by: Lourdes Cross, PharmD, BCACP, CDE and Tanya Ralliford, PharmD Candidate 2019
Sullivan University College of Pharmacy and Health Sciences/University of Louisville Hospital, Louisville, KY
In 2015, diabetes was deemed the 7th leading cause of death in the United States.1 The American Diabetes Association (ADA) as well as the American College of Cardiology (ACC) have both formally recognized that patients with diabetes are at greater risk for cardiovascular disease (CVD). The American Heart Association states that adults with diabetes are two to four times more likely to die from heart disease than adults without diabetes.2
2019 ADA Guideline Recommendations
In the 2019 ADA Standards of Medical Care in Diabetes Guideline, metformin continues to be the preferred initial medication for the treatment of type 2 diabetes (T2DM).3 In people who have established atherosclerotic cardiovascular disease (ASCVD), sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide 1 receptor agonists (GLP-1 RA) with demonstrated cardiovascular (CV) benefit are preferred add-on agents. In people with or at high risk for heart failure (HF), SGLT2i agents with evidence of reducing HF are preferred. If unable to add a SGLT2i, it is recommended to add a GLP-1 RA with proven CV benefit.
Medications with CV Benefit
Empagliflozin (Jardiance®) and canagliflozin (Invokana®) are preferred SGLT2i agents for people with T2DM and underlying CVD.3 In the EMPA-REG OUTCOME trial, empagliflozin showed a statistically significant decrease in major adverse cardiovascular events (MACE; composite outcome of CV mortality, myocardial infarction, and nonfatal stroke; HR 0.86 [95% CI 0.74-0.99], P=0.038) compared to placebo.4 The result was primarily driven by lower CV mortality, but there was also a lower rate of death from any cause and HF hospitalizations. Results from CANVAS showed that canagliflozin also had a statistically significant reduction in MACE (HR 0.86 [95% CI 0.75-0.97], P=0.02) and HF hospitalizations.5 In adults with T2DM and established CVD, empagliflozin has an FDA-indication for risk reduction of CV mortality, whereas canagliflozin is currently approved for decreasing risk for MACE.
Although empagliflozin and canagliflozin have shown beneficial results in reducing MACE, dapagliflozin (Farxiga®) did not have similar outcomes. The DECLARE-TIMI 58 trial evaluated a larger population of people with T2DM without prior CV events compared to other studies. It did not result in a statistically significant decrease in MACE but did show a lower incidence in the composite of CV death or HF hospitalization, which was driven by a reduction in HF hospitalizations (HR 0.73 [95% CI 0.61-0.88]).
SGLT-2 inhibitors facilitate elimination of glucose in the urine, which may cause genitourinary infections and diabetic ketoacidosis (rare). This class may also decrease weight and blood pressure by sodium and water loss. The CANVAS trial showed an increased risk of bone fractures and amputations in patients on canagliflozin.5 Risk factors for amputation include history of amputation, peripheral vascular disease, neuropathy, and diabetes related foot ulcers. Other important monitoring parameters include renal function and potassium levels.
The CV benefits of GLP-1 RAs are also not a class effect. LEADER and SUSTAIN-6 are two trials that have demonstrated CV event reduction for liraglutide (Victoza®) and semaglutide (Ozempic®), respectively. In the LEADER trial, liraglutide was superior in reducing MACE (HR 0.87 [95% CI 0.78-0.97], P=0.01), which was driven by lower CV mortality.6 Similar to canagliflozin, it has an FDA-approved indication for risk reduction of MACE in adults with T2DM and established CVD. SUSTAIN-6 also showed MACE reduction with semaglutide (HR 0.74 [95% CI 0.58 to 0.95], P<0.001), which was driven by a significant decrease in strokes.7 Additionally, an oral version of semaglutide has demonstrated noninferiority of MACE compared with placebo.8 Semaglutide has not yet received FDA approval for a CV indication.
ELIXA and EXCEL did not show any statistically significant CV improvement when lixisenatide (Adlyxin®) and exenatide extended-release (Bydureon®), respectively, were compared to placebo.9,10 The REWIND trial included a majority of people without established ASCVD at baseline, a first for the GLP-1 RA trials, and showed promise for dulaglutide (Trulicity®) in preventing an initial CV event.11 The results have yet to be published.
A barrier to use of GLP-1 RAs may be gastrointestinal side effects, although they have beneficial effects on body weight loss. They must also be injected subcutaneously. This class is contraindicated in people with multiple endocrine neoplasia type 2 and a personal or family history of medullary thyroid carcinoma due to an increased incidence in thyroid C-cell tumors seen in animal studies.
Medications that Increase CV Risk
A factor to take into consideration when treating T2DM are medications that may increase risk for CV morbidity or mortality. Thiazolidinediones (TZD) and certain dipeptidyl peptidase-4 inhibitors (DPP-4i) have been identified to cause or worsen cardiovascular conditions.
Pioglitazone (Actos®) and rosiglitazone (Avandia®) have a black box warning for causing or exacerbating heart failure. TZDs are contraindicated in patients with NYHA class III or IV heart failure. Use of rosiglitazone may also be associated with an increased risk of myocardial infarction, although risks have now been largely dispelled.
Heart failure hospitalizations are a concern for saxagliptin (Onglyza®) and alogliptin (Nesina®). In SAVOR-TIMI 53, saxagliptin showed a 27% increase in HF hospitalizations compared to placebo.12 In a post-hoc analysis of the EXAMINE trial, there was increased risk of HF hospitalizations in patients taking alogliptin without a history of HF but not in those with a preexisting history.13 Sitagliptin (Januvia®) and linagliptin (Tradjenta®) have not been shown to negatively impact HF outcomes.14,15
Given that people with T2DM are at high risk for cardiovascular morbidity and mortality, health care professionals should consider therapies with proven benefit in people at risk for CV events. Table 1 summarizes the effects on CVD and factors to consider when initiating medications in people with T2DM.
Table 1. Cardiovascular Effects of Diabetes Medications
- Black Box: amputation risk (canagliflozin)
- Genitourinary infections
- Renal dose adjustment
- Volume depletion, hypotension
- Weight loss
- Black Box: thyroid C-cell tumors
- GI side effect (nausea, vomiting, diarrhea)
- Renal dose adjustment (exenatide, lixisenatide)
- Weight loss
- Possible pancreatitis risk
- Renal dose adjustment (except linagliptin)
- Possible pancreatitis risk
Potential benefit: pioglitazone
- Black Box: HF
- Fluid retention, weight gain
- Bone fracture risk
- Bladder cancer (pioglitazone)
ASCVD: atherosclerotic cardiovascular disease
CHF: congestive heart failure
*FDA-approved for CV benefit
- American Diabetes Association. Statistics about Diabetes. http://www.diabetes.org/diabetes-basics/statistics/?loc=db-slabnav. Accessed March 1, 2019.
- Association American Heart. Cardiovacular Disease and Diabetes. https://www.heart.org/en/health-topics/diabetes/why-diabetes-matters/cardiovascular-disease--diabetes. Accessed March 1, 2019.
- American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90-S102.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657.
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844.
- Novo Nordisk. Oral semaglutide demonstrates favourable cardiovascular safety profile and significant reduction in cardiovascular death and all-cause mortality in people with type 2 diabetes in the PIONEER 6 trial. https://www.novonordisk.com/media/news-details.2226789.html?rel=0. Accessed March 7, 2019.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228-1239.
- Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373(23):2247-2257.
- Lilly. Trulicity (dulaglutide) demonstrates superiority in reduction of cardiovascular events for broad range of people with type 2 diabetes. https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-demonstrates-superiority-reduction. Accessed March 7, 2019.
- Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
- White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
- Rosenstock J, Perkovic V, Johansen OE, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019;321(1):69-79.
- Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-242.