Commentary on glucose reduction in type 2 diabetes (GRADE)
Journal
Journal of diabetes investigation
Date Issued
2023-02-17
Author(s)
Abstract
The Glycemia Reduction Approaches in Diabetes (GRADE) Study Research Group has recently published two original articles in The New England Journal of Medicine1, 2. Participants were people who had type 2 diabetes for <10 years who were receiving metformin with glycated hemoglobin levels from 6.8% to 8.5%. The effectiveness of four commonly used glucose-lowering medications were compared. Participants were randomly allocated to receive insulin (glargine U-100), the sulfonylurea (glimepiride), the glucagon-like peptide-1 receptor agonist (GLP1, liraglutide), or the dipeptidyl peptidase 4 inhibitor (sitagliptin). The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher. The results showed that all four medications, when added to metformin, lowered glycated hemoglobin levels. Comparative hazard ratios are demonstrated in Table 1; glargine and liraglutide were significantly effective in achieving and maintaining target glycated hemoglobin levels. Microvascular and cardiovascular outcomes were also analyzed, such as hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 mL per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. The results showed the incidences of microvascular complications were not significantly different among the four treatment groups2. Liraglutide was found to be protective for MACE, hospitalization for heart failure, cardiovascular death, all cause mortality, and any cardiovascular diseases. Generally speaking, this trial may be supportive for the administration of medications for type 2 diabetes, because there have been no systemic trials for evaluating the efficacies of hypoglycemic agents in the past. The medications in the trial (metformin, glimepiride, insulin glargine, liraglutide, and sitagliptin) were all well known to physicians, yet no one could define which medication was more suitable for glycemic control or for preventing microvascular and cardiovascular events. This trial provided a useful guide for physicians for choosing medications for type 2 diabetes. The GRADE study showed that the liraglutide group led to the lowest incidence of hypertension, and also pointed out that liraglutide had a significantly lower hazard ratio for any cardiovascular disease compared with the other three medications2. These results support the conclusions of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)3, which mentioned that the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. Therefore, for the patients to be potentially harmed by cardiovascular diseases, this medication may be considered. Gastrointestinal signs and symptoms were more prevalent among the liraglutide group. This is also in accordance with previous studies demonstrating how GLP-1 receptor agonists significantly increase the incidence of gastrointestinal adverse events compared with other types of anti-diabetic medications4. In this study, weight loss was the most pronounced in the liraglutide group and the sitagliptin groups, which resonated a Chinese, randomized, active comparator clinical trial, showing a higher efficacy of metformin combined with liraglutide than with sitagliptin in terms of weight reduction among diabetic patients5. Even with the prescription of anti-hyperglycemic medications, most of the participants who did not have a diagnosis of hypertension and dyslipidemia prior to this study developed these conditions within the next 5 years. A decrease in glycemic level may not necessarily lead to improvements in these conditions. Previous studies have shown that glargine triggers the reabsorption of sodium. In addition to glargine, further research is needed to investigate how metformin or other anti-hyperglycemic medications contribute to hypertension and dyslipidemia. However, it may be possible that excess glucose is reabsorbed in the proximal tubule via a sodium–glucose cotransporter, which increases sodium reabsorption, leading to hypertension. Additionally, the average body mass index was 34 ± 3.61, which is also a risk factor for hypertension and dyslipidemia. The GRADE study recruited nearly 5,000 participants from 36 medical centers in the United States, with a large and diverse population from various racial groups, and follow up for 5 years. Randomization was conducted by a centralized Web-based system. Sensitivity analyses for the effects of the coronavirus disease of 2019 (COVID-19), and stratification by subgroup analyses were performed, enhancing its applicability to populations with different age-group structures. Secondly, although the participants and the clinicians were aware of the trial, the investigators were unaware and could objectively record the results. Therefore, the trial could be well conducted, and the effects of the four add-on treatments are comparable. However, there were several limitations for GRADE. Firstly, there were no records for the patient's adherence to medications. Although all the participants were randomly allocated to different groups that would allegedly be treated under the same protocol, it is still unknown whether these medications were actually administered, or whether the hypoglycemic efficacy was affected by the patient's compliance. Secondly, there were also no details mentioned about the lifestyle of the participants. There were no records of food preference, so it is difficult to understand whether the hypoglycemic effects were truly influenced by the medication, or were actually affected by the food preference or lifestyle. Thirdly, sodium-glucose-cotransporter 2 (SGLT2) inhibitors that can slow down the progression of cardiovascular diseases and chronic kidney disease were not used in this study. Further research in this field may benefit people with type 2 diabetes who cannot tolerate the side effects of metformin and have no absolute contraindications to SGLT2 inhibitors6, 7. In most Asian countries, few people with diabetes prefer injected medications in the early stage of glycemic control. Fortunately, an oral GLP1-receptor agonist has been developed, and its efficacy was quite similar to liraglutide8. The results of this study may be applicable to Taiwan and other countries with an aging population structure, as more than 40% of the participants in this study were over the age of 60.
SDGs
Type
journal article