Current Drug Therapy

What role will ‘gliptins’ play in glycemic control?

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Sitagliptin and vildagliptin have undergone a large number of studies in patients with type 2 diabetes. Several dosing regimens were tested, but we will restrict this discussion to studies that used 100 mg once a day or 50 mg twice a day. Of note, the effect of 50 mg twice daily may somewhat exceed that of 100 mg once daily,18 so these studies should be interpreted with caution. Table 1 summarizes the effect of sitagliptin on HbA1c values in these studies.19–25

Sitagliptin is effective when used by itself,reducing a baseline HbA1c level of about 8% by 0.6% to 0.8%,19,20,24 and is similarly effective when combined with metformin21,22,25 or pioglitazone (Actos, a thiazolidinedione).23 It also decreases fasting blood glucose levels and improves other measures of glucose control.

A study comparing sitagliptin and the sul-fonylurea glipizide (Glucotrol) showed identical glucose-lowering over a 1-year period, with less hypoglycemia and weight gain with sitagliptin.25 Hypoglycemic episodes occurred in 32% of patients taking glipizide but in only 5% of those taking sitagliptin.

Studies noted several trends in laboratory values, though none was associated with clinical evidence of adverse outcome:

  • White blood cell counts were noted to increase in three of the studies by 4.7% to 10%, owing to increases in neutro-phils19,20,22
  • Alkaline phosphatase concentrations decreased in four studies19,20,22,23
  • Uric acid levels increased in four studies.19,20,22,23


Lower doses and periodic monitoring of renal function are recommended in patients taking sitagliptin who have some degree of renal insufficiency. Clearance of sitagliptin is delayed in patients with renal insufficiency (creatinine clearance < 50 mL/minute).

In a placebo-controlled study of sitagliptin safety, Scott et al26 found that the area under the sitagliptin concentration-time curve was 2.3 times greater in patients with moderate renal insufficiency (creatinine clearance rate 30–49.9 mL/minute), 3.8 times greater in those with severe renal insufficiency (15–29.9 mL/minute), and 4.5 times greater in those with end-stage renal disease (< 15 mL/minute).

The Januvia package insert27 recommends that the daily dose be decreased to 50 mg in patients with creatinine clearance rates of 30 to 49.9 mL/minute (serum creatinine > 1.7 mg/dL in men, > 1.5 mg/dL in women), and that the dose be decreased to 25 mg per day in those with creatinine clearance rates below 30 mL/minute (creatinine > 3.0/2.5 mg/dL).


Vildagliptin has also undergone extensive clinical testing (Table 2).28–36 The trials to date indicate that it is effective when used alone, reducing HbA1c levels by 0.5% to 0.9% from a baseline of 8%.28,29,34–36 The effect appears to be similar when vildagliptin is used in combination with metformin30,31 or pioglita-zone.32,36

A study comparing vildagliptin against metformin34 showed less glucose-lowering over a 1-year period with vildagliptin, albeit with fewer gastrointestinal side effects, while comparisons with rosiglitazone (Avandia)35 and with pioglitazone36 showed similar glucose-lowering ability.

In a 24-week study,33 256 patients with type 2 diabetes who had a mean body mass index of 33 kg/m2 and who were taking more than 30 units of insulin daily (an average of 82 units) were randomized to additionally receive either vildagliptin 50 mg twice daily or placebo. The HbA1c decreased by 0.5% with vildagliptin and by 0.2% with placebo, from a baseline level of 8.5%. Of interest, 33 patients receiving vildagliptin had a hypo-glycemic episode (a total of 113 events), compared with 45 patients in the placebo group (185 events). None of the episodes in the vildagliptin group was classified as severe, whereas six episodes in the placebo group were classified as severe. This suggests that adding vildagliptin in patients taking insulin can improve glycemia without causing excessive hypoglycemia.

A weakness of the design of this study is that it did not include patients who were receiving an insulin sensitizer, an approach that is typically taken. Given this, it is understandable that overall glycemic control was relatively poor. More effort is needed to explore the use of gliptins with insulin.


The evidence from the studies reviewed in this article suggests that gliptins can play an important role in the treatment of type 2 diabetes. In certain patient groups such as the elderly, who cannot take either metformin or a thiazolidinedione and in whom concerns about hypoglycemia are greatest, thus precluding sulfonylurea therapy, gliptins may be the agents of choice. The trials reviewed here suggest that gliptins have glucose-lowering efficacy similar to that of these classes of agents. Gliptins are also effective when combined with metformin or a thiazolidinedione and, as discussed above, may prove to be useful in combination with insulin.

The eventual role of gliptins in the treatment of type 2 diabetes will depend on the answers to several questions. For example, do they preserve beta cell function and reverse the progression of diabetes? Do they affect insulin resistance? Do they have cardiovascular benefits beyond glucose-lowering? Also, since DPP-4 is widely distributed in the body, and since we do not yet know the effects of all the proteins cleaved by this enzyme, will this affect the long-term safety of these drugs?

For now, we can state with reasonable certainty that gliptins lower blood sugar levels to a degree similar to that of other oral hypo-glycemic therapies, with minimal risk of hypo-glycemia, with few immediate adverse effects, and without requiring dose titration. These characteristics suggest that gliptins should be considered useful agents in monotherapy and combination therapy for the treatment of type 2 diabetes.

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