Efficacy and safety of sitagliptin
In our study, the HbA1c and FPG levels were reduced at 3 months (HbA1c: 0.59%, FPG: 15.5 mg/dl reduction) and at 12 months (HbA1c: 0.65%, FPG: 20.2 mg/dl reduction) after treatment with sitagliptin at a dose of 25 to 100 mg/day. Our results are similar to those of previous studies reported in the US and Japan. Nathan et al. reported that the expected percentage decrease in HbA1c levels is 1.0% to 2.0% with metformin monotherapy, 1.0% to 2.0% with sulfonylureas (SUs), 0.5% to 1.0% with glinides, 0.5% to 0.8% with α-glucosidase inhibitors (α-GI), 0.5% to 1.4% with thiazolidinediones (TZD) and 0.5% to 0.8% with DPP-4 inhibitors. Monotherapy with metformin or SU exhibits a stronger reduction of HbA1c levels than a DPP-4 inhibitor alone. However, metformin is associated with side effects such as GI symptoms and is contraindicated in patients with renal insufficiency. The major side effects of SUs are hypoglycemia and weight gain. In patients receiving treatment with SUs, the incidence of hypoglycemic episodes has been reported to be 17.6% per year. Side effects appear to be more frequently seen with metformin or SUs than with sitagliptin. The most common side effects of TZD are weight gain and fluid retention along with peripheral edema and an increased risk of congestive heart failure[14, 17]. In our study, body weight and BMI decreased and there was no evidence of heart failure during sitagliptin treatment. While metformin, glinides, and α-GIs are required to be taken three times daily, sitagliptin is only taken once daily. Therefore, sitagliptin should be associated with higher adherence compared to metformin, glinides, and α-GIs.
In our study, AEs after sitagliptin treatment were seen in 23 (11%) of the 207 enrolled subjects. In particular, direct sitagliptin-related AEs such as hypoglycemia and loss of consciousness were observed in only two subjects (0.96%). A previous pooled analysis reported that the overall incidence of AEs was similar between sitagliptin (100 mg/day) and other diabetic-comparator agents (except for other DPP-4 inhibitors), including placebos, pioglitazone, metformin, sulfonylureas, sulfonylureas + metformin, and metformin + rosiglitazone (overall side effects: 63.0% vs. 62.8%, hypoglycemia: 3.4% vs. 10.9%). Therefore, incidence of AEs in this study, including hypoglycemia, was lower than that reported in the pooled analysis. This discrepancy appears to be related to differences in dosage. In our study, subjects received doses between 50 and 100 mg/day of sitagliptin with only 24 (11.6%) receiving the highest dose of 100 mg. In the pooled analysis, all subjects received 100 mg/day. In previous studies, sitagliptin did not increase cardiovascular risk in patients with T2DM and sitagliptin reduced postprandial glucose fluctuation and stabilized blood glucose levels effectively in combination with miglitol through continuous glucose monitoring (CGM). On the other hand, vildagliptin twice a day calmed down the postprandial glucose level as compared to sitagliptin by CGM. The results of this study show that sitagliptin was safe and effective in this population; however, further studies are needed to evaluate the comparison of each DPP-4 inhibitor.
Effects of DPP-4 inhibitors on blood pressure and lipid profiles
Systolic and diastolic blood pressure decreased after 3 months of treatment with sitagliptin. The active isoforms of GLP-1 include GLP-1(7–36) amide and glycine-extended GLP-1(7–37). GLP-1(7–36) exhibits vascular actions via GLP-1 receptor signaling. Additionally, GLP-1(9–36), a metabolite of GLP-1 (7–36), has vasodilator effects independent of the GLP-1 receptor in a nitrous oxide/cyclic guanosine monophosphate (cGMP)-dependent manner. DPP-4 inhibitors increase the levels of GLP-1, possibly leading to vasodilatation and blood pressure reduction. In addition, Gutzwiller et al. showed that a pharmacological dose of GLP-1 increases sodium excretion in the proximal renal tubule in obese and insulin-resistant men. Therefore, GLP-1-induced increases in urinary sodium excretion might also contribute to blood pressure reduction after sitagliptin treatment.
In our study, serum levels of TC and TG also decreased after 3 months of treatment with sitagliptin. Qin et al. showed that GLP-1 decreases the intestinal lymph flow and reduces triglyceride absorption and apo B and apo A-IV production in rats. Vildagliptin, another DPP-4 inhibitor, has been shown to reduce the hepatic expression of genes important for cholesterol synthesis, including phosphomevalonate kinase and mevalonate decarboxylase in wild-type mice. Prolonged DPP-4 inhibition modulates the expression of genes important for fatty acid oxidation,including acyl-coenzyme dehydrogenase medium chain and Acyl-CoA synthetase. In addition, DPP-4 inhibitors reduce the levels of hepatic mRNA transcripts for acetyl coenzyme A acyltransferase 1 and carnitine palmitoyltransferase 1, independent of incretin receptor actions. Because these modulations depend on and/or are independent of incretin receptor actions, sitagliptin may have the ability to decrease the levels of TC and TG.
QOL and diabetes
QOL, whose evaluation is the major goal of our study, is improved after sitagliptin treatment. The sleep quality and PSQI scores decreased after 12 months of treatment with sitagliptin. Particularly, in the subgroup of poor sleepers with PSQI scores above 5.5 points, the scores were significantly reduced not only after 12 months of treatment, but also after 3 months of treatment. Sleep disorders are common in patients with diabetes. Sleep debts decrease carbohydrate tolerance and insulin resistance and increase sympathetic tone, cortisol levels, and nocturnal catecholamine levels[27, 28]. Improving sleep disorders with sitagliptin therapy might improve these states, possibly preventing cardiovascular disease in patients with T2DM.
Our own QOL assessment scores for diabetes, the Diabetes Symptomatic Scores, also decreased after sitagliptin treatment. Particularly, the scores regarding urinary frequency and paresthesia of the extremities significantly decreased 12 months after sitagliptin treatment. Urinary frequency, which often appears in T2DM patients, is caused by hyperglycemia-induced polyposia and/or neurogenic bladder. We suppose that polypepsia and polyposia are improved by reductions in FPG after sitagliptin treatment, thereby decreasing the urinary frequency. Paresthesia of the extremities is characterized by striking atrophy and/or loss of myelinated and unmyelinated fibers. Hyperglycemia leads to the development of macrovascular and endoneural microvascular disease in diabetic nerve tissue via several mechanisms, including the polyol pathway. We suppose that both reductions of FPG and vasodilatation, a direct action of DPP-4 inhibitors, leads to improved nerve blood flow and nerve fiber damage in patients with diabetic neuropathy.
The EQ-5D score represents an independent predictor of mortality and future cardiovascular events in patients with T2DM. In our study, however, the EQ-5D scores did not change after treatment with sitagliptin. Because the EQ scores before sitagliptin treatment were as high as 0.84 points, which is close to the cut-off point for a healthy state, they might not change significantly after sitagliptin treatment.
This was a preliminary, single-arm study of a small number of subjects. A large-scale, randomized study conducted over a longer period is needed in the future. However, we found that sitagliptin exerts significant effects, not only on glycemic control, but also on improving QOL, blood pressure, and lipid profiles in subjects with T2DM. Although our results showed efficacy of the drug, we could not precisely evaluate subjects’ adherence to their dosing regimens. As far as we know, there is no reported data on patient adherence to DPP-4 inhibitor treatment regimes. However, adherence to a drug taken once a day is supposed to be higher than conventional drugs taken two or three times a day, which may affect efficacy. In this study, the subjects whose rates of adherence were less than 75% were to be reported as “poor adherence”; all evaluated patients had good adherence to the dosing regimen.
In this study, treatment with sitagliptin achieved adequate reductions in the levels of HbA1c and significant increases in the rate of accomplishment of glycemic control. The use of sitagliptin was shown to be safe and improved the PSQI and Diabetes Symptomatic scores.