The 10^th Annual Cardiometabolic Health Congress General Session Highlights

KEYWORDS:

• Cardiometabolic
• type 2 diabetes
• heart failure
• dyslipidemia
• hypertension
• obesity
• preventative
• risk
• PCSK9
• antithrombotic

From October 21 through 24, 2015, the Cardiometabolic Health Congress (CMHC) held its 10^th annual meeting at the Sheraton Boston Hotel. The Congress convenes each year to address the needs of patients with diabetes, dyslipidemia, hypertension, and obesity, offering the largest multidisciplinary conference addressing the prevention, diagnosis, and management of cardiometabolic diseases in the United States.

The Congress agenda for the 4-day conference featured a variety of educational events, including keynote addresses, general sessions, workshops, symposia, and exhibits. The scientific sessions featured presentations by many of the world’s leading experts in cardiology, endocrinology, nutritional science, and obesity, including several medical scientists who have conducted original research in cardiometabolic disease and preventive medicine. The program for the Congress is available at http://www.cardiometabolichealth.org/2015/agenda.html.

The 2015 CMHC Co-Chairs were as follows:

George L. Bakris, MD, Professor of Medicine, Director, ASH Comprehensive Hypertension Center, University of Chicago Medicine, Pritzker School of Medicine, Chicago, IL

Christie M. Ballantyne, MD, Professor of Medicine, Chief, Section of Cardiovascular Research, Chief, Section of Cardiology, Department of Medicine, Baylor College of Medicine, Director, Center for Cardiovascular Disease Prevention, Baylor College of Medicine, Methodist DeBakey Heart Center, Houston, TX

Robert H. Eckel, MD, Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Cardiology, Professor of Physiology and Biophysics, Charles A. Boettcher II Chair in Atherosclerosis, Director, Discovery Translation Colorado Clinical & Translational Science Institute, University of Colorado Anschutz Medical Campus, Director, Lipid Clinic, University Hospital, Aurora, CO

Jay S. Skyler, MD, MACP, Professor of Medicine, Pediatrics, & Psychology, Division of Endocrinology, Diabetes & Metabolism, University of Miami Miller School of Medicine, Deputy Director for Clinical & Academic Programs, Diabetes Research Institute, Miami, FL

Thursday, 22 October 2015
Session I: Dyslipidemia, Atherosclerosis and Cardiovascular Disease Risk Reduction

Keynote Presentation

Genetics to Therapeutics: The Role of PCSK9

Jay D. Horton, MD

Hyperlipidemia remains a major contributor to coronary artery disease in the United States, and although statin therapy has had a significant impact on lipid levels, many patients do not respond to statins. Jay D. Horton, MD, has performed seminal research on PCSK9, the gene responsible for the synthesis of proprotein convertase subtilisin/kexin-type 9 serine protease, which plays a role in the regulation of the LDL receptor. His keynote presentation focused on the rapid progression from the initial discovery of the protease to the development of a therapeutic agent.

PCSK9 was discovered in 2003, which eventually led to animal studies in which Dr. Horton and his colleagues found that when PCSK9 was deleted, LDL receptor levels increased and plasma LDL-C declined. Between 2010 and 2015, human trials revealed that patients with loss-of-function mutations in PCSK9 had significantly lower plasma LDL-C.[1] Human studies also documented that loss-of-function mutations in PCSK9 can result in an 88% reduction in cardiovascular events.[2]

Subsequent research demonstrated that the circulating protease binds directly to the LDL receptor on the cell surface, which opened up the possibility of finding agents that inhibit the interaction between the PCSK9 protease and the LDL receptor. Clinical trials demonstrated that two FDA-approved PCSK9 monoclonal antibodies—alirocumab and evolocumab—were effective in lowering LDL-C by approximately 60%.[3] Bococizumab, a third PCSK9 inhibitor, is currently in development.

In light of the fact that 65% of patients with hypercholesterolemia do not reach their LDL-C goals and about 10% of patients cannot tolerate statins,[4,5] Dr. Horton emphasized the need for clinicians to have additional LDL-C-lowering agents in the armamentarium. PCSK9 inhibitors are viable options to fill that need.

Triglycerides & HDL: Where Are We Now and What’s on the Horizon?

Henry N. Ginsberg, MD

Several studies, including the Framingham Heart Study,[6] have found that elevated triglyceride levels are a risk factor for cardiovascular disease (CVD). Similarly, a meta-analysis of 17 studies found that triglyceride levels are an independent CVD risk factor.[7]

In statin trials, baseline triglyceride levels have predicted CVD outcomes regardless of whether a patient was in the placebo or statin cohort. Evidence to support the theory that triglyceride-rich lipoproteins are atherogenic comes from analysis of animal and human coronary lesions.

Among the therapeutic agents available to lower serum triglycerides are fibrates, including gemfibrozil, bezafibrate, and fenofibrate. In trials incorporating these agents, CVD was reduced by 27–78%.[8,9] Several trials have also found that fish oils can lower serum triglyceride levels and improve CVD outcomes.[10]

On the HDL horizon, some recent studies suggest this lipoprotein is not protective against CVD. On a similar note, recent studies designed to raise HDL with cholesteryl ester transfer protein inhibitors have proven unsuccessful. A trial of dalcetrapib, for example, increased HDL by 30% but was stopped because of futility; a clinical trial testing the value of torcetrapib was stopped because of increased mortality. Clinical study of evacetrapib was also halted recently. Anacetrapib, however, is currently in development as clinical trials have found more than a 100% increase in HDL, and a 35% reduction in LDL.[11]

Clinical research has demonstrated that hypertriglyceridemia significantly increases the risk of CVD,[7] but research to date is unclear about the utility of HDL as a marker for CVD health.

IMPROVE-IT: How Do We Go Forward with the Guidelines?

Moderator: Christie M. Ballantyne, MD

Discussants: Jennifer G. Robinson, MD, MPH; Roger S. Blumenthal, MD

Experts continue to debate the 2013 ACC/AHA cholesterol guidelines [12] and how to apply them in clinical practice. This session featured two respected authorities on the topic, who presented alternative views.

Jennifer Robinson, MD, MPH, pointed out that the guidelines moved away from LDL-C goals outlined in the ATP III guidelines and recommended initiating statin therapy based on patients’ risk, including the presence of clinical atherosclerotic cardiovascular disease (ASCVD), LDL-C levels at or above 190 mg/dL, and diabetes in patients 40–75 years of age. Replacing LDL-C goals with the risk-based approach will result in the prevention of 450,000 more ASCVD events over a 10-year period.

Roger Blumenthal, MD, on the other hand, drew attention to some of the controversial aspects of the ACC/AHA guidelines. One of the issues that clinicians contend with is the difficulty of assessing the percent reduction in LDL-C. Patients’ LDL levels may be falsely low when they present at a hospital with a myocardial infarction so it is not always possible to know if a 50% LDL-C reduction has been achieved over time.

Dr. Blumenthal also made the case for having goals for managing hypercholesterolemia, stating that in the management of hypertension and diabetes, there are target goals; why not targets for the treatment of hypercholesterolemia?

Integrating Biomarkers and Imaging for CV Risk Assessment and Treatment

Matthew J. Budoff, MD

Dr. Budoff’s take-home message in this presentation was summed up in his opening slide: ‘We can improve preventive screening.’ CVD screening is moving beyond traditional algorithms, which can overestimate cardiovascular risk. Measurement of carotid intima-media thickness (CIMT) is one option. The 2013 ACC/AHA guidelines state, however, that the addition of CIMT in the Framingham risk score was associated with a small improvement in risk prediction but is unlikely to be of clinical importance.[12] Advanced blood pressure cuffs, however, which take into account central blood pressure rather than brachial pressure, have merit because the risk of CVD increases by nearly 70% when central pulse pressure equals or exceeds 50 mmHg. In individuals <60 years, the increase in CVD is 150%.[13]

Highly sensitive troponin I, another preventive biomarker, is associated with a 7.7-fold increased risk of a major cardiovascular event while coronary artery calcium (CAC) score, a measure of early atherosclerosis, has been shown to predict long-term prognosis.[14] A patient has a 10.4-fold increased risk of a cardiac event if CAC score is elevated. In the Multi-Ethnic Study of Atherosclerosis study, a CAC score above 100 was associated with more than a 7.5% 10-year ASCVD risk.[15]

Although CIMT remains of questionable importance in clinical practice, research suggests that highly sensitive troponin I and CAC can be of value in identifying high-risk patients.[16]

Clinical Controversies in Lipid Management: Case-Based Presentations & Discussion

Moderator: Christie M. Ballantyne, MD

Presenters & Discussants: Roger S. Blumenthal, MD; Robert H. Eckel, MD; Henry N. Ginsberg, MD; Jennifer G. Robinson, MD, MPH

This expert panel reviewed several case studies that illustrated the need to better manage cardiometabolic disorders. For example, the group discussed the case of a 57-year-old male with diabetes, metabolic syndrome, and familial hypercholesterolemia. Details included the following:

• Age 50

• LDL 195 mg/dL

• MI 5 years ago, taking aspirin and clopidogrel

After starting 80 mg of atorvastatin, the patient’s readings were as follows:

• LDL 87 mg/dL

• HDL 40 mg/dL

• Triglycerides 152 mg/dL

• Fasting glucose 115 mg/dL

If this were your patient, what would you do next? The expert panel recommended that the following be done:

• Increase physical activity.

• Increase intake of fruits, vegetables, whole grain foods, and fish.

What type of pharmacological therapy would be appropriate?

• Based on the results of the IMPROVE-IT trial, it would be reasonable to add ezetimibe to the patient’s regimen.

• A PCSK9 inhibitor may also be worth considering but the cost of these new agents as well as patient preferences have to be considered.

• Niacin is not indicated for this patient.

In summary, the panel emphasized that ‘IMPROVE-IT [17] provides us with important information on the value of lowering LDL-C levels, regardless of the agent used. These data help emphasize the primacy of LDL-C lowering as a strategy to prevent CHD.’

Expert Debates in Antithrombotic Therapy

Moderator: Deepak L. Bhatt, MD, MPH

Presenters & Discussants: John Eikelboom, MBBS, MSc; A. Michael Lincoff, MD

One of the controversies in cardiometabolic disease management centers around whether dual anti-platelet therapy (DAPT), which combines aspirin with a P2Y12 inhibitor such as ticagrelor, should be continued indefinitely after MI. A meta-analysis, which evaluated extended DAPT following MI compared to 1 year of therapy, found a reduction in ischemic events.[18]

However, individual studies provide no evidence of a net benefit of extended DAPT. Meta-analyses of post-MI subgroups show no evidence of a reduction in total mortality, and long-term DAPT post-MI prevents recurrent MI and stent thrombosis but causes more bleeding and does not reduce mortality.

A second controversy focuses on whether anticoagulants should play a role in CAD. Some experts maintain they benefit CAD patients; the benefits of anticoagulation remain evident when used on a background of DAPT and other effective secondary prevention. The contrary position hinges in part on a trial of apixaban given after acute coronary syndrome that was stopped prematurely due to excessive bleeding without counterbalancing reduction in ischemic events.[19] A trial of rivaroxaban did reduce cardiovascular deaths, MIs, and ischemic stroke, but there was significant bleeding in these patients as well.[20]

The current guidelines recommend DAPT be stopped 12 months after an MI but an analysis of several trials suggest otherwise, concluding that it is accompanied by about a 1.7-fold increased risk of bleeding. Similarly, there is conflicting evidence to allow clinicians to reach a definitive conclusion on whether the benefits of anticoagulants in reducing cardiovascular events are outweighed by the significant bleeding risk.

Late-Breaking Clinical Trials and FDA Update

Presenters & Discussants: Christie M. Ballantyne, MD; Deepak L. Bhatt, MD, MPH; Robert H. Eckel, MD; Keith C. Ferdinand, MD; Jay S. Skyler, MD

In 2015, there were many exciting developments that are relevant to the field of cardiometabolic health. Dr. Skyler pointed out that the Trial Evaluating Cardiovascular Outcomes with Sitagliptin demonstrated that the drug had no harmful impact on cardiac mortality, non-fatal MI, nonfatal stroke (major adverse cardiac event [MACE]), and hospitalization for unstable angina, while also posing no cardiovascular risk to diabetic patients.[21] Similarly, the Evaluation of LIXisenatide in ACS study found that the GLP-1 agent does not increase the risk of cardiac mortality, non-fatal MI, non-fatal stroke, MACE, and hospitalization for unstable angina, demonstrating no increased cardiovascular risk.[22]

Dr. Eckel discussed new developments in obesity management, explaining that a recent clinical trial that compared bariatric-metabolic surgery to conventional medical treatment in obese patients with type 2 diabetes found that after 5 years, Roux-en-Y gastric bypass and biliopancreatic diversion reduced body weight substantially when compared to medical treatment. Half of the patients who underwent bariatric-metabolic surgery were also free of diabetes symptoms after 5 years.[23]

Dr. Bhatt discussed the CHARISMA and PEGASUS trials and recent FDA approvals, which demonstrated that dual antiplatelet therapy is indicated for at least 1 year after acute coronary syndrome. The CHARISMA subgroup data also suggest that there is a likely benefit for this type of treatment for at least 1 year in patients with a prior MI.[24,25]

Dr. Ballantyne reviewed the FDA approvals of the PCSK9 inhibitors alirocumab and evolocumab for the treatment of heterozygous FH or clinical ASCVD in adults who require additional lowering of LDL-C. Evolocumab is also approved for homozygous FH. Both therapies have shown reductions in LDL-C of approximately 60% in the OSLER and ODYSSEY Long-Term trials.[3,26] Results from CVD outcomes trials are expected in 2017. Programs evaluating antisense inhibitors of ApoCIII and Lp(a) have also shown promise.[27,28]

These and several other published research studies provide new management options for clinicians caring for patients with heart disease, diabetes, dyslipidemia, and obesity.

Friday, 23 October 2015
Session II: Hypertension and Cardio-Renal Syndrome

The Management of Resistant Hypertension

George L. Bakris, MD

Resistant hypertension (RH) remains a clinical challenge for most physicians. Defined as failure to reach goal BP of <140/90 mmHg despite adhering to full doses of an appropriate three-drug antihypertensive regimen including a diuretic, RH is a diagnosis of exclusion, eliminating secondary hypertension due to other drugs or disease, pseudo-hypertension due to lack of adherence, white coat hypertension, and a variety of other possible etiologies. Poor drug and diet adherence and high sodium intake are the most common causes of RH; therefore to improve adherence, clinicians need to take the time to establish a trusting relationship with patients.

In true RH, combination therapy is necessary. The preferred combinations include ACE inhibitor/diuretic, angiotensin receptor blocker/diuretic, ACE inhibitor/calcium channel blocker, or angiotensin II receptor blockers/calcium channel blockers.[29]

Renal denervation has also been used to manage RH that is not responsive to medication. Its value remains to be determined with further study. Newer approaches to renal denervation under investigation include the Kona Medical Surround Sound Hypertension Therapy, which is a noninvasive renal denervation technique.[30]

In summary:

• RH is a rule-out diagnosis

• Common causes include poor drug and diet adherence, and high sodium intake

• Single pill combination therapy is indicated

• Device therapy is still evolving as a treatment

Addressing the Unmet Need in Hyperkalemia Treatment

Rajiv Agarwal, MD

Hyperkalemia, an elevated serum potassium (K) level, is a common complication of renin-angiotensin aldosterone system (RAAS) inhibition, with the risk of hyperkalemia being especially profound in patients taking spironolactone. Other drugs that inhibit the RAAS, including losartan and eplerenone, have also been associated with elevated K levels.

Risk factors for hyperkalemia include chronic kidney disease (CKD)—especially in patients with glomerular filtration rate below 30—diabetes mellitus, decompressed congestive heart failure, volume depletion, potassium supplements, including salt substitutes and some herbs, and a variety of drugs. Among the drugs that can precipitate hyperkalemia are NSAIDs, beta blockers, heparin, cyclosporine, and ketoconazole.[31]

Treatment for chronic hyperkalemia is problematic because currently used medications may not be safe and effective. For example, administering sodium polystyrene sulfonate (SPS) with sorbitol is dangerous and should be avoided, especially postoperatively.[32] On the other hand, patiromer,[33] recently approved by the FDA, has been shown to reduce potassium levels by binding colonic potassium. A second new agent, zirconium cyclosilicate, which is pending FDA approval for the treatment of hyperkalemia, acts as a potassium trap.[34] Possible adverse effects include edema and hypokalemia.

In conclusion:

• Hyperkalemia occurs commonly in patients with CKD and CHF.

• Hyperkalemia is strongly associated with adverse outcomes, especially when not associated with CKD.

• Hyperkalemia is a common complication of RAAS inhibition.

• SPS works acutely but its use is associated with colonic necrosis (likely due to sorbitol).

• New and emerging therapies are available that have been shown to effectively and rapidly treat hyperkalemia.

Prevention and Treatment of Heart Failure: Novel Therapies

Clyde W. Yancy, MD, MSc, MACP

Although heart failure remains a major cause of death, evidence suggests that its incidence may be decreasing. A Mayo Clinic study found the incidence of HF has declined from 315/100,000 to 219/100,000. The decline in incidence has been greater for HF with reduced ejection fraction (HFrEF), −45.1%, compared to heart failure with preserved ejection fraction (HFpEF), −27.9%. However, hospitalizations for HF have increased by 34%, which suggests that today’s epidemic of heart failure is an epidemic of recidivism, defined by a marked increase in hospitalizations, predominance of non-CV death rate, and persistence and predominance of HFpEF.[35]

Newly approved drugs for HF include ivabradine for stable HF patients who have a resting HR of at least 70 bpm, and who are also taking the highest tolerable dose of a beta-blocker. The FDA also recently approved sacubitril/valsartan—formerly called LCZ-696. The combination drug has produced a profound benefit on HF morbidity and cardiovascular mortality.[36]

The clinical implications of the research on HF are as follows:

• The incidence of HF may be decreasing but hospitalizations and morbidity are increasing.

• Evidence-based medical therapy for HFrEF is efficacious and merits widespread implementation; however, HFpEF remains a challenge.

• For the first time in a decade, new therapies are available to treat heart failure, including ivabradine and sacubitril/valsartan.

Diabetes, Kidney Disease and Hypertension

Allan J. Collins, MD

Among the 30 million Medicare recipients in 2001, about 20% had a diagnosis of diabetes mellitus (DM), 14% had congestive heart failure (CHF), 4.8% had chronic kidney disease (CKD), and 1.1% had end-stage renal disease (ESRD). The costs of managing these patients, which totaled $183 billion, can be divided as follows: 15.9% for CKD, 40.9% for CHF, 35.2% for DM, and 7.2% for ESRD.[37]

Over a 10-year period, these statistics have increased significantly for some diseases but not others. In 2011, the Medicare population consisted of about 31.7 million patients, and prevalence statistics were DM 27.5%, CHF 13.2%, CKD 12.7%, and ESRD 1.4%. The cost of treating these patients, however, had increased from $183 billion to $355 billion.[37]

This increased cost has prompted a greater interest in prevention in the public health arena and in identifying the risks associated with these diseases. Death rates more than triple between CKD stages 3A and 3B. Cardiovascular disease events also accelerate with advancing CKD stage. Similarly, lack of blood pressure control in patients with CKD markers places them at greater risk of acute MI, CHF, and sudden death.

Public health implications for CKD to consider are as follows:

• Detection of this population is important to help guide therapy and address efficacy while managing the potential risks associated with fluctuations in potassium levels.

• ACE inhibitors/ARBs are the cornerstone of DM, CHF, and CKD therapy even in advanced stages.

• Management of heart failure and hypertension with advancing CKD is challenging because of the risk of hyperkalemia.

• Newer approaches are needed to determine how RAAS inhibitors can be continued to reduce risk of adverse events while maintaining efficacy for heart failure and hypertension treatment.

CVD Risk Reduction in Patients with Renal Disease: Cases and Panel Discussion

Moderator: George L. Bakris, MD

Discussants: Rajiv Agarwal, MD; Allan J. Collins, MD; Clyde W. Yancy, MD, MSc, MACP

Renal disease is especially challenging to manage in the context of cardiovascular disease, as the panel discussion led by Dr. Bakris illustrated. For example, the panel reviewed the case of a 66-year-old male African American former smoker referred because of difficulty controlling blood pressure and stage 3b CKD. The details include the following:

• A family history of MI and diabetes

• Aspirin 81 mg at bedtime

• Simvastatin 40 mg qHS

• Metformin 500 mg BID

• Linagliptin 5 mg

• Valsartan/hydrochlorothiazide 320/25 mg

• Amlodipine 10 mg/day

• Nebivolol 20 mg/day

• BP 162/94 mm Hg

Based on these findings, how would you proceed? To reach the goal of less than 140/90 mmHg, the expert panel recommended the following:

• Assess the patient’s low-sodium diet and sleep quality

• Encourage weight loss

• Discontinue valsartan/hydrochlorothiazide

• Start chlorthalidone, azilsartan

• Consider spironolactone if the patient is not responsive

To sum up the benefits that this patient derived after taking 25 mg chlorthalidone, 80 mg azilsartan and following a low-sodium diet for 1 month:

• BP dropped to 134/78 mm Hg

• Heart rate 68 bpm

• Creatinine increased from 1.7 to 2.0 mg/dL

• Potassium 4.5 mEq/L

Friday 23 October 2015
Session III: Lifestyle and Obesity Management

Keynote Presentation:

Update on Leptin and Metabolic Disease

Jeffrey M. Friedman, MD, PhD

The obesity epidemic facing Americans has proven resistant to treatment for several complex reasons, not the least of which is the fact that twin studies have demonstrated that obesity is to a large extent heritable. For example, a mutation in the gene that encodes the hormone leptin can lead to morbid obesity; leptin therapy in an obese patient who lacks the hormone will produce weight loss, a drop in body fat, and increases in insulin levels, reducing the presence of prediabetes and reducing the ravenous appetite seen in leptin deficiency.

Leptin mutations are rare but there is also evidence that leptin reduces weight in patients with low leptin levels, lipodystrophy, and other disorders. The acquired generalized form of lipodystrophy has been shown to respond to leptin therapy,[38] impacting hepatic steatosis, improving poorly controlled diabetes as evidenced by reduced HbA1c and elimination of the need for insulin, and by relieving severe hypertriglyceridemia. Cases like this prompted the FDA to recently approve leptin for complete, or generalized, lipodystrophy.

Dr. Friedman also presented evidence to suggest that lipodystrophy may be a spectrum of disorders, in which the generalized, monogenic form resides at one end and partial lipodystrophy at the other end. In the latter case, the condition appears to be polygenic and responsible for normal weight ‘metabolically obese’ patients.[39]

In summary, in addition to the role of leptin therapy in the treatment of generalized lipodystrophy, the hormone has the potential to serve as monotherapy for a subset of obese patients and may diminish weight regain in patients who have lost weight on a very low calorie diet.

Keynote Presentation:

The Science Behind Heart Healthy Nutrition and Weight Management

Frank M. Sacks, MD

Lifestyle changes are still the cornerstone for managing hypertension, preventing heart disease, and controlling weight. For example, to lower blood pressure, the AHA/ACC 2013 Guidelines recommend consumption of no more than 2,400 mg/day of sodium.[12] Further reduction of sodium intake to 1,500 mg/day can result in an even greater reduction in BP. Even without achieving these goals, reducing sodium intake by at least 1,000 mg/day lowers BP.

The best choice in dietary fats to help prevent heart disease are polyunsaturated vegetable oils, including soybean, corn, and canola. The next best choices are monounsaturated oils such as olive, sunflower, and safflower.

There is also evidence to support the value of consuming greater amounts of whole fruits, including blueberries and apples to reduce the risk of type 2 diabetes. Greater consumption of fruit juice, on the other hand, has been associated with a higher risk of the disease.

In summary,

• Successful diets for weight loss can emphasize a range of fat and carbohydrate intake.

• Ongoing counseling is important to achieve and maintain weight loss.

• Successful weight loss diets should meet individual patients’ personal and cultural preferences.

Pharmacotherapy in the Management of Obesity: New Drugs and Emerging Targets

Samuel Klein, MD

Although first-line therapy for obesity usually involves diet changes and exercise, pharmacotherapy has a place as an adjunct to lifestyle changes and behavioral therapy. The indications for obesity drugs in adults include BMI ≥30 kg/m² or ≥27 kg/m² and ≥one comorbidities, for example, hypertension, type 2 diabetes, or high cholesterol. Therapy can be continued, according to FDA guidelines, if the patient loses at least 5% of their body weight by 12 weeks.

The obesity pharmacotherapies phentermine and orlistat have been available the longest. Phentermine is the least expensive obesity drug and is only approved for short-term use. The longest trial involving phentermine found a 13% weight loss after 36 weeks, compared to 5% in the placebo group.[40] Among the side effects include dry mouth, insomnia, and nervousness. The drug is contraindicated in patients with a history of cardiovascular disease. Orlistat, which inhibits the digestion of fat, induces a 6–8% weight loss on average.[41]

In the last 2 years, there have been 4 new obesity drugs approved by the FDA: phentermine/topiramate, lorcaserin, bupropion/naltrexone, and liraglutide. A combination of phentermine and topiramate produces a mean weight loss of about 10%.[42] Among the side effects for this combination medication are constipation, insomnia, paresthesia, cognitive impairment, and increased heart rate. Lorcaserin was associated with a loss of at least 5% of baseline body weight compared with placebo.[43] Bupropion/naltrexone produced a 9.3% weight loss, compared to only 5.1% in patients given placebo.[44] Similarly, a clinical trial of liraglutide found that the recently approved higher dose of the drug (3 mg) has a significant effect on body weight, when compared to placebo over 56 weeks.[45]

The available pharmacotherapeutic options play an important role in obesity management, but clinicians must also recognize that they are far less effective if not combined with diet, exercise, and behavioral therapy.

Long-Term and Metabolic Effects of Bariatric Surgery

Lee M. Kaplan, MD, PhD; Francesco Rubino, MD

Experts debate the value of bariatric surgery versus medical management of obesity, but to make an informed recommendation, clinicians need to learn more about surgical options. Sleeve gastrectomy, for example, appears about 80% as effective as gastric bypass—for both obesity and diabetes. Gastric banding is much less effective than other procedures, with a less profound physiological effect. Duodenal switch and biliopancreatic diversion is more effective, but whether the added benefit is worth the added risk is not clear.

Long-term maintenance of weight loss is superior with bariatric surgery, when compared to medical management. Recent research also suggests that surgery is more effective than conventional medical therapy for the treatment of type 2 diabetes. One trial that involved patients with a BMI above 35 and diabetes for at least 5 years found that 75% of patients that underwent RY-gastric bypass surgery had diabetes remission at 2 years.[25] In contrast, none of the patients on lifestyle and drug therapy experienced remission after their medications had been discontinued for at least 1 year.

Clinicians should be aware of the benefits of bariatric surgery, as it causes durable weight loss and improvement in diabetes in overweight and obese individuals, with frequent complete remission of diabetes.[46]

Behavior Change: From Compliance to Collaboration

Martha M. Funnell, MS, RN, CDE

The current primary care approach to obesity management remains inadequate and explains why psychosocial issues, mental health, and medical comorbidities must be addressed to maximize outcomes. Although a multidisciplinary team is needed to maintain weight loss, there is no one magic diet or exercise regimen to enable patients to lose weight; however, there are a variety of methods to consider.

One viable option, called the ‘healthy food choices’ consists of the following:

• 3 balanced meals and snacks spread out over the day

• Consuming sugars in small amounts

• Eating high-fiber foods and 6 servings of fruits and vegetables daily

• Avoiding foods high in saturated fats

Another approach is to monitor portion sizes using the MyPlate method.[47] There are also a variety of effective weight reduction plans, including low-fat, low-carbohydrate, the DASH diet, and the vegan/vegetarian diet. Among the commercial programs, Weight Watchers has the most evidence to support it.

Current evidence does not support the use of low- to moderate-intensity physician counseling for obesity, by itself, to achieve clinically meaningful weight loss. Primary care practitioner counseling plus pharmacotherapy, or intensive counseling from a dietitian or nurse, plus meal replacements, may help patients achieve their goals.

In conclusion, Ms. Funnell emphasized that while clinicians cannot offer any single magic solution, a multidisciplinary team approach that incorporates diet changes, exercise prescriptions, and behavioral counseling can produce significant weight loss in motivated patients.

Obesity & Lifestyle Panel and Cases

Moderator: Robert H. Eckel, MD

Discussants: Martha M. Funnell, MS, RN, CDE; Lee M. Kaplan, MD, PhD; Samuel Klein, MD; Francesco Rubino, MD; Frank M. Sacks, MD

Caring for an obese patient frequently means managing hypertension, diabetes, and cardiac disease and its risk factors. The case presented to the expert panel highlighted all of these interrelated issues.

A 47-year-old man who had PCI plus a drug-eluting stent 2 years ago was referred for obesity and type 2 diabetes. Case details included the following:

• A sedentary job

• Excessive eating

• Weight gain of 40 lb over 15 years

• Diabetes diagnosed at age 42

• Weight 232 lb, BMI 33.3

• Positive family history for type 2 DM and late-onset CVD

The patient was taking the following:

• Lisinopril

• Aspirin

• Atorvastatin

• Metformin

• Liraglutide

• Canagliflozin

What would you do next? The expert panel recommended the following:

• A formal behavioral weight loss program

• Dietary changes that included reduced simple sugars and addition of fiber-rich carbohydrates including whole fruits and vegetables

• If dietary changes fail, consider an affordable obesity medication matched to the individual patient’s needs and preferences, since insurance reimbursement for obesity pharmacotherapy is a concern

• Bariatric surgery may also be an option, given his current BMI

Do you think surgery is the best option?

Several of the panelists concluded that the best approach is to move from the least invasive to the most invasive approach, while other panelists indicated that bariatric surgery is appropriate for this patient because his diabetes and weight have not responded to diet and several medications.

Saturday 24 October 2015
Session IV: Diabetes Management

Type 2 Diabetes Management Update 2015

John B. Buse, MD, PhD

2015 has seen numerous new developments in diabetes management, including an explosive growth in diabetes drugs. Physicians now have several anti-hyperglycemic drugs to choose from, with 14 different agents currently available.

Lifestyle modification and patient education remain the foundation upon which the diabetes treatment plan should be based but metformin is the second layer of therapy because of its high efficacy, low risk for hypoglycemia, weight neutrality, and low cost. Six classes of drugs are currently recommended as second-line therapy, which can also be used as first-line therapy in patients intolerant to metformin, or in combination with metformin in patients with HbA1c greater than 9%. In 2015, SGLT2 inhibitors were added to the list of recommended drugs, becoming the 6^th choice.[48]

In summary, the six drug classes recommended in the latest guidelines are sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and basal insulin. In addition to these agents, there are several repurposed drugs available, including colesevelam and bromocriptine-QR. Dr. Buse concluded by saying that new classes of drugs will continue to be developed and that the biggest challenge, particularly for the primary care community and those clinicians, other than endocrinologists, who care for patients with type 2 diabetes, will be determining the optimal drug for the individual patient.

Insulin Therapy: The State-of-the-Science

Matthew C. Riddle, MD

There has been a long history of scientific research focusing on the role of insulin in the treatment of diabetes. Advances began with highly purified beef, porcine, and human insulins and have progressed to include longer-acting formulations including protamine zinc insulin, ultralente insulin, and Lente insulin, and lastly, biosynthetic analog insulins such as lispro, aspart, glulisine, glargine, and PEG-lispro.¹

Among the controlled trials that have established the benefits of insulin therapy are the UKPDS and the DCCT-EDIC trials, which established its early microvascular benefits—over a period of 5–10 years of treatment—and the cardiovascular benefits, which surface in 20 or more years. The ACCORD and ACCORDION studies, however, found that there is some peril in the aggressive use of insulin in high-risk populations.

Experts agree that insulin is the best-studied treatment for diabetes. Control of fasting glucose with basal insulin is easy and safe and may be improved for some patients by taking the new basal insulins. However, control of glucose after meals is more difficult and will be a focus of research with mealtime therapies other than insulin.

Insulin Resistance and Polycystic Ovary Syndrome:

Pathogenesis, Evaluation, and Treatment

Andrea E. Dunaif, MD

Polycystic ovary syndrome (PCOS) is a major metabolic disorder that is associated with a four-fold increased risk of type 2 diabetes mellitus at a very young age.[49] PCOS is often regarded with some confusion by healthcare practitioners but, according to Dr. Dunaif, is actually straightforward to diagnose.

Diagnostic criteria for PCOS include hyperandrogenism, chronic anovulation, and the exclusion of other disorders. These criteria are the most effective means to identify patients at very high risk of metabolic dysfunction and insulin resistance. Like type 2 diabetes and obesity, PCOS is a complex genetic disease that aggregates in families. For example, a sibling of an individual with PCOS has a 5.7-fold increased risk of also developing PCOS. Thus, clinicians should screen family members of women diagnosed with PCOS.

Patients with PCOS who are at high metabolic risk include those who have irregular menses, which is defined as fewer than 6 menses per year. Hormonal evaluation includes high circulating testosterone levels. The metabolic evaluation includes a lipid profile and oral glucose tolerance testing. Metformin is the most common drug used to treat PCOS, prescribed off label; safety concerns about TZDs preclude their use in those who do not have type 2 diabetes.

An NIH workshop in 2012 recommended that the name PCOS be changed, stating that the current name was a distraction and an impediment to progress as there are no cysts in the ovaries and the term kept the disorder from being recognized as a long-term metabolic disorder. Responses from surveys given to women with PCOS and physicians who treat the disorder throughout Australia have proposed the name metabolic reproductive syndrome (MRS) although no consensus has yet been reached.[50]

Advances in Diabetes Technology

Anne L. Peters, MD

The technological tools used to manage diabetes have improved in the last few decades, moving from urinary test strips and syringes in the 1970s to smartphone apps, injection pens, blood glucose monitoring devices, and a variety of other technologies in 2015. Tools, however, are only helpful if patients can use them—emphasizing the need for education and follow-up.

Self-monitoring of blood glucose has been a major advance, but a drawback is the requirement of patients having to prick their fingers. The first glucose monitoring system that does not require finger pricks, the Abbott Freestyle Libre, is currently available in Europe. The patient attaches a disc to the arm that reads a sensor inserted under the skin. The disc communicates through a transmitter to a handheld device that records the readings. Devices such as this hold the potential to increase patients’ willingness to track their daily blood glucose levels.

The bolus calculator is another useful technology for patients who administer prandial insulin bolusing. This tool allows patients to input carbohydrate grams and blood glucose and obtain advice on the size of the bolus dose to administer. Finally, there has been progress in the development of inhaled insulin. Exubera has been withdrawn from the market, but has been replaced with Afrezza®, which is more convenient to use.

Dr. Peters’ take-home message was straightforward: If these new devices and technological advancements encourage patients to take more responsibility for their diabetes care, they are worth considering.

Keynote Presentation:

Insulin and Beta Cell Replacement: From Secretion to Action

Michael R. Rickels, MD, MS

Achievement of target glycemic control and avoidance of severe hypoglycemia remain challenges for most patients with type 1 diabetes who rely on traditional insulin delivery systems. Intrahepatic transplantation of purified islets isolated from a deceased donor pancreas may help some of these patients to restore physiologic insulin delivery.

The primary end point for evaluation of clinical islet transplantation is HbA1c < 7.0% without severe hypoglycemia episodes. Current protocols may result in recovery of sufficient β-cell secretory capacity to afford durable graft survival that resists metabolic exhaustion. The improved metabolic control results in normalization of hepatic and peripheral insulin sensitivity despite the need for immunosuppression.[51]

Although islet transplantation is promising for patients with type 1 diabetes, the benefits of the procedure on long-term improvement in glycemic control, especially amelioration of problematic hypoglycemia and glycemic lability, must be balanced against the risks for procedural complications and of the immunosuppressive drug therapy.

Diabetes Panel and Cases

Moderator: Jay S. Skyler, MD

Discussants: John B. Buse, MD, PhD; Andrea E. Dunaif, MD; Anne L. Peters, MD; Michael R. Rickels, MD, MS; Matthew C. Riddle, MD

The panelists for this final session of the Cardiometabolic Health Congress addressed a variety of complex issues in patient care. For example, they discussed the fact that spironolactone is the most potent antiandrogen in the US and has been used to treat the hirsutism of PCOS. Up to 200 mg/day in combination with an oral contraceptive has been shown to be effective for PCOS, but because spironolactone is an antiandrogen, it is teratogenic and would interfere with the masculinization of the male fetus. With that in mind, clinicians should ascertain if the patient plans to become pregnant.

Equally important in the care of young adolescent girls with PCOS is the fact that they are at risk for type 2 diabetes; prescribing metformin as a preventive measure is one option that is supported by data. Targeted lifestyle counseling would also be beneficial.

In previous sessions, several speakers spoke about the value of newer oral agents and insulin formulations for diabetes, but during this final panel discussion, they also discussed bromocriptine, which has been repurposed for the treatment of diabetes. The drug has been associated with a 50% reduction in cardiovascular risk. However, there has been a paucity of studies on this drug in relation to type 2 diabetes. The study that demonstrated cardiovascular benefits from bromocriptine lasted 1 year, so it is uncertain whether the effect was real.

Concluding remarks

As CMHC approaches its second decade, the Congress has seen major developments in the field, including several new oral antidiabetic drugs, new insulin formulations, advances in the surgical treatment of obesity, new treatment options for hypercholesterolemia, as well as new insights into the genetic underpinnings that contribute to cardiovascular disease, hypercholesterolemia, obesity, and diabetes. These new developments provide clinicians with the tools to improve patient outcomes and reduce the tremendous financial toll that these diseases take on patients and society as a whole.

Financial and competing interests disclosure

This paper was funded by The Cardiometabolic Health Congress. Paul Cerrato and Mary Mihalovic acted as Medical Writers, funded by The Cardiometabolic Health Congress. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

1. An announcement was subsequently made on 4 December 2015 that development of PEG-lispro would cease.