Dear Members,

   I would like to thank you for the opportunity to serve as President of VSHP. A year ago, we b egan to plan for the future, like we do every year, with a list of projects we hoped to complete. My strategy was not to accomplish them all, as I have seen many volunteer members of professional societies become overwhelmed and disengaged with extracurricular work. Rather, I hoped to accomplish 1 major project in each of the three pillars of our strategic plan (Membership, Stewardship and Leadership). Further, we chose to focus on our core P.R.I.D.E. values (Professionalism, Respect, Integrity, Diversity and Excellence) and create anew, a society that we could all call our professional home within the Commonwealth.

I believe that we have succeeded in our goal of simply making VSHP a stronger and more sustainable organization. Major initiatives such as the Commonwealth Leadership Forum (CLF), our new Vendor Relations Task Force and a redesign of the Membership Committee to focus on creating Member Services has yielded a significant amount of benefit to the Society. I believe that through the CLF, we have invigorated the leaders within the state to actively participate in VSHP. Further, the CLF can assist with the development of the leadership pipeline within the Commonwealth. The Vendor Relations Task Force, led by our Treasurer, Kim Hayes, has provided the Society with a strengthened partnership with our colleagues in Industry and allowed VSHP to prosper from that partnership. And, we have adopted the philosophy that simply calling members and asking them to join our society is not enough. We wanted to give all pharmacists in Virginia a value-based reason for joining (ex. networking, connecting, mentoring). We wanted to have focused and meaningful education and development programs that would draw new membership to us. As a result, our membership is the highest it has been in over 5 years thanks to the efforts of the Member Services Committee led by Emily Dyer.

There is still a lot of work to be done, however. This past year, we have also launched a Technician Task Force led by June Javier that began to explore the needs of our technician colleagues. I believe that the work of this task force should continue or evolve into developing focused resources designed for this sector of the profession. We launched a Resident and Student Committee, led by Rebecca Collins, which is designed to explore the burgeoning professional needs of our students and residents including ways to provide them with presentation and publication opportunities. And, we have re-established our Political Action Committee (PAC), which will be led by Lisa Hammond. The PAC provides VSHP with action to our political voice. And, the time has come for VSHP to have a strong voice backed up with powerful action.

I have been fortunate to have worked with an amazing team of volunteer leaders this past year. As I transition to Past-President, I do so knowing that the Society is STRONG and in GREAT HANDS. Thank you to Rodney Stiltner, Cindy Williams, Craig Kirkwood, Kim Hayes, Emily Dyer, June Javier, Celine Amabile (instrumental in kicking off a great year), and the leadership (Presidents and President-elects) of all the VSHP Regions for your hard work and dedication to our Society. And lastly, I would like to thank Steve Glass, Executive Director of VSHP, for his guidance and support. The man knows what he is doing.

Professionally,

Rafael Saenz
VSHP President
2016-2017

From the VSHP Historian

The records and archives of VSHP stretch back to 1955, we are fortunate that the history of the organization has been diligently saved and is now ensconced in the Virginia Historical Society. In 2016, the archives were thoroughly reviewed, indexed, and placed into archive - quality storage. These records are available to VSHP members and the public, an index of what is contained within them can be found here .

Perusing the archives has revealed many projects which VSHP has been involved in, which otherwise might never come to light. These include:

To visit the records, a visit to The Virginia Historical Society should be planned. Archives can be viewed in the reading room after providing one or two day's notice in advance. The Virginia Historical Society is located in Richmond, it is the official state historical society of the Commonwealth of Virginia.

brian.baird5@gmail.com

Cardiovascular Outcomes with Antihyperglycemic Agents

Kylie Weigel, PharmD, BCPS

PGY2 Internal Medicine Pharmacy Resident

VCU Health System

 

Cardiovascular disease (CVD), including myocardial infarction and stroke, is the leading cause of death worldwide and a significant source of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Data from the CDC, National Diabetes Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institutes of Health show that at least 68% of persons 65 years or older with diabetes die from some form of heart disease and 16% die of stroke.¹ Moreover, persons with diabetes are two to four times more likely to develop and die from CVD than those without diabetes.¹ The American Diabetes Association (ADA) considers DM to be one of the major controllable risk factors for development of CVD, and efforts directed at management of cardiovascular risk factors, such as hypertension and dyslipidemia, should be aggressively pursued to decrease cardiovascular events in diabetic patients.

Given the clear association between diabetes and adverse cardiovascular outcomes, glycemic control would appear important to decreasing cardiovascular risk. In fact, there is estimated to be an 11-16% increase in cardiovascular events for every 1% increase in hemoglobin A1c (HbA1c).² Several studies have examined the impact of intensive glucose control on the risk of cardiovascular complications of diabetes with mixed results. The first study to show benefit from control of hyperglycemia was the United Kingdom Prospective Diabetes Study (UKPDS). In this study, newly diagnosed patients with T2DM were randomized to receive intensive glycemic control with a sulfonylurea or insulin compared to diet alone. After a median follow-up of 10 years, intensive glycemic control to a median HbA1c of 7.0% with therapy versus diet to a median HbA1c of 7.9% was associated with a 25% reduction in microvascular complications without reduction in macrovascular complications.³ The 10-year follow-up of the UKPDS study, however, observed significant reductions in risk of myocardial infarction (MI) (15%, P=0.01) and death from any cause (13%, P=0.007).⁴

Other studies evaluating the effects of glycemic control on macrovascular complications include the Action in Diabetes and Vascular Disease (ADVANCE), the Action to Control Cardiovascular Risk in Diabetes (ACCORD), and the Veterans Affairs Diabetes Trial (VADT). In ADVANCE, intensive glucose control with the use of a sulfonylurea in combination with other therapies to achieve an HbA1c of 6.5% or less was compared to standard therapies. Intensive control resulted in a 10% reduction (HR 0.90, 95% CI 0.82-0.98) in incidence of combined major macrovascular and microvascular events due largely to a reduction in the incidence of nephropathy (HR 0.79, 95% CI 0.66-0.93). Reduction in macrovascular events alone was not evident.⁵ VADT included veterans with poorly controlled T2DM, some of which had a history of a cardiovascular event (40%), and compared a target absolute reduction in baseline HbA1c by 1.5% in the intensive arm with standard care. No significant effect on major cardiovascular event rates, death, or microvascular complications was found (HR 0.88, 95% CI 0.74-1.05).⁶ Lastly, the ACCORD trial sought to compare intensive (target HbA1c of <6.0%) or standard therapy (target HbA1c 7.0-7.9%) in 10,251 patients with T2DM. After a median follow-up of 3.5 years, the trial was discontinued early due to the finding of higher mortality (HR 1.22, 95% CI 1.01-1.46) in the intensive therapy group. The primary endpoint at this time, a composite of non-fatal MI, non-fatal stroke, or death from cardiovascular causes, had occurred at similar rates in both groups and was not statistically different (HR 0.90, 95% CI 0.78-1.04).⁷

When taken together, the results of these trials fail to show a clear benefit of intensive glucose control on the risk of cardiovascular events in T2DM. These effects, however, may have been attenuated by reported limitations of these studies such as good glycemic control in standard therapy groups, aggressive regimens associated with risk of hypoglycemia, and inclusion of persons with long-standing diabetes and possible advanced damage.⁸ Additionally, these trials included antihyperglycemic regimens heavily reliant upon insulin, sulfonylureas, and metformin, leaving the cardiovascular effects of other antihyperglycemic agents largely unknown.

The Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 requiring the assessment of the cardiovascular safety of all new antihyperglycemic drugs prior to approval for use. This guidance came in the wake of results of a 2007 meta-analysis, which revealed concerns for adverse cardiovascular effects, namely increased rates of MI and cardiovascular death, with the thiazolidinedione rosiglitazone. The resultant cardiovascular outcomes trialwhich did not show an increased risk of cardiovascular hospitalization or mortality, lead to the lifting of several restrictions imposed by the FDA surrounding use of rosiglitazone despite an observed increased risk of heart failure found in the trial. FDA. This CV risk was not the same across all thiazolidinediones. Notably, the PROactive study, assessing the cardiovascular effects of pioglitazone in high-risk patients with T2DM found no difference in the composite endpoint of all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle when compared to placebo but did find a significant difference in the secondary endpoint of all-cause mortality, non-fatal MI, and stroke favoring pioglitazone.¹¹ The FDA guidance has remained in effect and results from studies evaluating the use of newer antihyperglycemic agents such as glucagon-like peptide (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-4) inhibitors, and sodium-glucose co-transporter (SGLT-2) inhibitors have recently been published.

SGLT-2 inhibitors lower blood glucose through an insulin-independent mechanism whereby inhibition of sodium-glucose co-transport in the proximal renal tubule results in increased urinary excretion of glucose. These agents are approved for use in type 2 diabetes and include canagliflozin, dapagliflozin, and empagliflozin. On average, studies have found that SGLT-2 inhibitors lower HbA1c by 0.5-0.7%.¹² Additionally, these agents are known to lower blood pressure (1.6 to 9 mmHg reduction in systolic blood pressure) without increases in heart rate, increase HDL (0.8 to 8.4%) and LDL (4.5 to 8.5%), and decrease weight (1.9 to 3.6 kg) compared to placebo.¹³

Cardiovascular effects and safety of SGLT-2 inhibitors are currently being established through cardiovascular outcomes trial as mandated by the FDA guidance for industry. The EMPA-REG OUTCOME trial examined the effects of empagliflozin on cardiovascular morbidity and mortality compared to placebo in patients with type 2 diabetes at high risk for cardiovascular events. The trial enrolled 7,020 patients with established CVD and a HbA1c of 7-9% on no glucose lowering therapy or HbA1c of 7-10% on a stable glucose lowering regimen. Participants were randomized to receive empagliflozin 10mg, 25mg or placebo in addition to standard care and were followed for a median observation time of 3.1 years. The primary composite outcome of death from CV causes, non-fatal MI, or non-fatal stroke occurred in 490/4687 (10.5%) patients in patients treated with either dose of empagliflozin and 282/2333 (12.1%) patients treated with placebo (HR 0.86, 95% CI 0.74-0.99). Results of this outcome were driven mainly by a significant reduction in death from cardiovascular causes (HR 0.62, 95% CI 0.49-0.77) with no significant difference between groups in rates of non-fatal MI or stroke. Adverse effects seen in this trial were similar between empagliflozin and placebo groups with a higher rate of genital infection identified in patients treated with empagliflozin but notably no difference in rates of acute renal failure, acute kidney injury, hypoglycemia, or diabetic ketoacidosis.¹⁴ Similar cardiovascular outcomes trial are underway for canagliflozin and dapagliflozin (canagliflozin cardiovascular assessment study [CANVAS] and dapagliflozin effect on cardiovascular events [DECLARE-TIMI58]) and will be needed to determine if the cardiovascular benefit seen with emapagliflozin is a class effect.

            Other studies examining cardiovascular outcomes with newer antihyperglycemic agents such as DPP-4 inhibitors have been less fruitful. The cardiovascular effects and safety of saxagliptin was evaluated in the SAVOR-TIMI 53 trial which found no difference in comparison to placebo in the composite endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke (HR 1.00, P=0.99) and a small increase in the risk of admission for heart failure (HR 1.27, P=0.007).¹⁵ Similar results were seen in cardiovascular outcomes trials with sitagliptin (TECOS) and alogliptin (EXAMINE) where rates of adverse cardiovascular events were not increased with DPP-4 therapy.^16,17 The GLP-1 receptor agonist, lixisenatide, was also found to have neutral cardiovascular effects on patients with type 2 diabetes and acute coronary syndromes.¹⁸

            The most recent cardiovascular outcomes trial to be completed is the Liraglutide Effect on Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. Patients with HbA1c of 7.0% previously untreated or treated with oral antihyperglycemics or insulin, alone or in combination, were eligible for inclusion if they possessed at least one cardiovascular risk factor or coexisting condition. A total of 9,340 participants were randomized to receive liraglutide 1.8mg daily or placebo and were followed for a median of 3.8 years. The primary composite outcome of time to first occurrence of death from cardiovascular causes, non-fatal MI, or non-fatal stroke occurred in 608/4668 (13.0%) of patients in the liraglutide group compared to 694/4672 (14.9%) of patients in the placebo group (HR 0.87, 95% CI 0.78-0.97). This was mostly driven by a reduction in death from cardiovascular causes in the liraglutide group (4.7% vs. 6.0%, P=0.007). Rates of adverse events and serious adverse events were not different between groups but more patients in the liraglutide group experienced adverse events leading to permanent discontinuation of the trial regimen.¹⁹

            The 2017 ADA Standards of Care have been updated to reflect the results of these major cardiovascular outcomes trials. The recommendation for pharmacologic treatment is to consider use of empagliflozin or liraglutide in addition of standard care in patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic CVD to reduce CV and all-cause mortality.²⁰ The CVD and risk management section has been updated to include these results as well. Additionally, the FDA recently added reduction of risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease as a new indication for use of empagliflozin. Ultimately, it will be the responsibility of the providers to determine appropriate use of these agents in patients with type 2 diabetes and concomitant cardiovascular disease, taking into account patient specific factors and comorbidities.

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