We screened 60 patients, of whom 52 were included after applying the exclusion criteria (sitagliptin group: 30 vs control group: 22). Two patients declined to participate because of the visiting schedule. After 5 years, 19 subjects had dropped out (sitagliptin group: 21 vs. control group: 12). The final number of subjects who completed the study for ten years was 26 (sitagliptin group: 17 vs control group: 9) (Fig. 1). Period from the onset of T2DM to the start of this study was 9.1 ± 4.8 years in the final sitagliptin group, and 9.5 ± 6.7 years in the final control group. All combination medications including oral glucose-lowering drugs and other medications (antihypertensives and antihyperlipidemic agents) remained unchanged in both groups through the study. With regard to oral glucose-lowering drugs, the final number of sitagliptin monotherapy was 5 in 17 patients, and that of placebo monotherapy number was 2 in 9 patients.
In the sitagliptin group, no significant changes in body weight, BMI, or waist circumference were observed from the onset to 5 or 10 years of sitagliptin administration. Sitagliptin treatment for 6 months significantly lowered both systolic and diastolic blood pressures (SBP and DBP, respectively), an effect which continued through the study. A reduction in fasting blood glucose at 6 months (from 142 ± 38 mg/dL to 130 ± 19 mg/dL), and a reduction in HbA1c at 6 months (from 6.9 ± 0.92% to 6.3 ± 0.70%) were observed, both effects of which were maintained through the study. Triglyceride, total cholesterol, HDL-cholesterol, and LDL-cholesterol were not altered by sitagliptin treatment (data not shown). Finally, a significant reduction in hsCRP from 452 ± 308 ng/mL to 260 ± 131 ng/mL was observed at 6 months, and further decrease was observed through the study (Table 1).
In the control group, no significant changes in body weight, BMI, or waist circumference were observed from the onset to 5 or 10 years of placebo administration. A reduction in fasting blood glucose at 6 months (from 137 ± 17 mg/dL to 129 ± 14 mg/dL), and a reduction in HbA1c at 6 months (from 6.8 ± 0.25% to 6.3 ± 0.43%) were observed, both effects of which were maintained through the study. No significant changes in SBP, DBP, or hsCRP were observed during the study (Table 1).
ACR and eGFR
In the sitagliptin group, the mean value of urinary albumin excretion (measured as urinary albumin-to-creatinine ratio (ACR) in milligrams/gram of creatinine) did not change in the 6 months before sitagliptin treatment and markedly decreased in the 6 months after sitagliptin treatment, and these effects were gradually increased during the study. No changes in estimated glomerular filtration rate (eGFR) were seen throughout the study (Fig. 2a).
In the control group, the mean values of ACR tended to slightly increase and eGFR tended to slightly decrease during the study (Fig. 2b).
Change of mean ACR values in either group was not statistically significant because of big SD values. Thus, Table 2 showed the staging for diabetic nephropathy by the Japanese Diabetes Society  before and after treatment with or without sitagliptin. The number of patients with improved stage was increased in the sitagliptin group, while the number of patients with a deterioration in stage increased in the control group.
HOMA-β and HOMA-IR
In the sitagliptin group, HOMA-β values were reduced at baseline, significantly improved within 24 months, and then increased throughout the study. HOMA-IR values stayed within normal range during the study (Table 3). In the control group, HOMA-β values, which were similarly reduced at baseline, continued unchanged and HOMA-IR values also remained within normal range during the study (Table 3).
Safety and tolerability
Starting with 52 subjects, the final number of subjects after ten years was 26. Although half of the subjects dropped out, no episodes of hypoglycemia exhibiting marked severity (i.e., loss of consciousness or requirement for medical assistance), no heart failure and no acute pancreatitis was observed during the study in either group.