Research Spotlight

Packer, M. (2018). “Risk of heart failure in diabetic patients receiving sulfonylureas: reply.” Eur J Heart Fail 2018 Jun 11. [Epub ahead of print].

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Editors: I sincerely appreciate the comments of Vaccaro et al. regarding their experience in the TOSCA.IT trial. It seems clear that the TOSCA.IT investigators took specific steps to enroll a population of patients with type 2 diabetes, who were at low risk of developing heart failure during follow‐up. As a result, very few heart failure events were recorded in the trial, and consequently, the trial did not have adequate statistical power to determine if the risks of heart failure were truly similar in patients taking sulfonylureas and pioglitazone. In order to validly conclude that the two classes of drugs were associated with similar risks of heart failure, the TOSCA.IT trial would have had to record 10 times as many heart failure events. Given the low risk of the population that was studied, achievement of this target number of events would have required the enrolment of substantially more patients and a far longer period of follow‐up. Since this was not practical, the results of TOSCA.IT cannot provide reliable information concerning comparative risks of heart failure related to the use of sulfonylureas and pioglitazone. Even if additional data were to show that the increased risks of heart failure with sulfonylureas and pioglitazone were similar, it is important to worry about whether any increase in risk is acceptable, especially since certain antidiabetic medications (i.e. metformin and sodium–glucose co‐transporter 2 inhibitors) appear to reduce the risk of heart failure.1 Preventing heart failure and other macrovascular complications of diabetes is a critical goal of treatment. For most middle‐aged to elderly patients with type 2 diabetes, the heightened risk of macrovascular events is much greater and occurs much earlier than the risk of microvascular events. Furthermore, since risk reduction of macrovascular events is not clearly related to glycemic control, the appropriate choice of an antidiabetic medication must be determined not only by its effects to lower glycated hemoglobin but by its independent actions to reduce the risk of cardiovascular death, myocardial infarction and heart failure. (Full text of this letter; no abstract available.)

Packer, M. (2018). “Questioning the obvious: does dyspnoea really matter in heart failure?” Eur Heart J Jun 22. [Epub ahead of print].

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Dyspnoea is the cardinal manifestation of heart failure and remains its most perplexing feature. Those afflicted with chronic heart failure typically report both symptoms of dyspnoea and exercise intolerance, but does dyspnoea actually limit activities of daily living? It is maddeningly difficult to know if patients with heart failure stop exercising because they are short of breath or because they are limited for some other reason and incidentally report dyspnoea as an accompanying symptom. Although it may seem obvious that dyspnoea impairs quality of life in heart failure, it is time to question the obvious. Our thinking about dyspnoea in heart failure has long been heavily influenced by observations in patients with acute heart failure, particularly those who present with acute pulmonary oedema. This syndrome is characterized by abrupt and marked increases in cardiac filling and pulmonary venous pressures, which are accompanied by overwhelming dyspnoea at rest. Classically, patients exhibited pink frothy sputum upon coughing, the result of the transudation of fluid from the pulmonary capillaries into the alveoli. The presentation was so dramatic that it seemed reasonable to surmise that oxygen transport was impaired, and that the resulting hypoxaemia was responsible for the sensation of dyspnoea. However, most patients with acute heart failure following myocardial injury are not hypoxaemic, even though they are generally dyspnoeic. (Excerpt from the text of this editorial, p. 1; no abstract available.)

Packer, M. (2018). “Is the Popularity of Dipeptidyl-Peptidase-4 Inhibitors Justified? Insights From Mechanistic Studies and Clinical Trials.” Am J Med 131(7): e287- e289.

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Because of their ease of use and patient acceptability, dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly prescribed to lower blood glucose in type 2 diabetes, typically, together with metformin. DPP-4 inhibitors do not require parenteral administration, and unlike other incretin-based agents, they have few gastrointestinal adverse effects. When compared with older antidiabetic drugs, DPP-4 inhibitors do not cause weight gain and are unlikely to trigger episodes of hypoglycemia.1 In contrast to sodium-glucose transporter 2 (SGLT2) inhibitors, they do not lead to genitourinary infections. Collectively, these features contribute to the popularity of DPP-4 inhibitors in the management of diabetes. Yet, aside from the symptomatic benefits of controlling blood glucose, antidiabetic drugs should prevent macrovascular and microvascular events. So we should ask: is the prominent place of DPP-4 inhibitors supported by a favorable effect of these drugs on the course of type 2 diabetes? (Excerpt from text of this commentary, p. e287; no abstract available.)

Packer, M. (2018). “Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.” Int J Cardiol 261: 130-133.

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BACKGROUND: Current guidelines for the treatment of heart failure strongly recommend the use of inhibitors of the renin-angiotensin system and sympathetic nervous system in all patients with a reduced ejection fraction who can tolerate these drugs. Yet, there is no consensus about the efficacy of low doses of these drugs or the likely shape of the dose-response relationship for these agents. METHODS: Inferences were made by examining the effects of drugs in placebo-controlled trials before the protocol-specified opportunity for uptitration and by reassessing the results of large-scale trials with active comparators that inadvertently produced different intensities of neurohormonal blockade. RESULTS: In the case of inhibitors of the renin-angiotensin system, low starting doses appear to be effective in many patients, and 3-5 fold increases in dose do not have a mortality advantage over low doses. By contrast, in the case of beta-adrenergic blockers, although low starting doses appear effective in improving outcomes, achievement of target doses may yield substantial incremental mortality benefits, even such doses are accompanied by only small additional decreases in heart rate. CONCLUSION: When treating patients with heart failure to reduce mortality, the totality of evidence supports a relatively flat dose-response relationship for inhibitors of the renin-angiotensin system but a steep dose-response relationship for beta-adrenergic receptor blockers.

Packer, M. (2018). “Higher mortality rate in patients with heart failure who are taking commonly prescribed antidiabetic medications and achieve recommended levels of glycaemic control.” Diabetes Obes Metab 20(7): 1766-1769.

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Current guidelines for diabetes recommend that physicians attain a glycated haemoglobin (HbA1c) concentration less than or equal to 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies in patients with chronic heart failure that examined the relationship between the level of HbA1c and risk of death specified whether HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, the mortality rate was not higher among those with an HbA1c concentration <7.0%. By contrast, in patients who were treated with insulin, sulphonylureas and thiazolidinediones, an inverse or U-shaped relationship between HbA1c and the risk of death was generally observed, and mortality was lowest in patients with both heart failure and diabetes if the level of HbA1c was >7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c <7.0%.