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New therapies for diabetes: A prescription for reducing CV outcomes

Issue: August 2016

ByJeff Langford, PharmD, BCPS

BySarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology)

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Patients with diabetes are at a substantially increased risk for CVD, which is the leading cause of health complications and death in these patients.

Although chronic hyperglycemia is associated with increased CV risk, the effect of intensive glycemic control on outcomes such as MI and stroke has been variable in clinical trials, with results demonstrating increased or decreased risk. Analyses of these conflicting results have suggested that the CV benefit, or risk, of intensive glycemic control may vary depending on factors such as duration of diabetes and presence of established atherosclerosis.

Additionally, questions exist regarding the CV risk of antidiabetic therapies. This issue first surfaced in 1970 when data from the University Group Diabetes Project showed increased CV mortality with tolbutamide, a first-generation sulfonylurea. Nearly 4 decades later, scrutiny of this topic was renewed when a meta-analysis suggested that rosiglitazone use resulted in a 43% increase in the risk for MI and a 64% increase in risk for CV death. In response, the FDA mandated manufacturers demonstrate that new therapies for type 2 diabetes do not significantly increase CV risk. Based on this requirement, evidence is now emerging regarding CV outcomes with newer classes of antidiabetic agents, the dipeptidyl peptidase-IV (DPP-IV) inhibitors, glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Incretin-based therapies

Incretin-based therapies for the treatment of type 2 diabetes include the oral DPP-IV inhibitors alogliptin (Nesina, Takeda), linagliptin (Tradjenta, Boehringer Ingelheim), saxagliptin (Onglyza, AstraZeneca) and sitagliptin (Januvia, Merck), and injectable GLP-1 agonists albiglutide (Tanzeum, GlaxoSmithKline), dulaglutide (Trulicity, Eli Lilly), exenatide (Byetta, AstraZeneca), liraglutide (Victoza, Novo Nordisk) and lixisenatide (Sanofi Aventis). DPP-IV inhibitors act by preventing the breakdown of incretin hormones, whereas GLP-1 agonists mimic the action of these hormones at pancreatic receptors; both mechanisms result in increased insulin release, suppressed glucagon release and improved blood glucose control.

Data from animal and human studies suggest a variety of CV effects with incretin therapies. GLP-1 agonists may lower BP, lower body weight, reduce the size of damage to the heart muscle after an MI and improve ventricular function in HF. DPP-IV inhibitors may protect ventricular function after an ischemic event, enhance cellular repair at sites of vascular damage and reduce the inflammatory processes important in atherosclerosis.

Postmarketing studies examining CV outcomes with saxagliptin (SAVOR-TIMI 53), alogliptin (EXAMINE) and sitagliptin (TECOS) have been published recently. In each trial, patients with CV risk factors or established CVD were randomly assigned to treatment with a DPP-IV inhibitor or usual care. Average participants in these trials were aged 60 to 65 years, with modestly elevated HbA1c (mean, 7.2% to 8%) and a median diabetes duration of longer than 7 years.

Results of these trials showed that saxagliptin, alogliptin and sitagliptin neither increased nor decreased risk for CV events compared with the usual treatment of type 2 diabetes.

Results regarding HF hospitalizations, however, diverged across the three studies. Saxagliptin was associated with a 27% increase in HF hospitalizations (P = .007). Hospital admissions for HF were increased with alogliptin treatment, but this did not achieve statistical significance (HR = 1.19; 95% CI, 0.9-1.58). Sitagliptin did not show an increase in hospitalization for HF (HR = 1; 95% CI, 0.83-1.2).

In each study, CV risk was well managed with more than 75% of patients receiving aspirin, statin ACE inhibitor or angiotensin receptor blocker therapy. At the end of follow-up, HbA1c was modestly reduced in the DPP-IV inhibitor group as compared with placebo (range, 0.2% to 0.36%).

Although cases of pancreatitis have previously been reported with DPP-IV inhibitors, there was not a significant difference in rate of pancreatitis or pancreatic cancer with DPP-IV inhibitor treatment in these studies.

CV outcomes with the GLP-1 agonist liraglutide were examined in the recently published LEADER trial. Patients with type 2 diabetes and high CV risk were randomly assigned to liraglutide or placebo, in addition to usual care. Participants were, on average, aged 64 years, with an HbA1c of 8.7% and a diabetes duration of longer than 12 years. At baseline, more than 70% of patients were receiving statin and ACE inhibitor or angiotensin receptor blocker therapy, and more than 60% were receiving aspirin.

In contrast to the DPP-IV studies discussed above, liraglutide decreased the risk for CV events (combined CV death, MI or stroke) by 13% (P = .01), CV death by 22% (P = .007) and all-cause mortality by 15% (P = .02). MI, stroke and HF were reported less frequently with liraglutide, but the reduction of these endpoints when analyzed separately did not reach statistical significance.

At the conclusion of the LEADER trial, patients treated with liraglutide had reductions in HbA1c (0.4%), body weight (2.3 kg), systolic BP (1.2 mm Hg) and diastolic BP (0.6 mm Hg), but an increase in heart rate (3 bpm) compared with placebo.

Although not significantly different than placebo, acute and chronic pancreatitis were reported less often with liraglutide, whereas neoplasms, including pancreatic cancer, were reported more frequently. Adverse events leading to discontinuation occurred more often with liraglutide; this was largely driven by gastrointestinal events such as nausea, vomiting and abdominal discomfort.

The reduction in CV events and mortality seen with liraglutide contrasts with results reported for another GLP-1 agonist, lixisenatide, an agent available in other countries and currently undergoing FDA review. In the ELIXA trial, no difference in the rate of CV events, HF hospitalization or death was observed with lixisenatide; adverse effects were reported in a similar pattern to those observed with liraglutide.

SGLT2 inhibitors

SGLT2 inhibitors canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim) act in the proximal tubule of the kidney to decrease glucose reabsorption; this results in increased urinary excretion of glucose and reduced hyperglycemia. Other effects of SGLT2 inhibition, which could modify CV risk, include weight loss (approximately 2 kg to 3 kg during first year); decreased BP (approximately 3 mm Hg to 5 mm Hg systolic and 2 mm Hg diastolic); reduced arterial stiffness, vascular resistance and uric acid; and increased LDL and HDL (3 mg/dL to 7 mg/dL and 2 mg/dL to 5 mg/dL, respectively).

In the EMPA-REG OUTCOME trial, patients with type 2 diabetes and established CVD were randomly assigned to treatment with empagliflozin (10 mg or 25 mg) or usual care. At baseline, the average patient was aged 63 years with an HbA1c of 8% and an average diabetes duration of longer than 10 years.

Empagliflozin significantly reduced the primary composite CV outcome as well as HF hospitalizations and all-cause mortality. The primary endpoint, a composite of CV death, nonfatal MI and nonfatal stroke, was reduced by 14% (P = .04). Additionally, HF hospitalizations were reduced by 35% (P = .002) and all-cause mortality was reduced by 32% (P < .001). The reduction in the primary CV outcome was driven by a reduction in risk for CV death with no significant difference in nonfatal MI or stroke.

In June, an FDA advisory panel narrowly recommended expanding the indication for empagliflozin to include reduced incidence of CVD death (see related article, click here).

As in the DPP-IV inhibitor studies discussed above, use of medications to modify CV risk was high; aspirin, statin, and ACE inhibitor or angiotensin receptor blocker use at baseline were each reported at greater than 75%. At the end of follow-up, HbA1c was modestly lower in the empagliflozin group (< 0.4%) compared with placebo. Consistent with previous observations of the SGLT2 inhibitor class, empagliflozin treatment in EMPA-REG OUTCOME resulted in a modest reduction in BP, body weight, uric acid level, and a small increase in HDL and LDL. Although the mechanism for reduced CV outcomes and HF hospitalizations remains unclear, it is likely multifactorial with osmotic diuresis playing a role.

As previously observed with SGLT2 inhibitors, genital infections were reported more frequently with empagliflozin treatment. Other adverse events of interest (acute renal failure, diabetic ketoacidosis, fractures, urinary tract infections) occurred at similar rates between treatment groups.

Implications of findings

Findings from the SAVOR-TIMI 53, EXAMINE and TECOS trials confirm that saxagliptin, alogliptin or sitagliptin can be added to the usual management of type 2 diabetes to modestly reduce HbA1c without increasing or decreasing the risk for a CV event. The FDA has recently advised, however, that saxagliptin and alogliptin may increase the risk for HF hospitalization and recommends stopping these agents in patients who develop HF symptoms. Sitagliptin was not associated with an increased risk for HF hospitalizations.

Results from LEADER show a reduction in CV events and mortality with liraglutide. Additionally, liraglutide modestly reduced HbA1c, body weight and BP. The reduction in CV events and mortality were not observed with another GLP-1 agonist, lixisenatide, in the ELIXA trial. Considerations with the initiation of a GLP-1 agonist include administration of a subcutaneous injection and the frequency of gastrointestinal side effects.

Empagliflozin demonstrated a reduction in CV events, HF hospitalizations and mortality in EMPA-REG OUTCOME, making its inclusion in a treatment regimen for type 2 diabetes an attractive option. Appropriate patient selection will be essential to maximizing these potential benefits; factors for consideration include renal function (empagliflozin not recommended with glomerular filtration rate < 45 mL/min/1.73 m²) and evaluation of risk factors for potential adverse effects (genital or urinary infections, diabetic ketoacidosis, fractures and volume depletion). The FDA recently enhanced warnings for the SGLT2 inhibitor class regarding diabetic ketoacidosis and urinary infections.

The 2016 American Diabetes Association practice guidelines include GLP-1 agonists, DPP-IV inhibitors and SGLT2 inhibitors as possible second-line treatment options for type 2 diabetes. They are noted to provide HbA1c reduction with a low risk for hypoglycemia but a relatively high acquisition cost for patients.

Future directions of research in this area include ongoing CV outcome trials of DPP-IV inhibitors and SGLT2 inhibitors, GLP-1 receptor agonists and long-acting insulin (see Table). Additionally, SGLT2 inhibitors will be examined in HF populations (diabetic, non-diabetic, preserved and reduced ejection fraction) to determine HF outcomes and effects on left ventricular mass and function, HF biomarkers, HF symptoms and quality of life. This growing body of evidence will clarify the place in therapy for these treatments and refine future practice guidelines.

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• For more information:
• Jeff Langford, PharmD, BCPS, is from the department of pharmacy at University Health Care System. He can be reached at University Health Care System, 1350 Walton Way, Augusta, GA 30901; email: jlangford@uh.org. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 N. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.

Disclosure: Langford reports no relevant financial disclosures.