Pharmacy Update

The Contribution of Medications to Unawareness

John R. White, Jr., PA, PharmD

Hypoglycemia unawareness is defined bly best characterized as responders to Frequent hypoglycemia reduces the as the onset of neuroglycopenia before prolonged hypoglycemia rather than counterregulatory response to hypo- the appearance of autonomic warning acute responders. The central nervous glycemia by >_ 50%.7 Davis et al.6 symptoms.1 It is difficult to study in system triggers autonomic symptoms have shown that the magnitude of the its natural form because of its parox- of hypoglycemia at plasma blunting of the counterregulatory ysmal and unpredictable nature; levels between 54 and 90 mg/dl (Table response is proportional to the therefore, well-controlled trials are 1). These symptoms are aimed at antecedent hypoglycemia. In addition limited. However, much is known encouraging consumption of calories to a reduction in epinephrine secre- regarding risk factors, biochemical and are the harbinger of impending tion, a reduction in peripheral sensitiv- causes, and populations at greatest neuroglycopenia. If unchecked, the ity to epinephrine has also been risk for the development of hypo- hypoglycemia will cause neurogly- reported. Therefore, with the develop- glycemia unawareness. Less is known copenic symptoms (Table 1) and even- ment of hypoglycemia unawareness, a regarding the impact of medications tually seizures and coma. causal nexus is established in which on the development or recognition of The glycemic threshold at which hypoglycemia causes hypoglycemia this condition in patients with dia- this counterregulatory response occurs unawareness, which in turn results in betes. Several medications are thought is predictable in people without dia- worsening hypoglycemia. to worsen or promote hypoglycemia betes and can be reset to higher or Patients with type 2 may unawareness, whereas others may lower glucose levels with chronic also experience hypoglycemia have an attenuating effect on the or repeated hypo- unawareness. Patients early in the problem. This article will review glycemia, respectively.2–5 The intensity course of their disease probably retain hypoglycemia unawareness and sum- of the counterregulatory response most of their α-cell response marize the effects of medications that diminishes with increasing age in peo- (glucagon) to hypoglycemia, whereas may influence it. ple without diabetes.6 Sex and degree patients with advanced type 2 disease of physical activity also play a role in have virtually no α-cell response to Hypoglycemic Counterregulation determining the magnitude of the hypoglycemia.9 Patients with type 2 In individuals without diabetes, a pre- counterregulatory response. Females diabetes, like those with type 1 dia- dictable, organized response occurs have a reduced counterregulatory betes, also develop a blunting of their when blood glucose declines to hypo- response to hypoglycemia compared epinephrine response that is propor- glycemic levels (Figure 1). First, to men but have less blunting of their tional to antecedent hypoglycemia. secretion is suppressed as glu- response by antecedent hypoglycemia. cose falls to < 81 mg/dl.1 The suppres- Exercise has been linked to a blunting Insulin sion of insulin secretion has two of the counterregulatory response. A discussion of the effects of medica- effects: peripheral glucose utilization Alterations in the counterregulatory tions on hypoglycemia unawareness is reduced and hepatic glucose output response to hypoglycemia in patients would be incomplete without the men- is induced. This action typically termi- with type 1 or type 2 diabetes have tion of insulin. As previously noted, nates the episode. However, if glucose been described in detail elsewhere.1,7,8 insulin-induced antecedent hypo- decline continues to < 68 mg/dl, Patients with type 1 diabetes of > 5 glycemia is a strong predictor of subse- glucagon secretion from α-cells and years’ duration lose their α-cell– quent hypoglycemia unawareness. In epinephrine secretion from the adren- mediated glucagon response to hypo- addition, ever since human insulin was als are stimulated.1 These actions pro- glycemia. Therefore, the thrust of the introduced as a pharmacological mote hepatic glucose production via acute counterregulatory response is agent, there has been concern that it and glycogenolysis. carried by epinephrine. Unfortunately, might be associated with a higher inci- Growth and cortisol are the counterregulatory response is dence of hypoglycemia unawareness released as glucose levels decline even blunted in many patients because than insulin from animal sources. One further (to ~ 63 mg/dl) but are proba- of insulin-induced hypoglycemia. of the early double-blind, randomized,

77 Diabetes Spectrum Volume 20, Number 2, 2007 Pharmacy Update

Classification Counterregulatory response or physical consequence Lower boundary of physiological euglycemia 90 Endogenous insulin Hypoglycemia 72 Release of glucagon and adrenaline Release of growth hormone Release of cortisol Symptomatic hypoglycemia Onset of autonomic symptoms 54

Neuroglycopenia Cognitive deterioration 36

Severe neuroglycopenia Coma, seizures 18

Plasma glucose level (mg/dl)

Figure 1. Glycemic threshold values for counterregulatory response to and physical consequences of insulin- induced hypoglycemia. Adapted from Ref. 1.

with insulin from an animal source. glycemic effects of the β-adrenergic Table 1. Symptoms of However, the study did not compare antagonists (β-blockers).14 These Hypoglycemia these findings to patients who had con- agents have been reported to increase tinued on animal-source insulin. The the incidence of hypoglycemia in some Autonomic Neuroglycopenia fraction of patients reporting altered individuals.14 Labetolol administered symptoms of hypoglycemia was con- during a caesarean delivery was sistent with the fraction of all long- reported to cause hypoglycemia in the Palpitations Drowsiness term patients reporting these changes.12 twins postdelivery. Even ophthalmic Sweating One study13 evaluating patients dosage forms of β-adrenergic antago- Tingling Blurred vision who reported that they had developed nists have been reported to cause hypoglycemia unawareness after being hypoglycemia in a patient with type 1 Trembling Difficulty switched to human insulin reported diabetes. Hypoglycemia may be a Hypoglycemic with speech no differences in symptomatic or hor- possible sequela of the use of β-adren- unawareness monal responses to hypoglycemia. ergic antagonists, but if it is, it is A recent review of 45 randomized probably rare. Feeling faint controlled studies comparing animal The more troubling concern regard- Adapted from Ref. 1. to human insulin concluded that most ing β-blockers is their potential effect of the published studies were poorly on hypoglycemia unawareness and crossover trials comparing porcine to designed.14 The authors also conclud- blunting of the return to euglycemic human insulin reported that the initial ed that there were no clinically rele- levels after hypoglycemia has symptoms of hypoglycemia with vant differences between the two occurred. β-Blockers theoretically human insulin were more often neuro- insulin types. could suppress or even obviate all of glycopenic, whereas the symptoms the adrenergically mediated symptoms associated with porcine insulin were β-Adrenergic Antagonists of hypoglycemia. A study15 that evalu- more often adrenergic.10 11 Theoretically, almost any medication ated this possibility in patients with Another study reported that some that alters the effects of epinephrine (without hypoglycemia (36%) patients who switched to treat- could have potential effects on glucose unawareness) reported that adrenergic ment with human insulin experienced homeostasis and the hypoglycemic symptoms did occur at lower glucose more frequent hypoglycemia, impaired counterregulatory system. Concerns levels when patients were treated with recognition of hypoglycemia, and have been raised for years regarding β-blockers. However, this deficit was altered symptoms of hypoglycemia potential and reported adverse offset by higher hypoglycemia symp- than they did when previously treated 78 Diabetes Spectrum Volume 20, Number 2, 2007 Pharmacy Update

tom scores, which resulted from an sitivity in subjects with type 1 diabetes, with theophylline administration, and increased perception of cholinergically those with type 1 diabetes and hypo- scores of the patients with diabetes mediated diaphoresis. glycemia unawareness, and nondiabet- approached those of the nondiabetic Cardioselective agents reportedly ic subjects. β2-Adrenergic sensitivity control subjects. The authors conclud- cause less alteration in the perception was evaluated via forearm vasodilato- ed that theophylline improves the of hypoglycemia symptoms than do ry response to escalating doses of an counterregulatory response to and per- the noncardioselective agents.14 intra-arterial infusion of salbutamol. ception of hypoglycemia in patients Additionally, cardioselective β-block- Forearm blood flow (FBF) was mea- with type 1 diabetes who have hypo- ers may have less of an effect on cor- sured bilaterally by venous occlusion glycemia unawareness. This was a rection of hypoglycemia than do their plethysmography. No statistically sig- small trial and evaluated this phenom- noncardioselective counterparts, prob- nificant differences in baseline FBF enon acutely. ably because gluconeogenesis and were reported, and significant increas- Another trial in “free living” type 1 glycogenolysis are mediated via β2 es in FBF were reported for all subject diabetic patients evaluated the impact receptors in the and are relatively groups with the administration of of caffeine on the frequency and per- unaffected by antagonism of β1 recep- salbutamol. No significant differences ception of hypoglycemia over a period tors. β-Adrenergic antagonists have were observed in the magnitude of of 3 months.19 After a lead-in phase been used successfully in several large- change in FBF. The authors concluded during which patients adhered to a scale studies in patients with diabetes that β2-sensitivity is preserved in low-caffeine diet, 34 patients with with no significant adverse effects patients with type 1 diabetes who have type 1 diabetes were randomized to reported. These agents, and particu- hypoglycemia unawareness. twice-daily capsules of either 200 mg larly the cardioselective ones, should No long-term clinical trials evaluat- of caffeine or matched placebo. not be avoided in patients with dia- ing the usefulness of β2-agonists in the Hypoglycemia episodes were mea- betes but should be used with the prevention of nocturnal hypoglycemia sured throughout the study with capil- same caution as when any new med- or hypoglycemia unawareness have lary blood glucose measurements and ication is added to a patient’s thera- been reported. However, this option symptom questionnaires. No changes peutic regimen. seems worthy of further study. in glycemic control or lipid profiles were observed. Patients receiving caf- β-Adrenergic Agonists Methylxanthines feine had statistically significant more Several studies have evaluated the Several studies have evaluated the symptomatic hypoglycemia episodes effects of β-adrenergic agonists on effects of the methylxanthine deriva- and more intense warning symptoms. hypoglycemia and hypoglycemia tives caffeine and theophylline on The study concluded that modest unawareness. The nocturnal glycemic hypoglycemia unawareness and the amounts of caffeine enhance the sensi- effects of the β2-agonist terbutaline counterregulatory response to hypo- tivity of hypoglycemia warning symp- were compared to the amino acid ala- glycemia. Both have been shown to toms in patients with type 1 diabetes nine (alanine plus glucose), a standard magnify the counterregulatory hor- without altering glycemic control or snack, and control (no snack or med- mone (i.e., epinephrine, norepineph- increasing the incidence of severe ication) in 15 insulin-treated type 1 rine, and cortisol) response to hypo- hypoglycemia. patients.16 Terbutaline was associated glycemia, as well as recovery from Although ingestion of modest doses with statistically significant higher and perception of hypoglycemia in of caffeine or theophylline may have a glucose levels compared to 1) control patients with type 1 diabetes both positive impact on patients with type subjects during the first half of the with and without hypoglycemia 1 diabetes (larger trials are needed to night and 2) control subjects during unawareness.1 validate this), larger doses may carry the second half of the night. Glucose One study18 evaluating the impact risks. A case study of one patient with levels were also higher during the sec- of theophylline on the response to type 1 diabetes who drank five cups ond half of the night in patients tak- hypoglycemia compared 15 patients of instant coffee per day reported sig- ing terbutaline versus those treated with type 1 diabetes who had a history nificantly higher glucose levels at all with snack or alanine (statistics not of hypoglycemia unawareness to 15 time points measured compared to reported). Nocturnal hypoglycemia matched healthy control subjects. The levels after consumption of a noncaf- was treated on 23 occasions in subjects underwent hyperinsulinemic- feinated beverage (180, 216, 254, and patients in the control and snack arms hypoglycemic glucose clamp and ran- 360 mg/dl vs. 144 mg/dl).20 Although versus only one incident in the alanine domly received either theophylline or this is only a case study, it illustrates and terbutaline arm. The researchers placebo in a crossover fashion. During that more research is needed in this concluded that both alanine and these trials, counterregulatory hor- area to determine efficacy, toxicity, terbutaline effectively prevented noc- mone levels, various hemodynamic and dose-response curves. However, turnal hypoglycemia. parameters, sweat detection, and sub- low-dose theophylline (levels were One of the concerns about using β2- jective assessment of symptoms were about 8 mg/l in the above-referenced agonists for the treatment of hypo- evaluated. When compared with place- trial) or low-dose caffeine may be glycemia unawareness was associated bo, theophylline significantly increased effective at reducing hypoglycemia with reduced β2 sensitivity observed in responses of plasma cortisol, epineph- unawareness in patients with type 1 vitro. Recently, a three-way compari- rine, and norepinephrine in both diabetes at a low cost and without sig- 17 son trial evaluated β2-adrenergic sen- groups. Symptoms scores increased nificant toxicity. 79 Diabetes Spectrum Volume 20, Number 2, 2007 Pharmacy Update

The third naturally occurring clearly promotes subsequent hypo- 8Vignesh JP, Mohan V: Hypoglycemic unaware- methylxanthine, theobromine, which glycemia unawareness. ness. J Assoc Physicians India 52:727–732, 2004 is found in tea, has not been studied β-Blockers (particularly noncar- 9Segal SA, Panmore DS, Cryer PE: Hypoglycemia- for its potential effects on hypo- dioselective agents) may have a slight associated autonomic failure in advanced type 2 glycemia unawareness. The molecular moderating effect on adrenergic diabetes. Diabetes 51:724–732, 2002 and pharmacological similarities of symptoms of hypoglycemia and the 10Berger W, Kellar U, Honegar B, Jaeggi E: theobromine to the other naturally hepatic counterregulatory response to Warning symptoms of hypoglycemia during occurring methylxanthines provide hypoglycemia. However, β-blockers treatment with human and porcine insulin in Lancet considerable rationale for its study in have been shown to be reasonable diabetes mellitus. 333:1041–1044, 1989 this regard. choices for the management of hyper- 11Teuscher A, Berger WG: Hypoglycemia tension and for their cardioprotective unawareness in diabetics transferred from beef/pork insulin to human insulin. Lancet Selective Serotonin Reuptake effects in patients with diabetes. 330:382–385, 1987 Inhibitors Therefore, the use of cardioselective Three case reports have suggested a β-blockers should not be discouraged. 12Gale EAM: Hypoglycemia and human insulin. Lancet link between the development of β-Adrenergic agonists, methyxan- 332:1264–1266, 1989 hypoglycemia unawareness in patients thines, and even the amino acid 13Maran A, Lomas J, Archibald H, Macdonald with type 1 diabetes and the use of alanine may cause an upregulation of IA, Gale EAM, Amiel SA: Double blind clinical and laboratory study of hypoglycemia with selective serotonin reuptake inhibitors hypoglycemia awareness and should human and porcine insulin in diabetic patients 21 (SSRIs). In all three cases, different be studied further. SSRIs should be reporting hypoglycaemia unawareness after SSRIs (fluoxetine, sertraline, paroxe- used in patients with diabetes when transferring to human insulin. BMJ tine) were administered to young the risk-benefit considerations include 306:167–171, 1993 patients (17–21 years of age) with the possibility of reduction in hypo- 14White JR, Campbell RK:. Dangerous and com- type 1 diabetes and who glycemia awareness. mon drug interactions in patients with diabetes were previously able to recognize and Clinicians treating patients with dia- mellitus. Endocrinol Metab Clin North Am treat hypoglycemia symptoms. betes need to be aware of the increased 29:789–802, 2000 Hypoglycemia unawareness, more fre- risk for medication-induced hypo- 15Hirsch IB, Boyle PJ, Craft S, Cryer PE: Higher quent hypoglycemia, and severe hypo- glycemia episodes in their patients. glycemic thresholds for symptoms during beta- glycemia (unconsciousness or requir- adrenergic blockade in IDDM. Diabetes 40:1177–1186, 1991 ing outside assistance) occurred in all three patients within weeks of starting 16Saleh TY, Cryer PE:. Alanine and terbutaline in SSRI therapy. On discontinuation of prevention of nocturnal hypoglycemia in IDDM. References Diabetes 20:1231–1236, 1997 SSRI therapy, hypoglycemia aware- 1 de Galen BE, Schouwenberg BJJW, Tack CJ, 17 ness improved in all three patients. Smits P: Pathophysiology and management of de Galan BE, de Mol P, Wennekes L, Although SSRIs are frequently used recurrent hypoglycemia and hypoglycemic Schouwenberg BJJ, Smits P: Preserved sensitivity to β -adrenergic receptor agonists in patients in this population and usually without unawareness in diabetes. Neth J Med 2 64:269–279, 2006 with type 1 diabetes mellitus and hypoglycemic known glycemic problems, this obser- unawareness. J Clin Endocrinol Metab vation strongly suggests that in some 2Banarer S, McGregor VP, Cryer PE: Intraislet 91:2878–2881, 2006 hyperinsulinemia prevents the glucagon response patients, treatment with SSRIs may 18 to hypoglycemia despite an intact autonomic de Galan BE, Tack CJ, Lenders JW, Pasman alter the perception of hypoglycemia. response. Diabetes 51:958–965, 2002 JW, Elving LD, Russel FG, Lutterman JA, Smits The mechanism by which SSRIs might P: Theophylline improves hypoglycemic be associated with hypoglycemia 3Boyle PJ, Schwartz NS, Shah SD, Clutter WE, unawareness in type 1 diabetes. Diabetes unawareness is unknown, but it has Cryer PE: Plasma glucose concentrations at the 51:790–796, 2002 onset of hypoglycemic symptoms in patients with 19 been hypothesized that the effect may poorly controlled diabetes and in nondiabetics. Watson JM, Jenkins EJE, Hamilton P, Lunt MJ, be via an atypical presentation of N Engl J Med 318:1487–1492, 1988 Kerr D: Influence of caffeine on the frequency and perception of hypoglycemia in free-living serotonin syndrome resulting in auto- 4 patients with type 1 diabetes. Diabetes Care 21 Heller SR, Cryer PE: Reduced neuroendocrine nomic dysfunction. and symptomatic responses to subsequent hypo- 23:455–459, 2000

glycemia after 1 episode of hypoglycemia in non- 20 diabetic humans. Diabetes 40:223–226, 1991 Kerr D, Everett J: Coffee, diabetes and insulin Conclusions sensitivity. Diabetologia 48:1418, 2005 Hypoglycemia unawareness is a com- 5 Davis SM, Shamoon H: Counterregulatory 21 plex, difficult-to-study phenomenon adaptation to recurrent hypoglycemia in normal Sawka AM, Burgart V, Zimmerman D: Loss of that carries with it great risk to hypoglycemic unawarenessmans. J Clin awareness of hypoglycemia temporally associat- Endocrinol Metab 73:995–1001, 1991 ed with selective serotonin reuptake inhibitors. patients. Studies evaluating the effects Diabetes Care 24:1845–1846, 2001 of medications on this problem are 6Davis SN, Shavers C, Mosqueda Garcia R, scarce. The choice of the source of Costa F: Effects of differing antecedent hypo- insulin (human vs. animal) does not glycemia on subsequent counterregulation in normal humans. Diabetes 48:1328–1335, 1997 John R. White, Jr., PA, PharmD, seem to have a direct impact on the 7 is a professor in the Department development of hypoglycemia Briscoe VJ, Davis SN: Hypoglycemia in type 1 of Pharmacotherapy, College of unawareness. Conversely, insulin- and type 2 diabetes: physiology, pathophysiolo- gy, and management. Clinical Diabetes Pharmacy at Washington State induced (or probably any drug- 24:115–121, 2006 University in Spokane. induced) antecedent hypoglycemia

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