control since it was recommended in the routinely follow-up, due to its good correlation with the risk of diabetic complications [3]. Fasting glycaemia (FG), postprandial glycaemia (PPG) and average plasmatic glycaemia are strongly correlated with HbA1c [4, 5].

It has been shown that postprandial hyperglycaemia (PPH) is common among people with type 1 and type 2 diabetes [6, 7] even if considered controlled according to their levels of HbA1c [8]. PPH has been defined as a postprandial glucose > 180 mg/dL by the American Diabetes Association (ADA) or > 160 mg/dL by the International Diabetes Federation (IDF)0 [9, 10]. Epidemiological studies have shown an association between PPG levels and the development of diabetic complications and cardiovascular risk [11‐14]. It seems clear that PPG contributes to HbA1c levels and that this contribution is even greater than that from FG when HbA1c is closer to 7.0% (53 mmol/mol). A study using continuous glucose monitoring in patients with T2DM showed that FG was very similar between the groups with HbA1c < 6.5% (< 48 mmol/mol), 6.5% to < 7.0% (48 mmol/mol to < 53 mmol/mol), and 7.0% to < 8.0% (53 mmol/mol to < 64 mmol/mol), being the main difference the PPG [15]. These data suggest that reduction of HbA1c in patients who are closer to target will be best achieved if the therapeutic target is the control of PPG levels [9, 15, 16].

Prevalence of PPH is unknown in Spanish population. This study aims to estimate the prevalence of PPH in Spain among T2DM patients treated with basal insulin who present controlled levels of FG. This knowledge could help to identify the patient‘s profile that could benefit from optimized therapeutic management.

A total of 108 patients were included and 98 were valid for study analyses (43 [43.9%] females and 55 [56.1%] males). Mean (SD) age was 64.3 ± 10.4 years. Description of the study sample is summarized in Table 1. There were no changes in diet or physical activity during the study.

Regarding the T2DM characteristics, mean (SD) HbA1c was 7.9 ± 0.6% (63 ± 6 mmol/mol) and mean (SD) FG was 107.7 ± 16.8 mg/dL. Patients had a mean (SD) of 16.4 ± 8.5 years since diagnosis and 77.6% patients had been diagnosed more than 10 years ago. Diabetes-related complications were present in 61.2% patients. Retinopathy was the most frequent complication observed (32.7% patients), followed by other cardiovascular complications (25.5%) like acute myocardial infarction, angina, hospitalization due to heart failure, stroke, acute lung oedema or revascularization. Nephropathy was present in 24.5% patients and neuropathy in 10.2%. Comorbidities most commonly observed were dyslipidemia (64.3% patients) and hypertension (64.3%).

Analysed patients were treated with basal insulin for a median (P25/P75) of 4.4 (2.1/7.5) years prior to inclusion and the current dosage remained unchanged a median (P25/P75) of 11.9 (6.3/18.0) months before inclusion. Insulin dose median (P25/P75) in the basal visit was 28.0 (18.0/38.0) units per day and it remained unchanged over the study. A high percentage of patients (88.8%) added any oral antidiabetic drugs (OAD) to their treatment (Table 1). Around half of them (50.6%) received metformin combined with sulfonylureas, DPP4 inhibitors or both. Mean OAD treatment duration was 9.9 ± 6.9 years (metformin), 10.4 ± 7.3 years (sulfonylureas) and 2.4 ± 1.7 years (DPP4 inhibitors).

The purpose of this study was to estimate the frequency of PPG according to IDF [10] and ADA [9] guidelines in patients treated with basal insulin with control of FG but uncontrolled HbA1c (HbA1c > 7% [> 53 mmol/mol]). Describing clinical characteristics linked to patients with PPH was an additional aim.

Our results show that a nearly 60%/40% of treated T2DM patients have PPH (above 160/180 mg/dL) in at least 40% measurements, what means almost 1 out of 2 patients according to IDF criteria and more than 1 out of 3 of them according to ADA criteria. It is well-known that not only FG but also PPG contribute to HbA1c levels [9, 18] and that the triad FG, HbA1c and PPG is key for the adequate clinical control of T2DM [16, 19], though the role played by FG and PPG seems to be different. It has been shown that FG correlates better with the HbA1c level in patients with HbA1c value over 8.0%, while PPG appears to be strongly correlated with HbA1c level when this value is below 8.0% (64 mmol/mol) [20]. Our patients had a mean HbA1c of 7.9% (63 mmol/mol), so our data confirm the importance of PPG in the glycaemic control of patients with HbA1c fewer than 8% (64 mmol/mol).

PPH might play an important role in the development of diabetic microangiopathy [21] and may increase the risk of cardiovascular events [19, 22]. The large Diabetes Intervention Study [23], with an 11-year follow-up period, found that PPG was an independent risk factor for death. A more recent study [24] showed, after 14 years of follow-up, that both HbA1c and PPH are strong predictors for cardiovascular events and all-cause mortality in T2DM. In spite of this data, the relevance of targeting PPG in therapeutic schemes is still matter of some debate [25, 26], partially due to the results of the HEART2D trial [27]. This randomized controlled clinical trial comparing the effects of prandial versus fasting glycaemic control on risk for cardiovascular outcomes showed less than expected differences in PPG (0.8 mmol/L lower in prandial group, p < 0.01; however a difference of 2.5 mmol/L was initially presumed). Nevertheless, growing evidence points towards integration of PPG into daily diabetes control [28].

We also found that almost all patients presented at least one measurement > 160 mg/dL and/or > 180 mg/dL, with progressive increments of glycaemic values over the day. A recent work evaluating 500 patients with T2DM across different countries revealed that the highest PPG takes place after dinner, whereas the highest glucose increments occur after breakfast, pattern similar to that obtained in our study [29]. The awareness of this changing glucose pattern could be of importance for the appropriate management of these patients.

When the profile of patients with at least 40% PPH, according to ADA criteria, was studied, a significant difference of 0.3% higher HbA1c was found compared to those not showing such percentage.

Patients with at least 40% glucose readings > 160 mg/dL also showed to be treated with sulfonylureas for longer time. This feature is consistent with that obtained by Bonora et al. [6], who studied a large T2DM population and found that patients treated with sulfonylureas had greater postprandial glucose excursions that those patients not taking these drugs. These results consistently suggest that sulfonylureas do not have a preventive effect over PPH, so that patients with poor glycaemic control would benefit from alternative therapies with a higher impact in the PPH control.

Limitations to the interpretation of our results are related with the observational nature of the study. The recommendation provided by the study protocol was to self-monitor the PPG 2h after each meal following international guidelines [10, 17]. Some degree of heterogeneity regarding the time elapsed between each meal and glucose self-monitoring among participants may have over or underestimated glucose measurements. Nevertheless the high self-awareness and appropriate self-care of patients about the disease would minimize partially this variability.

In conclusion, PPH is a common feature in basal insulin-treated T2DM patients with elevated HbA1c despite controlled FG. Those patients with more PPH showed higher HbA1c, suggesting that control of FG is not enough and PPG should be also a therapeutic target to improve the diabetes control and to reduce the risk of diabetes related complications.