Hypoglycemia: Minimizing Its Impact in Type 2 Diabetes

ObjectiveTo review and discuss the risks and impact of hypoglycemia and provide guidance for the prevention of hypoglycemia in type 2 diabetes (T2DM).MethodsWe review and discuss the risks and impact of hypoglycemia, providing specific guidance regarding the prevention of hypoglycemia and judicial selection of glucose-lowering agents in individuals with T2DM.ResultsHypoglycemia in T2DM is underrecognized and underreported. Emerging evidence from large clinical trials suggest that hypoglycemia may be an important risk factor for morbidity and mortality in T2DM. In addition, hypoglycemia is associated with reduced quality of life, greater healthcare utilization costs, and poor adherence to medical regiments.ConclusionThese findings have led professional organizations to emphasize the prevention of hypoglycemia as an important consideration when initiating or intensifying treatment regimens. In clinical settings, particular attention should be paid to a patient’s risk for hypoglycemia when initiating or intensifying the pharmacological treatment regimen. The endocrinologist can play an important role in educating not only the patient, but also other members of the diabetes-management team regarding the need for individualized therapy. (Endocr Pract. 2013;19:526-535)     

Current Controversy Related to Glucocorticoid and Insulin Therapy in the Intensive Care Unit

ObjectiveTo review the controversy related to the widespread use of intensive insulin treatment (IIT) to maintain normoglycemia and of glucocorticoid replacement therapy in patients with sepsis in the intensive care unit (ICU).MethodsWe performed a MEDLINE search of the literature using a combination of words (critical/intensive care, endocrinology/endocrine, glucocorticoid/adrenal, insulin) to identify original studies and reviews on glucocorticoid therapy and IIT in the ICU.ResultsGlucocorticoid replacement therapy is advocated for patients with sepsis who have relative adrenal insufficiency. The current definition of relative adrenal insufficiency is poorly supported, and validated endocrine criteria that consistently identify ICU patients likely to benefit from glucocorticoid therapy are not yet available. IIT benefits postoperative patients at high risk of infection and patients who remain in the ICU more than 3 days. Potential harm caused by early IIT administration in medical ICU patients remains controversial. The role of early nutritional supplementation in major studies about IIT is largely unexplored. Improvements in insulin infusion protocols are needed to reduce the risk of hypoglycemia related to IIT.ConclusionEndocrine therapy in the ICU is entering a new era. Controversies remain related to glucocorticoid and insulin therapy even as interest in new, and old, endocrine therapies is being revived. (Endocr Pract. 2007;13:542-549)     

Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes

ObjectiveTo review the prevalence of, risk factors for, and prevention of hypoglycemia from the perspective of the pathophysiologic aspects of glucose counterregulation in diabetes.MethodsThis review is based on personal experience and research and the relevant literature.ResultsAlthough it can result from insulin excess alone, iatrogenic hypoglycemia is generally the result of the interplay of therapeutic insulin excess and compromised defenses against declining plasma glucose concentrations. Failure of β-cells of the pancreas—early in patients with type 1 diabetes mellitus but later in those with type 2 diabetes mellitus (T2DM)—causes loss of the first 2 physiologic defenses: a decrease in insulin and an increase in glucagon. Such patients are critically dependent on epinephrine, the third physiologic defense, and neurogenic symptoms that prompt the behavioral defense (carbohydrate ingestion). An attenuated sympathoadrenal response to declining glucose levels—caused by recent antecedent hypoglycemia, prior exercise, or sleep—causes hypoglycemia-associated autonomic failure (HAAF) and thus a vicious cycle of recurrent hypoglycemia. Accordingly, hypoglycemia is infrequent early in T2DM but becomes increasingly more frequent in advanced (absolutely endogenous insulin-deficient) T2DM, and risk factors for HAAF include absolute endogenous insulin deficiency; a history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se.ConclusionBy practicing hypoglycemia risk reduction— addressing the issue, applying the principles of aggressive glycemic therapy, and considering both the conventional risk factors and those indicative of HAAF— it is possible both to improve glycemic control and to minimize the risk of hypoglycemia in many patients. (Endocr Pract. 2008;14:750-756)     

Diagnosing Adrenal Insufficiency: Which Test is Best—The 1-μG or the 250-μG Cosyntropin Stimulation Test?

ObjectiveTo review the available literature on the low-dose cosyntropin stimulation test (CST) for the diagnosis of primary and secondary adrenal insufficiency in both nonstressed and acutely ill patients.MethodsWe performed a MEDLINE search of all English-language literature, published between 1965 and 2007, in which the 1-μg and the 250-μg CSTs were compared in patients with primary and secondary adrenal insufficiency.ResultsThe majority of published evidence suggests that the 1-μg CST is more sensitive than the 250-μg CST for the diagnosis of secondary adrenal insufficiency in nonstressed patients. In patients with primary adrenal insufficiency, the low-dose CST is unlikely to add any diagnostic sensitivity to the high-dose CST. In critically ill patients, the 1-μg test is also likely to be more sensitive than the 250-μg test when an appropriate cutoff value is used (25 μg/dL).ConclusionThe 1-μg CST with a cortisol level determined at 30 minutes after stimulation, with use of a cutoff level of 18 to 20 μg/dL in nonstressed patients and less than 25 μg/dL or an increment of less than 9 μg/dL from baseline in critically ill patients, is the best test that is currently available for establishing the diagnosis of secondary adrenal insufficiency. (Endocr Pract. 2008;14: 233-238)     

Addison’S Disease in Evolution: An Illustrative Case and Literature Review

ObjectiveTo present a case of symptomatic autoimmune adrenal insufficiency with initially normal serum cortisol and to caution about limitations of the current diagnostic algorithm for adrenal insufficiency, which does not reflect the pathophysiology of early disease.MethodsWe describe the clinical presentation and relevant investigations of a patient ultimately found to have Addison’s disease, which is followed by a focused review of the literature.ResultsA 41-year-old Caucasian woman with autoimmune hypothyroidism, premature ovarian failure, and microscopic colitis presented with nausea, salt craving, increased skin pigmentation, and postural hypotension. Initial bloodwork revealed a normal morning cortisol of level of 19.2 μg/dL (normal, 7.2 to 25 μg/dL) but an adrenocorticotropic hormone (ACTH) level 10 times normal, at 513.6 pg/mL (normal, < 52.5 pg/mL). Her potassium was normal, but her aldosterone level was 4.12 ng/dL (normal, 12.3 to 62.5 ng/dL) and her renin activity was increased (23.0 mg/dL/hour; normal, < 6.0 mg/dL/hour). Six weeks after initial presentation, she was found to have anti-adrenal antibodies. It was not until 10 weeks after her initial symptomatic presentation that her morning cortisol level was found to be subnormal and a formal diagnosis of adrenal insufficiency was made.ConclusionThe present case and literature review reveal that common diagnostic approaches will miss patients with (possibly symptomatic) early adrenal insufficiency. We suggest that serum ACTH level testing or tests of mineralocorticoid function be included in the initial step of investigation for suspected primary adrenal insufficiency. (Endocr Pract. 2014;20:e176-e179)     

Risk Factors for Hypoglycemia in Inpatients with Total Parenteral Nutrition and Type 2 Diabetes: A Post HOC Analysis of the Insupar Study

Objective: Treatment of hyperglycemia with insulin is associated with increased risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients receiving total parenteral nutrition (TPN). The aim of this study was to determine the predictors of hypoglycemia in hospitalized T2DM patients receiving TPN.Methods: Post hoc analysis of the INSUPAR study, which is a prospective, open-label, multicenter clinical trial of adult inpatients with T2DM in a noncritical setting with indication for TPN.Results: The study included 161 patients; 31 patients (19.3%) had hypoglycemic events, but none of them was severe. In univariate analysis, hypoglycemia was significantly associated with the presence of diabetes with end-organ damage, duration of diabetes, use of insulin prior to admission, glycemic variability (GV), belonging to the glargine insulin group in the INSUPAR trial, mean daily grams of lipids in TPN, mean insulin per 10 grams of carbohydrates, duration of TPN, and increase in urea during TPN. Multiple logistic regression analysis showed that the presence of diabetes with end-organ damage, GV, use of glargine insulin, and TPN duration were risk factors for hypoglycemia.Conclusion: The presence of T2DM with end-organ damage complications, longer TPN duration, belonging to the glargine insulin group, and greater GV are factors associated with the risk of hypoglycemia in diabetic noncritically ill inpatients with parenteral nutrition.Abbreviations: ADA = American Diabetes Association; BMI = body mass index; CV% = coefficient of variation; DM = diabetes mellitus; GI = glargine insulin; GV = glycemic variability; ICU = intensive care unit; RI = regular insulin; T2DM = type 2 diabetes mellitus; TPN = total parenteral nutrition     

Biochemical Diagnosis of Adrenal Insufficiency: the Added Value of Dehydroepiandrosterone Sulfate Measurements

ObjectiveTo review biochemical tests used in establishing the challenging diagnosis of adrenal insufficiency.MethodsWe reviewed the relevant literature, including our own data, on various biochemical tests used to determine adrenal function. The advantages and limitations of each approach are discussed.ResultsBaseline measurements of serum cortisol are helpful only when they are very low (≤ 5 μg/dL) or clearly elevated, whereas baseline plasma adrenocorticotropic hormone levels are helpful only when primary adrenal insufficiency is suspected. Measurements of baseline serum dehydroepiandrosterone sulfate (DHEA-S) levels are valuable in patients suspected of having adrenal insufficiency. Although serum DHEA-S levels are low in patients with primary or central adrenal insufficiency, a low level of this steroid is not sufficient by itself for establishing the diagnosis. A normal age- and sex-adjusted serum DHEA-S level, however, practically rules out the diagnosis of adrenal insufficiency. Many patients require dynamic biochemical studies, such as the 1-μg cosyntropin test, to assess adrenal function.ConclusionIn establishing the diagnosis of central adrenal insufficiency, we recommend measurements of baseline serum cortisol and DHEA-S levels. In addition to these, determination of plasma levels of aldosterone, adrenocorticotropic hormone, and renin activity is necessary when primary adrenal insufficiency is suspected. With a random serum cortisol level of ≥ 12 μg/dL in the ambulatory setting or a normal age- and sex-adjusted DHEA-S level (or both), the diagnosis of adrenal insufficiency is extremely unlikely. When serum DHEA-S levels are low or equivocal, however, dynamic testing will be necessary to determine hypothalamic-pituitary-adrenal axis function. (Endocr Pract. 2011;17:261-270)     

Danger of Hypoglycemia Due to Acute Tramadol Poisoning

ObjectiveTo report a case of prolonged hypoglycemia after acute tramadol poisoning.MethodsWe describe a patient’s clinical presentation and outcome with prolonged hypoglycemia attributable to acute tramadol poisoning. In addition, the possible mechanism for the hypoglycemia is discussed, and a brief review of the pertinent literature is presented.ResultsA 54-year-old woman had previously under- gone a partial hepatectomy because of involvement of her liver by a gastrointestinal stromal tumor. After ingestion of 3,000 mg of tramadol with suicidal intent, she developed prolonged hypoglycemia that necessitated treatment with continuous intravenous glucose infusion for 24 hours. Reports in the literature have described central nervous system depression, nausea, vomiting, tachycardia, seizures, and even death from tramadol overdoses.ConclusionThis report alerts clinicians to the potential danger of severe hypoglycemia in tramadol poisoning. (Endocr Pract. 2012;18:e151-e152)     

Effects of Pramlintide in Patients with Type 2 Diabetes Mellitus: An Analysis Using Daily Insulin Dose Tertiles

ObjectiveThe purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials.MethodsIn this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM.ResultsIn the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low.ConclusionThese results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use. (Endocr Pract. 2014;20:1070-1075)     

Insulin Therapy and Hypoglycemia in Type 2 Diabetes Mellitus

Background: Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes mellitus (DM), is the result of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations.Objective: The goal of this article was to review the available evidence on insulin therapy and hypoglycemia, with a focus on type 2 DM.Methods: This review was based on the author's clinical experience, his >3 decades of translational research in the area of hypoglycemia, and his knowledge of the relevant preclinical and clinical literature.Results: Glycemic defenses become compromised rapidly in type 1 DM but slowly in type 2 DM. As a result, the frequency of hypoglycemia increases progressively as patients approach the insulin-deficient end of the spectrum of type 2 DM. Indeed, it appears that most episodes of hypoglycemia, including those of severe hypoglycemia, occur in individuals with type 2 DM. The conventional risk factors for hypoglycemia are based on relative or absolute insulin excess. It is clear that the pathogenesis of hypoglycemia-associated autonomic failure, and thus an increased risk for iatrogenic hypoglycemia, stems fundamentally from insulin deficiency. Relevant additional risk factors include the degree of insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, or both, as well as recent antecedent hypoglycemia, prior exercise and sleep, and aggressive glycemic therapy per se in advanced type 2 DM, just as in type 1 DM. The prevention of hypoglycemia involves the practice of hypoglycemia risk reductionȔdiscussion of the issue, application of the principles of aggressive therapy, and consideration of both the conventional risk factors and those relevant to compromised glycemic defensesȔin advanced type 2 DM, just as in type 1 DM. With this approach, it is possible to improve glycemic control and reduce the frequency of hypoglycemia in many people with DM.Conclusions: Pending the prevention and cure of DM, people with this disease need safe and effective therapies. Ultimately, that will require glucose-regulated insulin replacement or secretion. In the meantime, insight into the mechanisms of hypoglycemia-associated autonomic failure may lead to interventions that will further improve the lives of people affected by DM by reducing the frequency of hypoglycemia without compromising glycemic control.(Insulin. 2007;2:127-133)     

Patients Achieving Good Glycemic Control (HBA1c <7%) Experience A Lower Rate of Hypoglycemia With Insulin Degludec Than with Insulin Glargine: A Meta-Analysis of Phase 3A Trials

Objective: Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A_1c [HbA_1c] <7% at end of trial).Methods: In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta-analysis compared hypoglycemia rates in patients achieving HbA_1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697).Results: In all trials, IDeg was noninferior to IGlar in HbA_1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA_1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar.Conclusion: Patients with T1DM and T2DM achieved HbA_1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period.Abbreviations: ERR = estimated rate ratio; HbA_1c = hemoglobin A_1c; IDeg = insulin degludec; IGlar = insulin glargine; NPH = Neutral Protamine Hagedorn; PG = plasma glucose; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus     

Iatrogenic Osteoporosis,Bilateral Hip Osteonecrosis,and Secondary Adrenal Suppression in an Hiv-Infected Man Receiving Inhaled Corticosteroids and Ritonavir-Boosted Highly Active Antiretroviral Therapy

ObjectiveTo report the first case of severe osteoporosis associated with a vertebral pathologic fracture and osteonecrosis of femoral heads in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted antiretroviral therapy.MethodsWe describe an HIV-infected man with severe osteoporosis, bilateral hip osteonecrosis, and secondary adrenal suppression, including detailed clinical, laboratory, and radiographic data, and review the related literature.ResultsA 60-year-old man with a 15-year history of HIV infection and a medical history of long-standing bronchiectasis treated with inhaled corticosteroids and hypogonadism treated with testosterone was referred to the endocrinology clinic after experiencing an osteoporotic vertebral fracture. He was taking ritonavir-boosted antiretroviral therapy. Osteonecrosis of both hips was also diagnosed, which required total hip replacement therapy.Laboratory evaluation revealed adrenal insufficiency due to increased effect of exogenous inhaled steroids and no other secondary causes of osteoporosis. A bone densitometry study showed osteoporosis of both hips and the lumbar spine. He was treated with intravenous pamidronate. During treatment, he developed bilateral femoral fractures after minor trauma.ConclusionsGiven the potential for increased serum levels of inhaled corticosteroids in patients taking ritonavirboosted highly active antiretroviral therapy, attention must be paid to the risk of bone loss in HIV-infected patients taking inhaled corticosteroids. Prescribing calcium and vitamin D supplementation and considering early osteoporosis screening are reasonable measures for this patient population. Interaction between inhaled corticosteroids and ritonavir may increase risk of hypothalamus-pituitary-adrenal axis suppression. (Endocr Pract. 2011;17:74-78)     

Identifying Risk Factors for Severe Hypoglycemia in Hospitalized Patients with Diabetes

ObjectiveSome of the deleterious effects of hypoglycemia in hospitalized patients include increased rates of mortality and longer length of stay. Our primary objective was to identify the risk factors associated with severe hypoglycemia to identify those patients at highest risk.MethodsThe medical records of 5,026 patients with diabetes mellitus (DM) admitted in 2010 were reviewed to identify those patients that developed severe hypoglycemia (blood glucose [BG] < 40 mg/dL). We performed c2 tests to assess statistical significance. Adjusted logical regression was used to determine the risk factors for hypoglycemia in the hospital.ResultsOut of 5,026 DM patients included in our review, 81 experienced severe hypoglycemia (1.6%). Statistically higher proportions of chronic kidney disease (CKD; 69.1% vs. 46.9%, P < .001), congestive heart failure (CHF; 48.1% vs. 28.5%, P < .001), sepsis (49.4% vs. 12.5%, P < .001), insulin use (45.7% vs. 26.04%, P = .000), type 1 DM (21% vs. 5.1%, P = .000), and cirrhosis (14.8% vs. 7.2%, P = .009) were seen in the severe hypoglycemic group compared to the nonsevere hypoglycemic group. Overall, 84% of patients who experienced an episode of severe hypoglycemia in the hospital (BG < 40 mg/dL) had a previous episode of hypoglycemia (BG < 70 mg/dL). The odds ratios (ORs) for type 1 DM, sepsis, previous hypoglycemia, and insulin use were 3.43 (95% confidence interval [CI] 1.81, 6.49), 2.64 (95% CI 1.6, 4.35), 46.1 (95% CI 24.76, 85.74), and 1.66 (95% CI 1.02, 2.69), respectively.ConclusionPrior episodes of hypoglycemia in the hospital, the presence of type 1 DM, insulin use, and sepsis were identified as independent risk factors for the development of severe hypoglycemia in the hospital. (Endocr Pract. 2014;20:1051-1056)     

A Bridge to Insulin Pump Therapy: Twice-Daily Regimen with NPH and Detemir Insulins During Initial Treatment of Youth with Type 1 Diabetes Mellitus

ObjectiveTo describe clinical outcomes in youth with new-onset type 1 diabetes mellitus (TlDM) treated with a modified, twice-daily regimen of a mixture of NPH insulin and rapid-acting insulin analogue at breakfast and separate injections of rapid-acting insulin analogue and insulin detemir at dinner.MethodsOur clinic database was used to describe changes in insulin doses, hemoglobin A_1c (A1C) levels, and frequency of severe hypoglycemia during the first year of therapy in young patients with T1DM diagnosed between September 2006 and April 2009. Data are presented as median values (25%, 75%).ResultsOverall, 108 patients (62 girls; mean age, 10.0 ± 0.4 years) were eligible for inclusion. Total daily insulin doses at 3, 6, and 12 months were 0.6 (0.4, 0.8), 0.7 (0.4, 0.9), and 0.8 (0.6, 0.9) U/kg, respectively. A1C levels were 9.8% (8.5%, 10.8%) at 2 weeks (baseline). Of the 108 patients, 19 had switched to insulin pump therapy by 3 months and 49 had switched by 12 months after initial diagnosis of T1DM. The 49 pump-treated patients had an A1C of 6.9% (6.6%, 7.3%), whereas the 59 injection- treated patients had an A1C of 7.2% (6.7%, 7.7%) by 12 months. There were only 6 severe hypoglycemic events in 5 patients; none occurred during the first 3 months, none occurred during the night, and all occurred in patients receiving insulin injection treatment.ConclusionA twice-daily insulin regimen that uses insulin detemir for overnight basal replacement and morning NPH insulin to avoid lunch and afternoon snack doses is an effective initial treatment for young patients with new-onset T1DM that can provide a smooth transition to intensive basal/bolus insulin pump therapy. (Endocr Pract. 2011;17:862-866)     

Adrenal Insufficiency Attributable to Adrenal Hemorrhage: Long-Term Follow-Up with Reference to Glucocorticoid and Mineralocorticoid Function and Replacement

ObjectiveTo describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage.MethodsWe performed a retrospective review of medical records of four patients who underwent follow-up for 6½ to 19 years.ResultsDespite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6½ to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5½ to 11½ years after bilateral adrenal hemorrhage in three of the four patients.ConclusionLong-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients. (Endocr Pract. 2004;10: 55-61)     

Efficacy and Safety of Insulin Lispro in Obese Patients with Type 2 Diabetes: A Retrospective Meta-Analysis of 7 Randomized Controlled Trials

ObjectiveTo evaluate the efficacy and safety of insulin lispro in the treatment of patients with type 2 diabetes (T2DM) who had a body mass index (BMI) ≥ 30 kg/m² (obese) compared with patients with BMIs < 30 kg/m² (nonobese).MethodsA retrospective analysis of predefined endpoints from 7 randomized clinical trials of T2DM patients treated with insulin lispro was performed. The primary efficacy measure was to assess the noninferiority of insulin lispro in obese patients versus nonobese patients as measured by the change in hemoglobin A1C (HbA_1c) from baseline to Month 3 (n = 1,518), using a noninferiority margin of 0.4%. The secondary measures included overall hypoglycemia incidence and event rates and relative change in body weight.ResultsMean changes in HbA_1c from baseline (9.06% for obese and 8.92% for nonobese) to Month 3 were similar for obese patients (–1.03%) and nonobese (–1.02%), with a least squares (LS) mean difference (95% confidence interval [CI]) of –0.05% (–0.17%, 0.07%; P = .384). The overall incidence of hypoglycemia (53% vs. 63%; P < .001) and rate of hypoglycemia (0.93 vs. 1.76 events per 30 days; P < .001) was significantly lower in obese patients compared with nonobese patients. The 2 BMI cohorts did not demonstrate a significant difference in mean percent changes in body weights (LS mean difference = 0.4% [–0.2%, 0.9%]; P = .202).ConclusionObese patients with T2DM treated with insulin lispro were able to achieve the same level of glycemic control as their nonobese counterparts, with some evidence supporting a reduced risk of hypoglycemia. (Endocr Pract. 2014;20:389-398)     

Significant Hypercortisolism During Fractionated Radiotherapy in a Patient with a Large Corticotroph Adenoma: A Case Report and Literature Review

ObjectiveWe describe a patient with a large, invasive corticotroph adenoma who developed severe hypercortisolism shortly after starting fractionated radiotherapy.MethodsWe reviewed the patient’s clinical course, along with relevant literature for similar reported cases.ResultsA 29-year-old man was referred for radiotherapy for a residual and recurrent, invasive corticotroph adenoma. Prior to radiotherapy, he had a normal urine free cortisol (UFC) level of 44.7 μg/24 hours, with minimal symptoms. Within 2 weeks of radiotherapy, he developed hypertension, ankle edema, and hypokalemia (potassium level, 2.8 mEq/L), with a markedly elevated UFC level of 9,203 μg/24 hours. His UFC gradually decreased and normalized by the end of radiotherapy. One month later, the patient became adrenal insufficient, with a nondetectable 24-hour UFC. His adrenal function slowly recovered in 3 months. We are aware of only one previous case report of clinically significant hypercortisolism following radiotherapy in Cushing disease.ConclusionRadiotherapy may result in acute severe hypercortisolism in patients with a large corticotroph adenoma. This uncommon, but clinically significant, acute adverse effect of radiotherapy suggests that clinical observation and biochemical monitoring during or soon after radiotherapy may be indicated. (Endocr Pract. 2014;20:e166-e170)     

A 24-Week,Prospective, Randomized,Open-Label,Treat-To-Target Pilot Study of Obese Type 2 Diabetes Patients with Severe Insulin Resistance to Assess the Addition of Exenatide on the Efficacy of U-500 Regular Insulin Plus Metformin

ObjectiveTo compare the efficacy of 500 U/mL (U-500) regular insulin + metformin with U-500 regular insulin + metformin + exenatide in improving glycemic control in patients with severely insulin-resistant type 2 diabetes mellitus (T2DM).MethodsThirty patients with T2DM and severe insulin resistance were screened, and 28 were randomized to regular insulin U-500 + metformin or the GLP-1 analog exenatide, U-500, and metformin. Glycated hemoglobin (HbA_1c) levels, body weight, and insulin doses were documented at baseline and at 3 and 6 months. The number and severity hypoglycemic episodes were noted.ResultsThere were 7 males and 7 females in each group (U-500 + metformin and U-500 + metformin + exenatide). Overall, U-500 insulin + metformin, either alone or with the addition of exenatide, resulted in a significant improvement in HbA_1c in both groups, with no significant difference between the 2 groups. There was no meaningful weight change in those utilizing exenatide. Those on U-500 insulin and metformin alone had a tendency toward some weight gain. No severe hypoglycemia occurred during the study period. Symptomatic hypoglycemia was more common in the group on exenatide, but this occurred in only 5 patients, and the clinical significance of this is uncertain. Insulin dosage changes on U-500 regular insulin were variable but tended to be lower in those subjects on exenatide.ConclusionsU-500 regular insulin + metformin is effective for the treatment of T2DM patients with severe insulin resistance. The addition of exenatide may ameliorate potential weight gain but provides no additional improvement in glycemia. (Endocr Pract. 2014;20:1143-1150)     

Autoimmune Hyperthyroidism due to Secondary Adrenal Insufficiency: Resolution with Glucocorticoids

ObjectiveTo describe the course of autoimmune hyperthyroid disease in a patient with corticotropin (ACTH) deficiency treated with glucocorticoids.MethodsWe report the clinical presentation, laboratory data, imaging studies, and management of a patient with weight loss, fatigue, apathy, hallucinations, and arthritis.ResultsAutoimmune hyperthyroidism (positive thyroperoxidase and thyroglobulin antibodies and borderline positive thyrotropin receptor antibody) was diagnosed in a 71-year-old woman. New psychotic symptoms prompted brain magnetic resonance imaging, which revealed a partially empty sella. Undetectable morning cortisol, undetectable ACTH, and failure to stimulate cortisol with synthetic ACTH (cosyntropin 250 mcg) secured the diagnosis of long-standing secondary adrenal insufficiency. Hydrocortisone replacement improved the patient’s symptoms, resolved the thyroid disease, and decreased thyroid antibody titers. In retrospect, the patient recalled severe postpartum hemorrhage requiring blood transfusion at age 38 years. A Sheehan event probably occurred 33 years before the patient presented with corticotropin deficiency. Hyperthyroidism accelerated cortisol metabolism and provoked symptoms of adrenal insufficiency.ConclusionsThe hypocortisolemic state may precipitate hyperimmunity and autoimmune thyroid disease. Rapid resolution of hyperthyroidism and decreased thyroid antibody titers with glucocorticoid treatment support this hypothesis. (Endocr Pract. 2011;17:85-90)     

Diabetes Duration and the Efficacy and Safety of Insulin Glargine Versus Comparator Treatment in Patients with Type 2 Diabetes Mellitus

ObjectiveTo evaluate the effect of diabetes duration on efficacy and safety in patients with type 2 diabetes mellitus (T2DM) using insulin glargine versus comparator (oral antidiabetic drugs [OADs], dietary changes, or other insulins).MethodsData were pooled from randomized controlled clinical trials conducted in adults with T2DM with at least 24-week treatment with insulin glargine or a comparator, where predefined insulin titration algorithms were utilized to achieve fasting plasma glucose (FPG) concentrations of ≤ 100 mg/dL. Glycated hemoglobin A1C (A1C), FPG, and insulin dose and safety (hypoglycemia) outcomes were analyzed.ResultsNine studies were included in the analysis of 2,930 patients. Patients with shorter duration of diabetes were more likely to have greater reductions in A1C compared with those who had longer-duration disease (P < .0001). Disease duration did not affect change in FPG concentrations (P = .9017), but lower weight-adjusted insulin dose was correlated with longer-duration disease (P < .0001). Patients with longer-duration diabetes had increased risks of symptomatic hypoglycemia, confirmed hypoglycemia (self-monitored blood glucose < 50 mg/dL and < 70 mg/dL), and nocturnal hypoglycemia (all P < .001). No significant relationship was found between severe hypoglycemia and duration of diabetes. However, treatment with insulin glargine lowered A1C values more effectively than comparator treatments with fewer hypoglycemic episodes.ConclusionPatients with shorter-duration T2DM better achieved target A1C levels and had less hypoglycemia than those with longer disease duration. Insulin glargine was associated with reduced A1C and fewer hypoglycemic events than comparators, regardless of disease duration. (Endocr Pract. 2014;20:120-128)