Many chronic conditions affect patient’s overall health. These can have an impact on the patient’s quality of life and are

often interrelated, one chronic condition aggravating the other. An example of this is the relationship between obesity,

diabetes and cardiovascular risks.

People who are overweight or obese have more risk factors for Cardiovascular Disease (CVD), and are at higher risk of

developing Hypertension (HTN), Coronary Artery Disease (CAD), Heart Failure (HF), Atrial fibrillation (AF or A-fib) and

Diabetes (DM), often developing insulin resistance as both obesity and diabetes progress.

Cardiovascular Disease

Risk Factors High blood pressure, high low-

density lipoprotein (LDL) cholesterol

and smoking are key heart disease

risk factors for cardiovascular

disease. There are several other

medical conditions and lifestyle

choices that can also put people at

a higher risk for cardiovascular

disease, including:

– Diabetes

– Overweight and obesity

– Poor diet

– Physical inactivity

– Excessive alcohol use

– Family history

– Genetic predisposition

– Environmental and behavioral

Obesity Risk Factors Obesity usually results from a combination of causes and contributing factors, including:

– Genetics: familial tendency

– Family lifestyle

– Environmental and behavioral

– Sex: women more susceptible

– Inactivity

– Unhealthy diet

– Medical problems

– Certain medications (e.g. antidepressants, anti-

seizure medications, diabetes medications,

antipsychotic medications, steroids and beta

blockers)

– Psychogenic: emotional deprivation/depression

– Alcohol: problem drinking

– Social and economic issues

– Age (obesity can occur at any age, even in young

children. But as people age, hormonal changes and

a less active lifestyle increase the risk of obesity)

– Pregnancy

– Quitting smoking

– Lack of sleep

Risk enhancing factors of cardiovascular disease established in the 2019 ACC/AHA Guideline take into account family

history of premature atherosclerotic cardiovascular disease (ASCVD), primary hypercholesterolemia, metabolic syndrome,

chronic kidney disease and chronic inflammatory conditions. A history of premature menopause (before age 40 y) and

Obesity, Diabetes and Cardiovascular Risk

Common Medical Conditions – Latest Trends

Figure 1. Mechanisms by which Obesity Augments Cardiovascular Risk 1

October 2019 | Page 2

history of pregnancy-associated conditions that increase later ASCVD risk, such as preeclampsia can also predispose

women to having cardiovascular disease. Other patient specific factors such as ethnicity, lipids/biomarkers (elevated high-

sensitivity C-reactive protein (≥2.0 mg/L), elevated lipoprotein (a) (≥50 mg/dL or ≥125 nmol/L), elevated apolipoprotein B

(apoB) (≥130 mg/dL), and Ankle-Brachial Index (ABI) (<0.9)) can increase the risk as well.

Protective Factors Related to Lifestyles in the Management of Cardiovascular

Disease and Obesity Dietary and lifestyle modifications should be the initial approach in the majority of patients, with pharmacologic and

surgical therapy considered in selected patients. The American Heart

Association has proposed improving overall cardiovascular health by

promoting 7 components of ideal cardiovascular health, including health

behaviors (not smoking, regular exercise, and healthy diet) and health

factors (ideal body mass index, cholesterol, blood pressure, and blood

glucose)2.

Weight loss can improve or prevent many of the obesity-related risk factors for cardiovascular disease. Benefits include:

– Decreased blood pressure in hypertensive patients – Decreased incidence of diabetes mellitus – Improved lipid profile – Decreased insulin resistance – Reduced C-reactive protein concentration – Improved endothelial function

Diabetes Background Information and Statistics Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in the secretion of insulin, insulin action or both. The most common types of DM are: type 1 diabetes mellitus, type 2 diabetes mellitus (90-95% of total cases), and gestational diabetes mellitus. Several factors can contribute to the development of type 1 diabetes, such as genetics and certain viruses. Type 2 diabetes is a serious chronic disease, and commonly the result complex interaction between inheritance and the environment, along with other risk factors.

The prevalence of diabetes has increased over time, and has been the third leading cause of death in Puerto Rico for more than two decades. According to a survey conducted by the Puerto Rico Health Insurance Administration (ASES), the prevalence of diabetes in Puerto Rico has increased from 10.8% in 1996 to 17.2% in 2017. These statistics represent approximately 474,000 adults 18 years of age or older, of which 65.4% have a regular or poor state of health. This represented a total cost of use for these patients of $429,375,885.72.

According to the most up-to-date data from the Division of Disease Prevention and Control Chronicles of the Department of Health provided by the Puerto Rican Diabetes Association (APD), the age-adjusted rate of diabetes mortality is 71.9 deaths per 100,000 inhabitants. Also, as reported by ADP, the municipalities with the highest prevalence of diabetes are: Culebra (20.6%), Adjuntas (19.4%), Vieques (18.4%), Las Marías (17.4%), Arroyo (17.0%), Maricao (17.0%), Lajas (16.9%) and Guánica (16.6%). In contrast to the U.S. population, 30.3 million people have diabetes (23.1 million diagnosed); representing 9.4% of the U.S. population with a range of 3.8% to 20.8%. Among people of Hispanic

October 2019 | Page 3

ethnicity, Mexicans had the highest prevalence (13.8%), followed by Puerto Ricans (12.0%), Cubans (9.0%) and Central or South American (8.5%).

Diabetes Treatment Options in accordance to Guidelines and other

considerations Both type 1 and type 2 DM can be treated with insulin. Generally, insulin requirements can be estimated based on weight, with an initial dosing strategy ranging from 0.4 to 1.0 units/kg/day. Higher amounts are required in puberty, pregnancy and illness. For type 2 DM it used to be counseled to hold off on the use of insulin as much as possible; this is no longer the case. The early introduction of insulin should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C levels (>10% [86 mmol/mol]) or blood glucose levels (≥300 mg/dL [16.7 mmol/L]) are very high. Studies have found that the introduction of insulin early-on allows for faster improvement in patients with high A1C and the possibility of discontinuing its use if patient is able to control his condition.

Type 2 Diabetes Mellitus (T2DM) The treatment approach to T2DM should begin with an assessment of cardiovascular disease (CVD) status, other comorbidities such as Chronic kidney disease (CKD) and Heart Failure (HF), and patient preferences, according to a 2018 joint consensus statement from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) presented on October 5, 2018 at the EASD Annual Meeting in Berlin and published in Diabetes Care and Diabetologia. Major changes were made in type 2 diabetes management where the approach is patient centered, expecting that people must assume an active role in their care. The goals of treating diabetes are to prevent or delay complications and maintain quality of life. Treatment plans for meeting these goals should be created integrating patients. The evidence obtained from the latest cardiovascular outcomes studies (since 2014) was an important tool to develop all these new recommendations.

First Step: Assess Cardiovascular

Status (ASCVD) and other

Comorbidities:

For Patients with Heart Failure and Chronic

Kidney Disease In general, the ADA/EASD document advises assessment

of cardiovascular status as the first step in determining

treatment approach. ADA will also address patients with

atherosclerotic cardiovascular disease (ASCVD) and those

with HF or CKD.

Lifestyle modification and metformin are still considered the cornerstones of treatment because of low cost and proven safety and efficacy. The presence of comorbidities is now a compelling indication for the selection of certain glucose-lowering drugs. If hemoglobin A1C is still above target, then physicians should proceed as below:

– For patients in whom ASCVD predominates, a GLP-1 receptor agonist with proven CVD benefit or a SGLT2 inhibitor with proven CVD benefit (provided the patient has adequate kidney function) are recommended, in that order.

– In patients for whom HF predominates: listed first is an SGLT2 inhibitor with evidence of reducing HF and/or CKD progression in a CV outcomes trial (if the patient has adequate kidney function), or a GLP-1 receptor agonist with proven CVD benefit as an alternative option.

October 2019 | Page 4

Within the classes, preference is given to liraglutide (Victoza®) among GLP-1 receptor agonists, based on the LEADER trial, and empagliflozin (Jardiance®) among SGLT2 inhibitors, based on EMPA-REG OUTCOME trial.

For Patients without CVD, HF or CKD Focus on Other Individual Factors For patients without ASCVD, HF or CKD the next priority is to focus on the individual patient's needs and preferences for avoiding weight gain and hypoglycemia. The document provides guidance for specific agents by therapeutic class: DPP4 inhibitors, thiazolidenidiones (TZDs), GLP-1 receptor agonists and SGLT 2 inhibitors. Other sections incorporate new information about medical nutrition therapy, metabolic surgery, initiation of injectables — with a new preference for GLP-1 receptor agonists over insulin — and advice about down-titrating patients from oral medications once injectables are started.

Cost of medications are also being addressed, with the acknowledgement that it may still be necessary to prescribe sulfonylureas, TZDs, or older insulins if that's all the patient can afford (see next table).

Newer Antihyperglycemic Drugs

Sodium Glucose Co-Transporters 2 (SGLT-2) Inhibitors – Mechanism of Action - SGLT2 is the predominant transporter responsible for reabsorption of glucose from the

glomerular filtrate back into the circulation. By inhibiting SGLT2, these agents reduce renal reabsorption of filtered

glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion, glycosuria.

October 2019 | Page 5

– There are currently four molecular

entities of SGLT-2 inhibitor products

approved by the FDA for the treatment of

type 2 diabetes either as monotherapy or in

combination with other glucose lowering

drug classes: canagliflozin (Invokana®),

dapagliflozin (Farxiga®), empagliflozin

(Jardiance®) and ertugliflozin (Steglatro®).

All agents are also available in one tablet

combined with metformin:

Invokamet®/Invokamet® XR, Xigduo® XR,

Synjardy® and Segluromet®. Combinations

with DPP4 inhibitors also available in the

market are Qtern®, Glyxambi® and

Steglujan®.

– CV outcomes studies have demonstrated the benefit of using SGLT-2 inhibitors in lowering the risk of cardiovascular

disease in patients with established ASCVD, and their use was recently supported by ADA, EASD, AACE and ACE.

– Adverse events among the SGLT-2 Inhibitors include urinary tract infections and female genital mycotic infections.

During the CV studies, the safety profile for this class of medications was similar except for Invokana®, which

exhibited an increased rate of amputations and fractures in patients with Type 2 Diabetes.

– Invokana® and Jardiance® are the only SGLT-2 inhibitors approved by the FDA to reduce the risk of

cardiovascular disease. Based on the recent publication of the DECLARE-TIMI trial results, it is expected that

dapaglifozin’s indication will be updated to include its use for cardiovascular disease risk reduction during this year.

The Dosage and Administration section of its package insert was updated in February 2019 to require renal function

of each patient prior to initiating treatment with the agent. The use of Farxiga® is not recommended when the

glomerular filtration rate (eGFR) is less than 45 mL/min/1.73 m2.

GLP-1 Receptor Agonists – Mechanism of Action - GLP-1 Receptor agonists activate the GLP-1 receptor, a membrane-bound cell-surface

receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. GLP 1 agonist

increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose

concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.

The mechanism of blood glucose lowering also involves a delay in gastric emptying. Among other effects that GLP-1

have on the body, specifically in the central nervous system, GLP-1 induces satiety, leading to reduced weight gain.

– There are currently five molecular entities of GLP-1 Receptor agonists approved by the FDA: dulaglutide

(Trulicity®), exenatide immediate and extended release (Byetta® and Bydureon®), liraglutide (Victoza®), lixisenatide

(Adlyxin®) and semaglutide (Ozempic®). Liraglutide and lixisenatide are also available in combination with insulin

degludec (Xultophy®) and glargine (Soliqua®). Albiglutide (Tanzeum®) is not available since May 2018.

– All are indicated as adjunct to diet and exercise to improve glycemic control in adults with Type 2 Diabetes.

Liraglutide also has indication to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-

fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular

disease.

– GLP-1 Receptor Agonists target Type 2 Diabetes with positive effects on both alpha and beta cell dysfunction and

provide improvements in HbA1c with a relatively low risk of hypoglycemia accompanied by a weight loss.

October 2019 | Page 6

– There are some clinical relevant differences between the compounds. Thus, the continuous-acting GLP-1R

agonists seem to be preferable if a great reduction in HbA1c is of primary concern and when frequent administration

and daily timing of injections are undesirable for the patient. While short-acting seem preferable if PPG excursions

are the major problem.

Utilization Data – Utilization of antidiabetics during 2018 shows that metformin is the most utilized of oral agents, followed by SU and

DPP4 inhibitors alone and in combination with metformin, in that order (see graph no.1). This pattern follows current guidelines, where metformin is still the first line of treatment.

– SU accounts for 24% of utilization under Vital, showing the impact that cost considerations has on clinicians’ decisions.

– Insulins account for 29% of utilization and Humulin is the most prescribed. It is important to note that Lantus also has a significant number of prescriptions, 10% of total utilization.

– Utilization shows a small number of patients using GLP-1's and SGLT-2's approved by health plans in 2018 through the exceptions process.

Graph No.2 Antidiabetics Paid Amount by Therapeutic Class

Graph No.1 Antidiabetics Prescriptions by Therapeutic Class

October 2019 | Page 7

Last year, drug spend on Diabetes Mellitus treatment in Vital was $131,659,417 with Humulin (32%) - being the highest spend - followed by Lantus (31%) and Humalog (20%), in that order (see Graph No.2, above). Antihyperglycemic oral agents, most of them generic available, accounted for the remaining 17% of spend.

Diabetes Management Key points Overall, the guidelines strongly emphasizes that all treatment decisions be made in collaboration with the patient: Put Patient at the Center of the Treatment Decision.

The patient is at the center of everything… Hence, clinicians should assess key patient characteristics and consider specific factors that will impact choice of treatment, and then come to shared decision making to create a management plan. It is very important that the patient agrees on this plan, and that this plan is revised as the life of the patient progresses.

The choice of second-line glucose-lowering agents after metformin will be driven by new evidence from cardiovascular outcomes trials and by areas of medical need, including weight reduction and avoidance of hypoglycemia. And for injectables, glucagon-like peptide (GLP)-1 agonists are preferred over insulin. CKD is now included for assessment, and cost is also an issue to consider. Guidelines reconfirm the choice of metformin as a first-line treatment for most patients with type 2 diabetes.

The use of insulin is key in both T1DM and T2DM. Understanding insulin dosing principles and matching them to the patients’ needs will be essential in the successful management of Diabetes.

References 1. Medicine Today. November 2015, Volume 16, Number 11 https://medicinetoday.com.au/sites/default/files/cpd/MT2015-11-034-PARATZ.pdf

2. American College of Cardiology Foundation and the American Heart Association, Inc. (2019, March 20). 2019 ACC/AHA Guideline on the

Primary Prevention of Cardiovascular Disease. Retrieved from A Report of the American College of Cardiology/American Heart Association

Task Force on Clinical Practice Guidelines: https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000678

3. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW,

MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD,

Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and

management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on

Clinical Practice Guidelines. Hypertension. 2017;00:e0000–e0000.

4. http://www.salud.pr.gov/Estadisticas-Registros-y-Publicaciones/Estadisticas%20Vitales/Informe%20de%20la%20Salud%20en%20Puerto%20Rico%202016.pdf

5. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.

6. American Diabetes Association Diabetes Care 2018 Jan; 41(Supplement 1): S73-S85. https://doi.org/10.2337/dc18-S008 7. American Diabetes Association Diabetes Care 2019 Jan; 42(Supplement 1): S90-S102. https://doi.org/10.2337/dc19-S009

Drug Information Center 1.877.741.7470

All treatment decisions

should be made in

collaboration with the

patient.

Put patient at the

Center of the

Treatment Decision.