Editorial Commentary Long-Standing Problem of β-Blocker–Elicited Hypoglycemia in Diabetes Mellitus Edoardo Casiglia, Valérie Tikhonoff See related article, pp 103–110
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he role of β-blockers on patients with a diagnosis of diabetes mellitus is controversial. They have been considered time-to-time neutral or able to induce hypoglycemia or, on the contrary, hyperglycemia. Physicians learned early in the β-blocking era to fear the reduction of the peripheral effects of hypoglycemia that accompanied β-blockade as a consequence of its antiadrenergic effects.1,2 The initial signs of an incipient hypoglycemia (such as peripheral tremulousness and tachycardia) could be masked, and patients remained unaware of a potential danger, such as severe hypoglycemia. Moreover, via an action on muscle and liver, β2-blockade can suppress glycogenolysis, which prevents correction of hypoglycemia. Later, many data and meta-analysis were shown about the beneficial or adverse effects of β-blockers in diabetes mellitus. These studies were often biased by the fact that patients under treatment or with comorbidities were commonly included. It was, therefore, difficult to discriminate the effects of β-blockade from those of the personal pathological profile.3 The study by Tsujimoto et al4 represents a step of this itinerary. It includes only patients with a diagnosis of diabetes mellitus without controls, and the number of subjects, particularly after case-to-case matching, is probably too small to avoid β error, but the results of the study are interesting enough to deserve some comments. Hypoglycemia is the most common metabolic complication experienced by patients with diabetes mellitus.1 The analysis by Tsujimoto et al4 does not concern directly a side effect of β-blockers, but rather the prognostic effects of hypoglycemia in patients with a diagnosis of diabetes mellitus. β-Blocking therapy was correctly included in the analysis and, as expected, was accepted in multivariate model of outcome in a minority of subjects, those undergoing intensive antidiabetic therapy. It is indisputable that hypoglycemic crises occur more frequently in β-blocked than in non-βblocked patients. In this respect, statistics are irreproachable. Nevertheless, hypoglycemic crises even with blood glucose <50 mg/dL, like those described by the authors, occur also in patients untreated with β-blockers and even in subjects without diabetes mellitus. Modern diabetologists are aware of the
occasional hypoglycemia in patients with a diagnosis of diabetes mellitus, sometimes favored by β-blockade as suggested by Tsujimoto et al,4 sometimes apparently spontaneous or idiopathic. For this reason, they tend, today, not to pursue values of blood glucose or of glycohemoglobin too low or even to near normalcy by limiting de facto the number or doses of the antidiabetic drugs. Not only this, but an important glycemic drops can be observed in people free from diabetes mellitus too, surprisingly also in the post prandium5 (Figure). The pathophysiology of the adverse effects of severe hypoglycemia in patients with diabetes mellitus are well known today. With the method of the hyperinsulinemic–hypoglycemic clamp, an increase of catecholamines is evident.6 At the same time and as a consequence, the ECG shows silent ST-segment depression and T wave abnormalities and even changes in ventricular depolarization.6 The increase of the QT interval and the arrhythmogenic effect are 2 typical patterns of hypoglycemia.6 Acute hypoglycemia is, therefore, accompanied/followed by sympathoadrenal activation, oxygen demand, and myocardial workload increase because of a rise in cardiac output, heart contractility, and heart rate. At the same time, systolic blood pressure increases while diastolic blood pressure decrease, so producing an unwanted rise in pulse and in central blood pressure that is notoriously dangerous in terms of outcome particularly in patients already having stiffer arterial walls.7 Many inflammatory substances leading to endothelial injury are also produced. Although this sequence of events is not so dangerous if occasional, its recurrence increases de facto cardiovascular events. Finally, severe hypoglycemia has also been independently associated to QTc prolongation, a factor that tends to triplicate a risk of cardiac arrest. The increase of incident cardiovascular events in hypoglycemic diabetic patients found by Tsujimoto et al4 is, therefore, not at all surprising. As mentioned, the opportunity not to force the antidiabetic therapy goes for more today. For instance, the ADVANCE (Action in Diabetes and Vascular Disease Controlled Evaluation) and the VADT (Veteran’s Affairs Diabetes Trial) showed no benefit when the glycemic control was aggressive.1 Hsu et al8 performed at the Taiwan National Health Research Institute a nationwide population-based prospective study among more than 77 000 diabetic patients: the 1844 ones with hypoglycemic crisis had, in comparison to those without hypoglycemia, higher incidence of stroke, coronary heart disease, and cardiovascular diseases, and even allcause hospitalization showed a 2-fold increase. In a 15-year follow-up conducted at the Johns Hopkins Bloomberg School of Public Health, all-cause mortality was doubled in diabetic patients who had at least 1 hypoglycemic episode, and about one third of them died within 3 years from the episode.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, University of Padova, Italy. Correspondence to Edoardo Casiglia, Department of Medicine, University of Padova, Via Giustiniani, 2 I-35128 Padova, Italy. E-mail
[email protected] (Hypertension. 2017;70:00-00. DOI: 10.1161/HYPERTENSIONAHA.117.09378.) © 2017 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.117.09378
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Figure. The effects of an episode of hypoglycemia leading to an adverse event (ie, coronary). Hypoglycemia acts mainly through a sympathoadrenal activation and an increase of coagulation. An endothelial injury is often present as well. The effects of β-blockers are also shown (dashed lines). The net effect of β-blockade in subjects with diabetes mellitus represents a balance between the facilitation of hypoglycemia and the limitation of its effects. ↑ and ↓ indicates increase or decrease; CO, cardiac output; CPR, circulating C-reactive protein; HR, heart rate; O2, myocardial oxygen; PP, pulse pressure; PR, peripheral resistance; SBP, systolic blood pressure; SV, stroke volume (cardiac contractility); and vW, von Willebrand factor.
Hypoglycemia is, therefore, a real cause of morbidity and mortality, not only during the episode but also outside of it. The analysis by Tsujimoto et al4 does not add new elements to fear β-blocker-induced hypoglycemia, rather limits it to the cardiovascular events only and, in the range of them, only to the diabetics treated intensively and having a glycemia <50 mg/dL. This is in any case interesting, particularly because it tends to reduce, not to increase, the physicians’ feeling of danger, addressing the attention toward patients more at risk. This is useful to target resources and energies in the correct direction, paying greater attention to those diabetic patients who are at greater risk. It is likely that this is particularly relevant for general practitioners following diabetic outpatients. As the market and research offer today a wide range of molecules whose antihypertensive and prognostic effects are comparable,9 there is no real reason to prefer β-blockers to reduce blood pressure in the diabetic, so running the risk of eliciting glycemic fall and consequently cardiovascular events. An exception is represented by the hypertensive patients who have or had a myocardial infarction, where the protective effect of the β-blockers (particularly, the most modern ones) on relapses probably exceeds the risk of favoring hypoglycemia for at least 2 years after the event.10 Personalizing of treatment via targets is becoming necessary to balance the benefits of glycemic control with its potential risks, taking into account the adverse effects of glucose-lowering medications (particularly hypoglycemia), and the patient’s age and health status10: this patient-centered approach seems the most prudent today and is also a Statement of both the American Diabetes Association and the European Association for the Study of Diabetes,10 and hypoglycemia is a cause of morbidity and mortality not only during the episode but also outside of it. As a matter of fact, hypoglycemic episodes could represent a general state of poor health and, thus, portend a bad outcome that would occur even if they were avoided.
Disclosures None.
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Long-Standing Problem of β-Blocker−Elicited Hypoglycemia in Diabetes Mellitus Edoardo Casiglia and Valérie Tikhonoff Hypertension. published online May 30, 2017; Downloaded from http://hyper.ahajournals.org/ by guest on July 10, 2018
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