This patient has been treated with lifestyle changes and pharmacotherapy with increasing doses of metformin for his diabetes. At least one component of the disease progression in this patient is likely caused by declining β-cell function. Options for further treatment aimed at reducing the patient's HbA1c level include the use of combination therapy with metformin or a switch from metformin to another therapy.
The natural history of T2DM typically involves progressive pancreatic islet cell dysfunction and worsening glycemic control. Traditional antihyperglycemic agents—thiazolidinediones and sulfonylureas—often fail to maintain glycemic goals long-term, in part, because they do not target the underlying pathophysiologic processes of T2DM, which include a progressive decline in β-cell function and impaired incretin response. Incretin-based therapies address these mechanisms and offer the advantage of potentially slowing disease progression by enhancing insulin secretion and suppressing glucagon release.
Evidence from a recent clinical trial
3 involving the glucagon-like peptide-1 (GLP-1) agonist exenatide showed a sustained improvement in HbA
1c levels in patients with T2DM who completed at least 3 years of treatment. Patients who enrolled in a randomized, double-blind, parallel-group, 30-week study had the option to continue in their open-label extensions; completers were then given the option to enroll in a single, open-ended, open-label extension. During the blinded portion of the study, patients received combination therapy of exenatide with either metformin or a sulfonylurea, or triple therapy with exenatide, metformin, and a sulfonylurea.
3 Patients who completed 156 weeks of treatment with exenatide reduced HbA
1c levels by a mean (SD) of -1.0% (0.1%) (
P<.0001) and reduced FPG by -23.5 (3.8) mg/dL (
P<.0001). These findings demonstrated a sustained and durable control of HbA
1c in patients completing 3 years of treatment with exenatide (
Figure 1).
3
With other T2DM interventions, an initial improvement in glycemic control is followed by increasing levels of HbA1c over time. However, the results of this analysis suggest some stability and durability in the HbA1c response when exenatide is used as a component of the combination therapy. When discussing treatment options with patients, physicians should explain that, based on clinical trial evidence, the addition of exenatide to metformin could potentially reduce HbA1c levels by a percentage point or more.
Sitagliptin, a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, has also shown efficacy in lowering HbA
1c levels in patients with T2DM when used as monotherapy. One 24-week study
4 demonstrated reductions in HbA
1c of 0.79% and 0.94% for 100 mg and 200 mg sitagliptin, respectively (
P<.001 for both vs placebo). In addition, 41% and 45% of patients in the respective sitagliptin groups achieved an HbA
1c of less than 7.0%, compared with only 17% in the placebo group (
P<.001).
4
Similar results were seen in combination therapy with metformin: at 24 weeks, sitagliptin significantly reduced baseline HbA
1c by -0.65% (
P<.001).
5 The percentage of patients achieving an HbA
1c of less than 7.0% was 47% in the sitagliptin group and 18.3% in the placebo group (
P<.001).
5 As add-on therapy with ongoing pioglitazone, sitagliptin significantly reduced both HbA
1c (-0.7%;
P<.001) and FPG (-17.7 mg/dL;
P<.001), and the percentage of patients reaching the target goal was 45.4% and 23.0% in the sitagliptin and placebo groups, respectively (
P<.001).
6
In populations with a baseline HbA
1c of 8.8%, sitagliptin also demonstrated moderate efficacy in combination with high-dose metformin. At week 24, the combination of sitagliptin (50 mg twice daily) with high-dose metformin (1000 mg twice daily) resulted in an HbA
1c reduction of -1.9% vs baseline, and -2.07% vs placebo.
7 Evidence from a 104-week study also suggested a durable and sustained reduction in HbA
1c with sitagliptin as add-on therapy to metformin (
Figure 2).
8 Results with both exenatide and sitagliptin demonstrated durable and apparently sustainable reductions in HbA
1c, and could theoretically cause islet or β-cell function regeneration or an improvement in viability of β cells. However, further study will be needed to determine whether such increases in β-cell mass or function are occurring.
Results with saxagliptin, another DPP-4 inhibitor, in combination with metformin have also demonstrated significant reductions in HbA
1c and have shown evidence of durability during a 2-year study (
Figure 3). In this case, however, the HbA
1c pattern did not appear to show a plateau effect, but instead indicated an initial response was followed by a gradual increase between 30 and 102 weeks.
9 Further follow-up may be needed to determine whether the efficacy of saxagliptin is sustainable over the long-term.