In the present study, 67% of the type 2 diabetes outpatients were above internationally recommended personalized HbA1c levels and 58% were above target blood pressure levels. In contrast, in National Health and Nutrition Examination Survey (NHANES) cross-sectional data from 2013 to 2016, only 36% of adults with diabetes did not meet individualized A1C target levels, with a mean HbA1C of 7.5%, and just 30% did not achieve recommended blood pressure control (15). Nevertheless, similar to our findings, a meta-analysis of observational studies including North-America, Europe and Asia populations, demonstrates that 64% of type 2 patients did not meet HbA1c goals (16). Alike our findings, this meta-analysis describes that lower age, a higher proportion of females and non-Caucasians were all associated with a higher failure rate of achieving glycemic control.
While only 35% of diabetes-related health expenditure is spent in low- and middle-income countries, 87% of diabetes-related deaths occur there (1). Improved glycemic control in diabetes is associated with a lower risk of diabetes complications and reduced all-cause and cardiovascular mortality (17). In patients with type 2 diabetes, an HbA1c level outside the target range was found to be the strongest predictor of stroke and acute myocardial infarction, the main cause of death in this population (18). Nevertheless, the HbA1c target should be individualized according to a number of factors, such as age, diabetes duration, comorbid conditions, life expectancy, risk of hypoglycemia, and patient adherence/preference. According to international consensus, an HbA1c level < 7% is recommended for non-pregnant adults, while 7.0–8.0% is suggested for patients with co-morbidities or advanced age (8,9,13,19). HbA1c targets of 7.5–8% were suggested in the most recent International Diabetes Federation clinical practice recommendations (1). Stricter HbA1c goals, such as 6.5%, are suggested for selected patients if they can be attained without significant hypoglycemia or other adverse effects (19). In our study, a less stringent HbA1c target of up to 8% was considered for patients with stage III DKD and ischemic heart disease (10). It has not been consistently shown that intensive glycemic control to HbA1c levels < 7% reduces clinical microvascular and macrovascular events or death (20). Moreover, lowering HbA1c requires more anti-hyperglycemic medications at higher doses, which can lead to more adverse events (21,22). Thus, personalizing glycemic goals in DM patients should include consideration of the benefits and hazards of pharmacotherapy.
In our cohort, patients not in the HbA1c target range were mostly women, younger and black and were more frequently insulin users. In NHANES sample, younger age (18–44 years), female sex, and nonwhite adults with diabetes, presented worse glycemic control over the study period (15). Manicardi et al. (23) observed that women were 33% more likely to have higher HbA1c levels than men in a sample of type 1 diabetes patients (23). A study of type 2 diabetes patients found similar results, with women reaching HbA1c targets less often than men (24). It does not seem that our findings can be explained by differences in treatment or BMI between genders, since they were not significantly different. The access to the health service does not seem to be responsible either, since our sample is composed mostly of women and global diabetes-related health expenditure seems to be slightly higher in women than in men (1). Instead, these results could be related to a sex difference in carbohydrate metabolism during exercise, since women oxidize more lipids and less carbohydrates as a metabolic substrate than men (25). In addition, prior research has demonstrated sex differences in drug response regarding pharmacodynamic and pharmacokinetic factors (26). Although it is tempting to speculate that lifestyle elements, such as the amount and type of physical activity could also be involved, we did not collect such data.
Younger age has also been associated with worse glycemic control in diabetes in other studies (27–31). Individuals developing type 2 diabetes at an earlier age seem to represent a different phenotype that requires more aggressive interventions to achieve glycemic control (29). Rozenfeld at al. found older adult patients with type 2 diabetes to have improved adherence to antidiabetic medications (30). A 10% increase in adherence to oral antidiabetic medications was associated with a 0.1% decrease in HbA1c, when controlled for baseline HbA1c and therapy regimen (30).
Another clinical characteristic that affected glycemic control included the use of insulin. Patients with type 2 diabetes who require insulin, alone or in combination with oral antidiabetic medications, consistently have higher HbA1c values than those taking no medication or oral medications only (16,28,32). Furthermore, sustained poor glycemic control was observed in patients with diabetes taking more medication of any kind (31). Insulin use could represent disease severity to some extent (27).
Regarding skin color, a sub-analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that patients who failed to reach the HbA1c target were more likely to be black and on insulin therapy, which agreed with our results (33). It is important to point out that some studies suggest that black subjects have higher HbA1c levels than whites, which could not be related to glycemic control itself, but rather to differences in HbA1c glycation patterns. Although our black patients presented higher HbA1c, their fasting plasma glucose levels were similar. A meta-analysis that included non-diabetic subjects found that HbA1c levels were around 4.7% higher in blacks than whites (34). These results are similar to those of previous studies in diabetic patients, which indicated a 0.65% higher HbA1c level in African Americans than in non-Hispanic whites (35). Such ethnic disparities could be explained by genetic and/or environmental factors. One study has claimed that socioeconomic factors are the main cause of this disparity (36). However, other studies have reported that genetic variants may be responsible for increasing or reducing the enzyme activity in HbA1c metabolism, which consequently affects HbA1c levels, possibly with distinct patterns in different races (37). Although we did not collect data on socioeconomic status in our cohort, this was probably not the major explanation for the discrepancy, since only black women had higher HbA1c.
Regarding blood pressure goals, 58% of the patients in our cohort did not meet the target levels, despite adjustment for cardiovascular risk status. These patients were older and had a higher prevalence of ischemic heart disease, stroke and DKD, which could reflect the difficulty of achieving the stricter goals required for these specific groups or that they indeed had a previous past of worse blood pressure control. In a 2014 cross-sectional analysis of patients in a Belgium hospital, Camara et al. (38) found that approximately 68% of type 2 diabetes patients had SBP levels > 130 mmHg (38). In our study, BP control was defined according to recent ADA and ESC/AHA/ACC guidelines, with desirable BP values < 140/90 mmHg, except for patients with high cardiovascular risk and DKD, when < 130/80 mmHg was recommended (39,40). Although optimal BP targets are still under discussion, it has been demonstrated that lowering BP levels in hypertensive type 2 diabetes patients is definitely beneficial (18,41). A meta-analysis found a significantly lower risk of mortality, cardiovascular events, coronary heart disease, and heart failure in DM patients whose baseline SBP was ≥ 140 mmHg and then reduced 10 mmHg with treatment (41). Additionally, lowering a baseline SBP ≥ 130 mmHg by 10 mmHg was associated with a lower risk of stroke, albuminuria and retinopathy (36). In patients with DKD, the recommended goals of SBP < 130 mmHg and DBP < 80 mmHg helped prevent macrovascular and microvascular outcomes (42,43). Accordingly, we defined our BP cut-off points based on these findings, requiring stricter values for patients with DKD.
In our cohort, the patients who did not achieve the BP control goals were older. This finding could be explained by certain theories. First, the definition of hypertension in the general population is the same for any age category. However, several important studies have claimed that SBP and, mainly, DBP goals should not be the same for people over 75 years of age (44,45). In this subset of patients, SBP and DBP targets of < 150 mmHg and < 90 mmHg, respectively, are recommended. According to the Brazilian Cardiology Society, it would be safer to keep the SBP goal around < 150 mmHg rather than 140 mmHg in older adults to avoid the consequences of hypotension (39,40,46). However, since the benefits of more restricted targets are undeniable, even for older people, we did not make distinctions for advanced age (45). The ADVANCE study (Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation) investigated older hypertensive type 2 diabetes patients in a specific sub-analysis (42). The authors emphasized that adequate hypertension treatment in individuals > 65 years of age (i.e. reducing SBP by approximately 5.6 mmHg in a sample with a baseline mean BP of 145/81 mmHg) led to a corresponding reduction in the risk of mortality and major macrovascular and microvascular complications, mainly albuminuria (42). However, this study may have analyzed a sample of healthier diabetic patients, since the ADVANCE study did not include type 2 diabetes patients on long-term insulin therapy (47). We decided not to adapt the BP goals in our cohort according to age.
Regarding diabetic chronic complications in our population, it was observed that 56% had DKD, 47% had retinopathy, 43% had peripheral neuropathy, and 33% had macrovascular disease. These numbers seem to be on the high end of the most recent International Diabetes Federation data, in which the reported prevalence of diabetic peripheral neuropathy ranged from 16–66% and the prevalence of any retinopathy was 35% (1). Likewise, there was a high prevalence of DKD and cardiovascular disease in our sample, since global statistics show ranges of 12–55% and 12-31.7%, respectively, for these complications (1,48,49). Patients at the target HbA1c levels had a higher prevalence of macrovascular disease. The possible explanations are that this group was older and that the adopted HbA1c target for patients with previous ischemic heart disease or stroke were higher, facilitating this sub-sample to achieve HbA1c target. In addition, patients with macrovascular disease might have more intense health care attention due to these higher risk conditions. On the other hand, patients in the uncontrolled blood pressure group had a higher prevalence of ischemic heart disease or stroke and DKD. These results could be explained by the fact that poor lifelong blood pressure control resulted in kidney damage, but also that impaired kidney function indeed interferes with blood pressure control.
Limitations: Since we evaluated cross-sectional data, the results are snapshots of diabetes care during the survey periods. Our study was conducted in a specialized tertiary health center involving patients with a predictable worse glycemic and blood pressure control, since those with good results are discharged to primary care units. Furthermore, for the same reason, the prevalence of chronic complications is overrepresented. Therefore, it reflects a specific setting. An additional limitation was that data on physical exercise and socioeconomic profile were not collected, and this limits the interpretation of the results regarding the ethnic and gender differences found in the analysis. More distinct mechanisms and associations still remain to be clarified.
Strengths: Data was collected from the expressive number of 602 outpatients, for about 5 years, in a number of well-characterized categories that involved diagnosis and monitoring of diabetes and its complications, following a comprehensive and standardized protocol. Thus, our large sample was able to identify specialized care figures and comorbidity risks with great reliability. There have been few studies on the profile of diabetic patients that involved so many variables in our geographic area.