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Reducing New-Onset Type Diabetes with Dalcetrapib

May 26, 2020
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Chardae Whitner, 2020 PharmD. Candidate, Lake Erie College of Osteopathic Medicine

Can cholesteryl ester transfer protein inhibitors like dalcetrapib reduce incident type 2 diabetes? 

There has shown to be a correlation between acute coronary syndrome and diabetes. The data reports that approximately 30% of patients with the acute coronary syndrome  (ACS) have a prior history of type 2 diabetes.  The data further states that 10% of the patient hospitalized for ACS in the hospital may be diagnosed with diabetes while hospitalized and another 10% may receive a diabetic diagnosis following the five years after the ACS diagnosis.  With the heightened risk of microvascular and macrovascular complications in diabetic patients, there has been much interest in reducing the incidence of type 2 diabetes. Cholesteryl ester transfer protein (CETP) inhibitors, used initially as cardiovascular medications, have shown to reduce plasma glucose and insulin significantly.  It is believed cholesteryl ester transfer protein inhibitors can reduce incident type 2 diabetes. The dual-OUTCOMES trial goal was to compare the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. 

 

This broad study was conducted in 27 countries at 935 sites for four years between 2008 and 2012. A total of 15, 841 patients were randomized 4-12 weeks after the index ACS event, which is when they were considered clinically stable. The inclusion of the study consisted of participants being at least 45 years of age, had recent ACS, and had completed all planned coronary revascularization procedures. Exclusion criteria included New York Heart Association Functional Classification III or IV symptoms of heart failure or class II symptoms with left ventricular ejection fraction 40%, uncontrolled hypertension, serum creatinine > 2.2 mg/dL, or fasting triglycerides >400 mg/dL. At baseline, participants were serum glucose, and hemoglobin was obtained following every 1, 3, 6, 9, and 12 months for the serum glucose and 6 and 12 months for hemoglobin A1c.  At baseline using base-case criteria, 5,141 patients (32.5%) were classified with diabetes (dalcetrapib, 2,573; placebo, 2,568) and 10,645 (67.1%) without diabetes (dalcetrapib, 5,326; placebo, 5,319). Diagnostic criteria were missing for 85 patients (0.5%). Among those without diabetes, 6,695 (62.9%) were classified as prediabetic and 3,950 (37.1%) as normoglycemic.  

Considering cardiovascular outcomes, treatment with dalcetrapib versus placebo did not affect the risk of the primary endpoint in those with diabetes at baseline (HR 1.06, 95% CI 0.91–1.25, P 5 0.79) or those without diabetes at baseline (HR 1.02, 95% CI 0.88–1.19, P 5 0.45). Hemoglobin A1c levels were slightly lower with dalcetrapib at 6, 12, 24, and 36 months, without differences in fasting glucose. As determined from base-case criteria, incident diabetes developed in 403 of 5,326 patients (7.6%) in the dalcetrapib group and 516 of 5,319 patients (9.7%) in the placebo group, corresponding to an absolute risk reduction of 2.1%. Dalcetrapib prolonged time to onset of diabetes (HR 0.77, 95% CI 0.67–0.89, P, 0.001), with a need to treat 40 patients for three years to prevent one incident case. Of the 919 patients who developed diabetes, 837 (91%) had prediabetes, and 82 (9%) had normoglycemia at baseline.  Those participants with prediabetes at baseline, incident diabetes developed in 364 of 3,394 patients (10.7%) in the dalcetrapib group and 473 of 3,301 patients (14.3%) in the placebo group, corresponding to an HR of 0.74 (95% CI 0.65–0.85, P, 0.001) and a need to treat 25 patients for three years to prevent one incident case. Restricting the analysis further to 3,371 patients with impaired fasting glucose (100–125 mg/dL) at baseline, incident diabetes developed in 251 of 1,681 patients (14.9%) in the dalcetrapib group compared with 321 of 1,690 (19.0%) in the placebo group (HR 0.80, 95% CI 0.68–0.95, P 5 0.009). In the sensitivity analysis using more stringent criteria to classify patients as not having diabetes at baseline, incident diabetes occurred in 254 of 4,602 patients (5.5%) in the dalcetrapib group and 324 of 4,602 patients (7.0%) in the placebo group (HR 0.78, 95% CI 0.66– 0.92, P 5 0.003). At baseline, median (IQR) fasting glucose was 5.3 (4.9–5.7) mmol/L, insulin was 8.3 (5.5–12.4) mU/mL, and HOMAIR was 1.9 (1.3–3.0), without differences between treatment groups. At month 3, the median fasting glucose was unchanged, and fasting insulin increased slightly in both groups. However, dalcetrapib did not affect the change in these measurements from randomization to month 3, nor did dalcetrapib have a discernible effect on new-onset diabetes at month 3.  

This trial revealed that dalcetrapib reduces incident diabetes by 23% (absolute reduction 2.1%) over a median follow-up of 30 months in patients with ACS who do not have diabetes at baseline. Therefore, dalcetrapib might have utility as a well-tolerated agent to prevent or delay the onset of diabetes in patients at high risk for that condition.  

Practice Pearls: 

  • This trial revealed that dalcetrapib reduces incident diabetes by 23%. 
  • Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.  
  • In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.  
  • More extended observation could prove that dalcetrapib could be a long-term cardiovascular benefit of preventing diabetes. 

Schwartz, Gregory G., et al. “Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients with Coronary Heart Disease.” Diabetes Care, American Diabetes Association, March 4. 2020, care.diabetesjournals.org/content/early/2020/02/27/dc19-2204. 

Chardae Whitner, 2020 PharmD. Candidate, Lake Erie College of Osteopathic Medicine