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What You Need To Know When Adding A DPP-4 Inhibitor

Reduce the dose of sulfonylureas when adding DPP-4 inhibitor treatment in patients with type 2 diabetes, study warns.

The purpose of the study was to quantify the risk of hypoglycemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas.

Hypoglycemia is a potentially life threatening event associated with an increased risk of hospital admission, cardiovascular disease, and mortality. The ACCORD (Action to Control Cardiovascular Disease in Diabetes) trial of intensive glucose lowering in people with type 2 diabetes found a 2.5-fold increase in hypoglycemic events. That trial was prematurely stopped due to increased mortality possibly related to the unfavorable effect of hypoglycemia in susceptible participants, such as those with underlying coronary diseases.

Hypoglycemia has emerged as a leading complication of diabetes in older adults (>60 years) with a longer history of the disease. It is the second cause of admission to the hospital in people with type 2 diabetes, accounts for 20-25% of hospital admissions for adverse drug reactions, and might precipitate heart failure in those at greatest risk. More generally, it can result in falls and fractures in people age 65 years or more, has a negative effect on quality of life, and, in the long term, may impair the maintenance of euglycemia and the full benefit of treatments. Therefore, hypoglycemia is a serious adverse event that must be considered when studying the safety of glucose lowering drugs such as DPP-4 Inhibitors.

DPP-4 inhibitors are a recently marketed class of oral glucose lowering drugs. They are indicated as second line treatment in people with type 2 diabetes mellitus not adequately responsive or intolerant to metformin, or in whom other glucose lowering drugs such as sulphonylureas or thiazolidinediones (TZDs) do not achieve glycemic control. These drugs have different mechanisms of action.

Several randomized clinical trials have studied DPP-4 inhibitors both as monotherapy and, more often, in patients treated with other glucose lowering drugs, metformin in particular.  DPP-4 inhibitors have been used as monotherapy; the incidence of hypoglycemia was comparable to that of placebo or metformin (around 5%), and a number of randomized controlled trials indicate that this risk is not increased when DPP-4 inhibitors are used in patients treated with metformin or TZDs, thus confirming their acceptable safety profile.

Conversely, when DPP-4 inhibitors are used with sulphonylureas, an increased incidence of hypoglycemia  has been noted. This could be related to the higher incidence of hypoglycemia among patients treated with sulphonylureas (about 20%, which increases with treatment duration), which is further increased when patients are treated by a second drug acting on insulin secretion. Although the summaries of the product characteristics of DPP-4 inhibitors acknowledge the increased risk of hypoglycemia due to this association,  this risk remains insufficiently assessed.

Francesco Salvo (University of Bordeaux, France) and co-researchers found that adding a DPP-4 inhibitor increased the likelihood of hypoglycemia by 52%.

The meta-analysis included 10 randomized controlled trials with 6,546 participants who received sulfonylureas plus either DPP-4 inhibitors or placebo. Most of the studies followed up patients for no more than 6 months; during this time 479 of 4,020 patients taking DPP-4 inhibitors had a hypoglycemic event, as did 169 of 2,526 taking placebo, equating to absolute risks of 11.9% versus 6.7%.

Four trials included patients given a low dose of a DPP-4 inhibitor, and these patients had a nonsignificant 33% increased risk of hypoglycemia. The researchers note that the 95% confidence interval (0.92-1.94) does not exclude an increased risk, but given the significant 66% increased risk with full-dose DPP-4 they say their findings imply a dose response.

This meta-analysis found about a 52% increase in the risk of hypoglycemia associated with the addition of DPP-4 inhibitors to sulphonylureas in people with type 2 diabetes. This adverse event, commonly experienced by people treated for diabetes, would lead to the occurrence of one excess case of hypoglycemia in every 17 treated patients treated for six months. This potentially represents a huge number of attributable cases worldwide. These results clearly highlight the need to respect existing recommendations for dose reduction of sulphonylureas when initiating treatment with DPP-4 inhibitors, and the urgency to determine the efficacy of this measure in minimizing the risk of hypoglycemia.

Practice Pearls:

  • Hypoglycemia is a serious adverse event that must be considered when studying the safety of glucose lowering drugs.
  • Hypoglycemia is the second cause of admission to the hospital in people with type 2 diabetes, accounts for 20-25% of hospital admissions for adverse drug reactions, and might precipitate heart failure in those at greatest risk.
  • The results clearly highlight the need to reduce the dose of sulfonylureas when adding DPP-4 inhibitors to treatment.

Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis. The BMJ. May 2016353 doi: http://dx.doi.org/10.1136/bmj.i2231