By Walter Alexander and Rick McGuire

Right from the beginning, the power of statins proved undeniable—and alluring. They reduced LDL and improved outcomes with a single bound, and soon whispers of “put them in the water supply” practically became a clarion call. Turn on the Bat Signal and statins came to the rescue. Pile them on, and the milligrams per deciliter of “bad” lipids melted away.

As Stan Lee tells us in Spiderman, with great power comes great responsibility, and the lesson from statins seemed to be that cardiovascular disease (CVD) could be overpowered with aggressive therapy. The responsible approach: aggressively treat metabolic abnormalities and the lower they go, the better.

Yet, in the real world, it’s not that simple. New European Society of Cardiology (ESC) guidelines (discussed in last month’s CardioSource WorldNews), for example, have reversed course on previous recommendations supporting aggressive blood pressure–lowering in high-risk groups. In discussing highlights of the ESC.13 meeting, Frank Ruschitzka, MD, University Hospital, Zurich, Switzerland, said “Cardiologists are happy about these new target lines: below 140 over 90 is just fine. The days where we squeeze it down to 120/80—to where the patients could not stand it anymore—we knew intuitively that this could not be right in patients with CAD. Those days are over.”

(Note: The new ESC guidelines for managing arterial blood pressure do make an exception in the case of diabetes and recommend a diastolic target of 80-85 mm Hg, although the 140 mm Hg or less systolic target remains in place for these patients. But the guidelines find limited or no evidence supporting previous recommendations of <130/80 mm Hg in specific high-risk groups; indeed, there is evidence of some harm with pushing blood pressure that low.)

Dr. Ruschitzka does think the new guidelines missed in terms of combination therapy. While the new document is less obsessed with numbers, still he said, lowering blood pressure is not enough. “Cardiologists want to see the lowering of blood pressure translate into meaningful benefit; we need to lower blood pressure, lower MI, and improve survival,” he said. “That has only been delivered by the ACE inhibitors; that’s why I thought there should have been a stronger statement on that in the guidelines.”

Similarly, aggressive therapy now appears to equal Kryptonite in terms of glucose control and our “obsession with numbers” and diabetes, noted Barbara Casadei, MD, University of Oxford, United Kingdom. “We target specific glycated hemoglobin levels with the expectation that this will always influence macrovascular complications, but that is not happening and there is a suggestion that there is harm.”

That suggestion was a signal of increased heart failure (HF) in the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trial, which randomized patients to a selective dipeptidyl peptidase 4 (DPP-4) inhibitor or placebo.¹ The investigators reported no excess or reduction in the risk of the primary composite endpoint of myocardial infarction (MI), stroke, or cardiovascular death, which was the primary safety goal of the study, but there was an increase in hospitalization for HF in the saxagliptin arm. One bright spot: the DPP-4 inhibitor did demonstrate better control of glucose versus placebo. By the way, SAVOR-TIMI 53 was not alone at ESC: disappointing results were also evident in the EXAMINE trial, which evaluated another DPP-4 inhibitor (alogliptin) in patients with type 2 diabetes and recent acute coronary syndrome (ACS).

Well, maybe “disappointing” depends on your point of view. Following presentation of the data, Dr. Ruschitzka said, “My endocrinologists walked out of the room saying, ‘Great, we lowered glucose and didn’t do any harm,’ except maybe a signal of more heart failures. Cardiologists, however, have to look at the same data and ask, ‘What is all this lowering of glucose for if we do not lower MI, stroke, and mortality?’ Some of the endocrinologists actually weighed the lower glucose as being of greater value than the possible increased risk of heart failure. I think we have to rethink that just a bit.”

Keith A.A. Fox, MD, University of Edinburgh, United Kingdom, and Dr. Casadei, who co-hosted a broadcast of ESC highlights after the Amsterdam meeting, agreed that, based on the evidence, no one should consider glycated hemoglobin a good biomarker of macrovascular complications. Sanjay Sharma, MD, St. George’s University of London, said good glycemic control benefits microvascular disease but not macrovascular disease. “We need to ease off on the ‘sweet spot’ for glycated hemoglobin and focus more on other risk factors for atherosclerosis because in high-risk individuals, there is evidence that long-acting insulins have precipitated MI and now the glitazones and gliptins have been associated with heart failure.” Dr. Ruschitzka added, “It really seems to be a class effect of glucose-lowering drugs and the risk of heart failure. We have seen it with pioglitazone and rosiglitazone, and now one of the gliptins in the trial presented here.”

It should be noted that SAVOR-TIMI 53 is the largest diabetes trial ever carried out, conducted at 788 sites across 26 countries. It is also the first study since the US Food and Drug Administration and the European Medicines Agency revised regulations to give more robust assurance of cardiovascular safety in glucose-lowering therapies following concerns that these drugs may have substantial deleterious effects.

Overall, Dr. Sharma felt we were giving our power away to pills rather than focusing more on the metabolic syndrome and pushing harder to get patients to increase activity to improve their metabolic profile. Even just a brisk 1-hour weekly walk would significantly reduce CVD risk as well as all-cause mortality, he said: “For every metabolic equivalent increase in exercise you reduce your cardiovascular risk by 13%. That makes it more powerful than statins or any other intervention you can name—and it’s free.”

In addition, noted Dr. Ruschitzka , it’s critically important to utilize optimal medical therapy to reduce the general cardiovascular risk in patients with diabetes, including statin therapy, ACE inhibitors, and other approaches known to improve outcomes.

Twin Peaks

Despite heightened attention and awareness, we keep hitting new annual highs for diabetes mellitus and obesity, underscoring an urgent need to better understand the interrelationships between body mass index (BMI), metabolic abnormalities, and cardiac pathology. ESC 2013 gave us some data to chew on there as well.

Research conducted along varied avenues of inquiry examined obesity in relation to CV risk, outcomes, and treatment. Antonini-Canterin et al. found a significant (p < 0.001) relationship between BMI and left ventricular (LV) mass in the presence of “superobesity,” defined as BMI ≥50 kg/m² as compared with morbid obesity (BMI between 40 and 50 kg/m²). After indexing for height, investigators compared 160 asymptomatic morbidly obese patients with 38 superobese patients, finding greater LV mass (66.0±14.7 vs. 59.9±11.9 g/m2; p = 0.007), higher left atrial volume (13.8±4.5 g/m vs. 12.2±3.9 g/m; p = 0.029), greater LV end-diastolic volume, and greater end-systolic volumes, as well, among the superobese. Ejection fractions were similar between groups, but the superobese patients showed more insulin resistance.

Sergio Raposeiras Roubin, MD, and colleagues from University Clinical Hospital of Santiago de Compostela, Spain, looked at the association between BMI and prognosis following ACS, confirming the “obesity paradox” but only in men. They studied 1-year mortality in 3,436 consecutive ACS patients. The initial analysis showed higher mortality in patients with BMI >25 kg/m² (8.0% vs. 4.9% with lower BMI; p = 0.002) for both ST-elevation MI (STEMI) and non-STEMI patients. Subanalysis showed the mortality reduction for higher BMI patients resided predominantly in patients with BMI between 30 and 35 kg/m² (8.0% vs. 3.2%; p < 0.001). After adjusting for predictors of 1-year mortality, however, BMI was inversely associated with mortality in men only (p = 0.049 for men, p = 0.894 for women).

Sex doesn’t always matter, but it appears weight does: Researchers from Uppsala University, Sweden, took advantage of data from a 15-year-old health survey to compare body weight increases in patients experiencing an acute myocardial infarction (AMI) versus controls without AMI from the same region (132 case-control pairs). Over the prior 15 years, they found a body weight increase of 4.4 kg for patients who experienced versus a smaller increase of 2.6 kg among sex- and age-matched controls who did not experience an AMI (p = 0.04).

Two analyses by Arjun K Ghosh, MD, of the International Centre for Circulatory Health, Imperial College, London, delved into long-term data from participants in the United Kingdom’s longest-running birth cohort study: the Medical Research Council National Survey of Health and Development, with data accumulating from 1946 (n = 1,650). They evaluated the relationships between BMI across adult life and LV mass index (LVMI) and diastolic function. The first analysis, of factors associated with future increases in LVMI, revealed that increases in BMI and being overweight from 20 years of age onward were associated with increased LVMI. Increased BMI and overweight status from 43 years onward were associated with increased relative wall thickness (RWT). Earlier age of first overweight status, in addition, was associated with greater subsequent LVMI and RWT.

The second analysis of data from the same cohort, examining diastolic dysfunction, found that increased BMI and overweight status from 20 years onward were associated with poorer diastolic function, and this earlier age at first detection of overweight status was associated with worse diastolic function. The author’s conclusion: “This emphasizes the importance of life-long prevention of overweight and obesity to maintain cardiac health in older age.”

WHAP! POW! The One-Two Punch of Surgery

One aggressive approach against obesity and diabetes continues to show benefit: weight reduction through bariatric surgery. In 40 patients with severe obesity, surgery led to improvements in arterial remodeling after only 6 months. Justyna Domienik-Karlowicz, MD, and colleagues of the Medical University of Warsaw, Poland, reported that mean BMI reductions from 47.73 to 35.22 (kg/m²) were accompanied by improvements in intima-media thickness (0.59 to 0.52 mm), pulse wave velocity (8.53 to 7.82 m/s), nitroglycerine-mediated dilatation (21.47% to 28.54%), and flow-mediated dilatation (12.83% to 17.52%).

Positive findings for bariatric surgery were extended in a paper published soon after ESC 2013.² Stacy Brethauer, MD, from the Cleveland Clinic, and colleagues studied glycemic outcomes 6 years after Roux-en-Y gastric bypass (n = 162), gastric banding (n = 32), or sleeve gastrectomy (n = 23). Analysis showed that a mean excess weight loss of 55% was associated with a mean HbA1c reduction from 7.5% to 6.5% (p < 0.001) and a decrease in fasting blood glucose (FBG) from 155.9 mg/dL to 114.8 mg/dL (p < 0.001). Long-term effects on LDL, HDL, triglyceridemia, and hypertension were also positive.

While admitting that the term “cure” remains controversial with respect to diabetes, Dr. Brethauer noted that 24% of all patients and 31% of gastric bypass patients achieved long-term complete remission of diabetes with an HbA1c less than 6%. Also, 27% of the gastric bypass patients sustained these levels of glycemic control off medication continuously for more than 5 years. (Complete remission is defined in the American Diabetes Association consensus statement as HbA1c <6% and FBG <100 mg/dL for 1 year in the absence of diabetes medications.)

Unmasking Reperfusion Choices for Diabetes

In this era of stringent reperfusion therapy (primary PCI), Jan Christoph Karcher, MD, of the OPTAMI Study Group, Ludwigshafen, Germany, reported that hospital mortality is not significantly higher among patients with diabetes than for those without diabetes in both STEMI and NSTEMI. OPTAMI (Optimized Therapy of Acute Myocardial Infarction) enrolled 3,136 consecutive patients with AMI in 33 German centers. The OPTAMI results indicated:

• STEMI hospital mortality was higher in diabetic patients than nondiabetic patients (7.2% vs. 5.6%; p = 0.26),
• NSTEMI hospital mortality was higher in patients with diabetes (6.2% vs. 5%; p = 0.33)
• STEMI mortality at 1-year follow-up was higher in diabetic patients (19.1% vs. 9.4; p < 0.001)
• NSTEMI mortality at 1-year follow-up was also higher in diabetic patients (21.9% vs. 12.3%; p < 0.0001)

Multivariate analysis showed diabetes and renal failure were predictors of mortality for NSTEMI and STEMI.

When the patient in the cath lab has diabetes, what special considerations face the interventional cardiologist? In a presentation at ESC, Nikolaus Marx, MD, University Hospital, Aachen, Germany, emphasized that the diabetic patient bears the burden of both vulnerable vessels and vulnerable blood. The coronary lesions in ACS patients with diabetes are characterized by a larger necrotic lipid core, more macrophages, and a thinner fibrous cap compared to lesions of stable patients. The platelet dysfunction and hypofibrinolysis of the blood of diabetic patients produces a denser fibrin structure and denser clots. This picture is further complicated by increased endothelial dysfunction, more fatty streaks, and more complicated lesions.

How do these factors influence treatment choices? At ESC, new guidelines were released for managing patients with diabetes, pre-diabetes, and CVD. Among the take-home messages relating to revascularization options for these patients:

• Acute coronary syndrome: Early angiography and culprit lesion revascularization should be offered.
• Stable coronary artery disease: CABG is preferred if the myocardial area at risk is large (i.e., multivessel disease, complex coronary lesions), but PCI with drug-eluting stents may be performed for symptom control in single- and two-vessel disease.
• Peripheral artery disease: Critical limb ischemia and symptomatic carotid artery disease should be revascularized.

Going “Hulk” on Diabetes

One area where aggressive therapy for diabetes may still hold sway: antithrombotic therapy. According to Dr. Marx, this is based on the reduction of events in diabetes patients seen with more intensive therapy in TRITON-TIMI 38 (prasugrel vs. clopidogrel; HR = 0.79), PLATO (ticagrelor vs. clopidogrel; HR = 0.88), and CURRENT-OASIS 7 (PCI cohort analysis comparing high- vs. standard-dose clopidogrel; HR = 0.87).³

Results from the FREEDOM trial were recently reported, and among 1,900 patients with diabetes and multivessel disease, there were significant advantages for CABG over PCI, based on death, MI, or stroke (p = 0.005) and death (p = 0.049) after 5-year follow-up.⁴ (Please see an ACCEL summary of the FREEDOM trial on page 18.) Consequently, the ESC guidelines recommend CABG in patients with diabetes and multivessel or complex CAD (SYNTAX score >22) to improve survival from major cardiovascular events (Level of Recommendation: IA).

In his center, how do interventionalists manage patients with diabetes? Dr. Marx said they first assess ischemia via stress echo or frequently with fractional flow reserve, and refrain from placing stents in areas without evidence of ischemia. For patients with three-vessel or left main disease, there is a daily review of all images and data by a team including a cardiac surgeon. “This is absolutely necessary,” he said, “to have this ‘heart team’ making decisions for the best treatment of diabetic patients.” In other words, demonstrating great responsibility before exercising great power....

References

1. Scirica BM, et al. N Engl J Med. 2013 Sep 2. [Epub ahead of print]
2. Brethauer SA, et al. Ann Surg. 2013;258:628-37.
3. Roffi M, et al. Eur Heart J. 2011;32:2748-57.
4. Farkouh ME et al. N Engl J Med. 2012;367:2375-84.