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Economic Impact of and Treatment Options for Type 2 Diabetes
Jan D. Hirsch, BSPharm, PhD, and Candis M. Morello, PharmD, CDE
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Overview of the Cardiovascular Benefit With Diabetic Agents and Novel Combination Products for Type 2 Diabetes
Candis M. Morello, PharmD, CDE
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Utilizing Advances in Diabetes and Targeting Medication Adherence to Enhance Clinical Outcomes and Manage Costs for Type 2 Diabetes Posttest

Overview of the Cardiovascular Benefit With Diabetic Agents and Novel Combination Products for Type 2 Diabetes

Candis M. Morello, PharmD, CDE
Cardiovascular Risk Considerations and Diabetes Medication Concerns
HF Risk Increased
Patients with T2D are at an increased risk of developing HF; the combination of HF and diabetes substantially worsens prognosis.1,6 The risks of HF in diabetes are multifold and may be attributed to comorbid conditions, including myocardial ischemia, atherogenesis, coronary artery disease, hypertension, and diabetic cardiomyopathy.7 As a result of the FDA CV study outcomes requirements, some negative outcomes have come to light with specific DPP-4 inhibitors. The DPP-4 inhibitor class includes 4 drugs (sitagliptin, saxagliptin, linagliptin, and alogliptin), all of which decrease hyperglycemia by increasing GLP-1 and gastric inhibitory polypeptide (GIP) concentrations. These gut-derived hormones stimulate insulin secretion in a glucose-dependent manner and mildly delay gastric emptying.1 Alogliptin and saxagliptin carry an FDA-required HF warning on prescribing information sheets. Prescribers are cautioned not to initiate these agents in patients who have HF or are at risk for HF (defined as having low estimated glomerular filtration rate, or elevated N-terminal pro b-type natriuretic peptide, or previous HF), and to discontinue an agent if HF develops.8-10

In SAVOR-TIMI 53, saxagliptin was associated with an increased risk for hospitalization for HF.11 Patients at highest risk had elevated natriuretic peptide concentrations, prior history of HF, or chronic kidney disease with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min. At 24 months, 3.5% of patients in the saxagliptin group were hospitalized for HF compared with 2.8% of those in the placebo group (HR, 1.27; 95% CI, 1.07-1.51; P = .007), equivalent to a 27% increase in the rate of hospital admission for HF (number needed to harm [NNH]: 143 over 2 years).

The EXAMINE trial showed that alogliptin was noninferior to placebo for major adverse cardiac event (MACE) rates (composite primary endpoint of CV death, MI, or stroke) in patients with T2D and recent acute coronary syndromes (11.3% vs 11.8%; HR, 0.96; upper boundary of the 1-sided 95% CI, 1.16).12 Because of concerns about excessive rates of HF hospitalizations with saxagliptin, the EXAMINE trial data were assessed for hospital admission for HF.13 Alogliptin was not associated with increased risk of HF outcomes, such as hospital admission for HF, compared with placebo (3.1% vs 2.9%, respectively; HR, 1.07; 95% CI, 0.79-1.46). However, hospital admissions for HF occurred significantly more often in patients without prior history of HF treated with alogliptin compared with placebo (HR, 1.76; 95% CI, 1.07-2.90; P = .026).13

HF Concerns: A DPP-4 Inhibitor Class Effect?
Randomized controlled trial (RCT) data are conflicting regarding the increased risk of HF with DPP-4 inhibitors.14 Some DPP-4 inhibitors appear to increase risk while others do not; thus, the HF concerns may not be a class effect. The TECOS trial found no association of sitagliptin with HF (relative risk [RR]: 1.00; 95% CI, 0.83-1.19).15 A recent meta-analysis evaluated 100 RCTs (N = 79,867), assessing the association between HF and DPP-4 inhibitors given for 24 weeks or more. Overall, 96% (1192/1244) of HF events were identified, blindly adjudicated, and required hospital admission.14 Pooled results suggest a 13% increase in HF (RR: 1.13; 95% CI, 1.01-1.26). If only the 3 large CV trials are included (SAVOR-TIMI 53, EXAMINE, and TECOS; n = 36,543), a similar but nonsignificant increase is observed (RR: 1.14; 95% CI, 0.97-1.32; NNH 246). SAVOR-TIMI 53 (saxagliptin) demonstrated increased HF.14 In a smaller placebo-controlled CV study of 9459 patients, 5847 received 5 mg of linagliptin once daily and experienced CV events similar to those receiving placebo (P >.05).16 Both linagliptin and sitagliptin appear safe to use in persons with diabetes and HF.

A mechanism for the association between DPP-4 inhibitors and HF has not been found.14 CV clinical trials to assess individual DPP-4 effects are underway; however, no large CV-safety trials comparing DPP-4 inhibitors with one another are ongoing. Therefore, results from these trials will address individual but not within-class differences. Long-term studies that include patients with HF (which may uncover higher risks) are needed to evaluate the long-term safety of these lifelong therapies.14

Two trials assessing CV effects of DPP-4 inhibitor therapy are ongoing in patients with T2D and CV disease or high CV risk. The CAROLINA (NCT01243424) trial will evaluate patients with early-onset T2D and compare linagliptin with glimepiride, each added to metformin.17 The CARMELINA (NCT01897532) trial will examine CV and renal microvascular outcomes of linagliptin in high-risk individuals with T2D.18

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