Improved glucose control with reduced hypoglycaemic risk when linagliptin is added to basal insulin in elderly patients with type 2 diabetes.

AIM: To assess the efficacy, hypoglycaemia risk and other safety markers of linagliptin as an additional therapy in older patients (aged ≥70 years) inadequately controlled with basal insulin. METHODS: A prespecified safety analysis from the linagliptin trials programme was carried out to explore the hypoglycaemia risk when linagliptin was added to background basal insulin therapy in elderly patients (≥70 years). To do this, two eligible, randomized, placebo-controlled, clinical trials (NCT00954447 and NCT01084005) of 24 and ≥52 weeks, respectively, were analysed. RESULTS: A total of 247 elderly individuals [mean ± standard deviation (s.d.) age 74 ± 4 years, glycated haemoglobin (HbA1c) 8.2 ± 0.8%] on basal insulin (mean ± s.d. baseline dose 36 ± 25 IU/day) were identified. Alongside placebo-adjusted change in HbA1c with linagliptin of -0.77% [95% confidence interval (CI) -0.95 to 0.59; p < 0.0001] after 24 weeks, the hazard ratios (HRs) of both overall and confirmed hypoglycaemia [blood glucose ≤3.9 mmol/l (70 mg/dl)], were significantly lower with linagliptin than with placebo: HR 0.61 (95% CI 0.39-0.97) versus 0.59 (95% CI 0.37-0.94), respectively (both p < 0.05). Moreover, significantly less confirmed hypoglycaemia was present in linagliptin-treated patients with renal impairment [HR 0.45 (95% CI 0.27-0.76)], moderate hyperglycaemia [HbA1c 7.5 to <9.0%; HR 0.51 (95% CI 0.27-0.99)], lower fasting plasma glucose levels [<152 mg/dl; HR 0.49 (95% CI 0.28-0.86)] and those treated with higher insulin doses [insulin ≥35.6 IU/day; HR 0.46 (95% CI 0.23-0.91); p < 0.05 for all]. Severe hypoglycaemia was rare and the incidence was lower with linagliptin (0.8%) versus placebo (2.5%): HR 0.21 (95% CI 0.02-2.30). CONCLUSIONS: Despite improvements in hyperglycaemia and no relevant on-trial insulin dose reductions, adding linagliptin to basal insulin appears to decrease hypoglycaemia risk. The biological basis of this phenomenon warrants further research but may involve counter-regulatory effects of incretin hormones.

Progression to insulin therapy among patients with type 2 diabetes treated with sitagliptin or sulphonylurea plus metformin dual therapy.

AIM: To assess time to insulin initiation among patients with type 2 diabetes mellitus (T2DM) treated with sitagliptin versus sulphonylurea as add-on to metformin. METHODS: This retrospective cohort study used GE Centricity electronic medical records and included patients aged ≥18 years with continuous medical records and an initial prescription of sitagliptin or sulphonylurea (index date) with metformin for ≥90 days during 2006-2013. Sitagliptin and sulphonylurea users were matched 1 : 1 using propensity score matching, and differences in insulin initiation were assessed using Kaplan-Meier curves and Cox regression. We used conditional logistic regression to examine the likelihood of insulin use 1-6 years after the index date for each year. RESULTS: Propensity score matching produced 3864 matched pairs. Kaplan-Meier analysis showed that sitagliptin users had a lower risk of insulin initiation compared with sulphonylurea users (p = 0.003), with 26.6% of sitagliptin users initiating insulin versus 34.1% of sulphonylurea users over 6 years. This finding remained significant after adjusting for baseline characteristics (hazard ratio 0.76, 95% confidence interval 0.65-0.90). Conditional logistic regression analyses confirmed that sitagliptin users were less likely to initiate insulin compared with sulphonylurea users [odds ratios for years 1-6: 0.77, 0.79, 0.81, 0.57, 0.29 and 0.75, respectively (p < 0.05 for years 4 and 5)]. CONCLUSIONS: In this real-world matched cohort study, patients with T2DM treated with sitagliptin had a significantly lower risk of insulin initiation compared with patients treated with sulphonylurea, both as add-on to metformin.

A quantitative measure of diabetes risk in community practice impacts clinical decisions: the PREVAIL initiative.

BACKGROUND AND AIMS: While predictive tools are being developed to identify those at highest risk for developing diabetes, little is known whether these assays affect clinical care. METHODS AND RESULTS: Thirty sites who used the PreDx(®) (Tethys BioScience, Emeryville, CA) abstracted clinical information from baseline clinic visits prior to a PreDx test and from the most recent visit at time of abstraction. All visits occurred between May 2008-April 2011 (median follow-up 198 days, IQR 124-334). The primary analysis was the influence of the PreDx test (5-year diabetes prediction) on subsequent care; descriptive statistics were used to summarize baseline and follow-up variables. Overall 913 patients with 2 abstracted visits were included. Relative to baseline, median SBP decreased 1.5 mmHg (p = 0.039), DBP decreased 2 mmHg (p < 0.001), LDL-C decreased 4 mg/dL (p = 0.009), and HDL-C increased 2 mg/dL (p < 0.001) at follow-up. Behavioral or lifestyle counseling was not significantly different from baseline to follow-up (71.2% vs. 68.1% (p = 0.077), but BMI was lower by 0.2 kg/m(2) at follow up (p = 0.013). At follow-up, more patients were prescribed metformin (13.7% vs. 9.7%, p < 0.001). A higher PreDx score was significantly associated with metformin prescription (p = 0.0003), lifestyle counseling (p = 0.0099), and a lower BMI at follow-up (p = 0.007). CONCLUSION: The use of a prognostic test in patients perceived to be high risk for diabetes was associated with a modest but significant increase in the prescription of metformin and lifestyle interventions and a reduction in BMI.

Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function.

AIMS: The effects of sitagliptin and pioglitazone, alone and in combination, on α- and ß-cell function were assessed in patients with type 2 diabetes. METHODS: Following a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4 mmol/l were randomized (1 :1 :1 : 1) to sitagliptin, pioglitazone, sitagliptin + pioglitazone or placebo. At baseline and after 12 weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. RESULTS: After 12 weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin + pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin + pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin + pioglitazone versus pioglitazone or placebo. Φ(s), a measure of dynamic ß-cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin + pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin + pioglitazone versus placebo. The disposition index, a measure of the relationship between ß-cell function and insulin sensitivity, improved with all active treatments versus placebo. CONCLUSIONS: Sitagliptin and pioglitazone enhanced ß-cell function (increasing postmeal Φ(s)), and sitagliptin improved α-cell function (decreasing postmeal glucagon) after 12 weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.

Mechanism by which metformin reduces glucose production in type 2 diabetes.

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.

Clinical review 61: Effects of growth hormone on human bone biology.

GH has considerable importance in the normal development and growth of bone. An additional role in the maintenance of the adult skeleton is suggested by the alterations in bone mineral density observed in states of deficient or excess GH secretion and in the bone formation response to GH replacement in GHD patients. Deficiency in the secretion of GH is also observed, with increasing and striking frequency after middle-age despite the lack of any defined pituitary disease or injury. Although a causal relationship between hyposomatotropism and osteopenia in normal elderly patients is hypothetical, intriguing therapeutic questions are raised. Preliminary trials of hGH in osteoporosis have not resulted in increases in BMD, but such studies suffer from methodological limitations, chief of which is the failure to account for the GH/IGF-I status of their subjects. Osteopenic patients with the lowest IGF-I levels may need to be assessed independently. The utility of hGH may be in preventing the senile component of osteoporosis, which appears to result mainly from defective bone formation. Such studies will require appropriate patient selection, longer treatment periods, and more sensitive measures of bone density. Combination and/or coherence therapy with other agents, particularly those that attenuate bone resorption, may also prove useful.

Parathyroid hormone (PTH)-related protein(1-36) is equipotent to PTH(1-34) in humans.

Humoral hypercalcemia of malignancy (HHM) results from the production of PTH-related protein (PTHrP) by human tumors. One previous study has reported the results of human (h) PTHrP(1-34) infusion into humans. In that report, hPTHrP(1-34) was found to be qualitatively similar to but 3- to 10-fold less potent than hPTH(1-34). Because hPTHrP(1-36) and not hPTH(1-34) is likely to be the actual amino-terminal secretory form of PTHrP, and because this previously reported lack of potency was unexpected, we repeated these studies using hPTHrP(1-36) and compared the results with those obtained with hPTH(1-34). Healthy subjects (n = 30) were infused over 6 h with either vehicle alone, hPTH(1-34) at a dose of 8 pmol/kg.h, or hPTHrP(1-36) at doses of 8 or 80 pmol/kg.h. Both hPTH(1-34) and hPTHrP(1-36) caused an increase in serum ionized calcium, a decrease in serum phosphorus, an increase in the fractional excretion of phosphorus, a decrease in the tubular maximum for phosphorus, an increase in nephrogenous cAMP excretion, and suppression of endogenous PTH(1-84). Unlike events observed in HHM, hPTHrP(1-36) induced an increase in plasma 1,25-dihydroxyvitamin D2. In addition, fractional excretion of calcium was reduced by both hPTH(1-34) and hPTHrP(1-36). In their actions on serum calcium, renal calcium and phosphorus handling, and nephrogenous cAMP excretion, hPTHrP(1-36) and hPTH(1-34) appeared equivalent in potency. These studies indicate that short-term infusion of hPTHrP(1-36) into humans reproduces most but not all of the features of HHM. In contrast to the reported findings with hPTHrP(1-34), we found the potency of hPTHrP(1-36) to be comparable with that of hPTH(1-34) in vivo in humans. In addition, unlike the situation in HHM, hPTHrP(1-36) produces an increment in plasma 1,25-dihydroxyvitamin D2. Finally, hPTHrP(1-36) has been shown for the first time to have anticalciuric effects in humans. This would suggest that, in addition to osteoclastic bone resorption, tubular reabsorbtion of calcium by hPTHrP may contribute to the hypercalcemia in patients with HHM.

Insulin resistance and risk for stroke.

BACKGROUND AND PURPOSE: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance. METHODS: The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications. RESULTS: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke. CONCLUSION: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

Pulmonary hypertension caused by Graves' thyrotoxicosis: normal pulmonary hemodynamics restored by (131)I treatment.

We describe a case of pulmonary hypertension, initially thought to be idiopathic, which resolved after treatment of Graves' hyperthyroidism. Results of pulmonary artery catheterization before and after treatment are reported, and the effects of thyrotoxicosis on hemodynamics and pulmonary function are briefly reviewed. Possible mechanisms for development of pulmonary hypertension caused by hyperthyroidism include pulmonary vascular endothelial dysfunction or damage because of autoimmunity or the high cardiac output state, or increased metabolism of intrinsic pulmonary vasodilators.

Ectopic thymic carcinoid masquerading as a thyroid nodule.

A 26-year old woman presented with a thyroid nodule. Ultrasound and scintigraphy confirmed the presence of a 3.5-cm non-functioning mass in the left lobe. A fine needle aspiration demonstrated unusual, malignant-appearing cells, and thyroidectomy was performed. At gross pathological sectioning, the lesion was clearly attached to, but not part of, the thyroid. Microscopic features indicated an atypical carcinoid arising in a cervical remnant of the thymus. This appears to be the first case of ectopic thymic carcinoid presenting as a thyroid nodule.

Papillary thyroid carcinoma metastatic to the pituitary gland.

Many malignancies may present with metastases to the pituitary gland. The association of thyroid carcinoma with pituitary metastases is, however, very rare. This report describes two patients in whom metastases from a papillary thyroid carcinoma to the pituitary gland resulted in panhypopituitarism with blunted endogenous thyrotropin (TSH) production following withdrawal of levothyroxine. Both required the use of recombinant human TSH prior to radioiodine therapy. Symptoms of hypopituitarism may be difficult to distinguish clinically from those of hypothyroidism in the setting of levothyroxine withdrawal. Clinicians should be aware of the clinical and biochemical manifestations of this rare association.

Sequential hypoglycemia, hyperglycemia, and the carcinoid syndrome arising from a plurihormonal neuroendocrine neoplasm.

OBJECTIVE: To describe the first patient with a neuroendocrine tumor secreting serotonin, insulin, and glucagon and having the corresponding clinical syndromes. METHODS: We present a detailed case report, including serial laboratory and clinical findings, in a man with type 2 diabetes, symptomatic hypoglycemia, and the carcinoid syndrome and in whom a plurihormonal metastatic neuroendocrine neoplasm was ultimately diagnosed. RESULTS: In a 58-year-old man with type 2 diabetes, which was treated effectively with a sulfonylurea for 7 years, episodes of hypoglycemia developed. After discontinuation of the orally administered agent, the hypoglycemic episodes initially resolved but then recurred and were associated with inappropriately increased plasma insulin concentrations. In addition, the patient had symptoms and biochemical evidence of the carcinoid syndrome. Computed tomography of the abdomen showed multiple hypodense lesions in the liver, and ultrasound-guided fine-needle aspiration of a liver mass was performed. Undifferentiated neuroendocrine tumor with hepatic metastatic involvement was diagnosed. After a hepatic artery embolization procedure, the hypoglycemia was alleviated, but hyperglycemia soon recurred, associated with inappropriately increased serum glucagon concentrations. The patient's course strongly suggested the presence of a plurihormonal tumor secreting serotonin, insulin, and glucagon. CONCLUSION: To our knowledge, this is the first reported case of a patient with a neuroendocrine neoplasm secreting serotonin, glucagon, and insulin, manifested by the carcinoid syndrome, hyperglycemia, and hypoglycemia.

Relapsing and remitting severe hypoglycemia due to a monoclonal anti-insulin antibody heralding a case of multiple myeloma.

CONTEXT: We report a novel case of insulin autoimmune syndrome (IAS) presenting with hypoglycemia due to production of a monoclonal anti-insulin antibody in a patient subsequently found to have multiple myeloma (MM). OBJECTIVE: The aim of the study was to describe the 5-yr clinical course of a patient with IAS and MM and to characterize the origin and function of the pathogenic antibody. METHODS: We conducted a longitudinal case history with laboratory investigations to characterize the anti-insulin antibody subtype, specificity, affinity, and origin. RESULTS: The patient presented with IAS, which worsened during treatment of hepatitis C. The patient was then discovered to have a monoclonal gammopathy that progressed to MM. Treatment of the MM induced remission of the neoplasia and IAS, which then followed a synchronized course of progression and response to therapy. An anti-insulin IgG(3)-λ that bound specifically but with low affinity to the insulin B chain (amino acids 9-30) and that was distinct from the primary MM IgG(3)-κ clone was recovered from the patient and cloned. The antibody bound insulin and showed mutations of normal affinity maturation. CONCLUSIONS: We describe a case of MM heralded by IAS, where full characterization of the pathogenic antibody revealed that the monoclonal anti-insulin antibody had originated from a self-reactive clone.

Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs).

OBJECTIVE: Our purpose was to develop a geographically localized, multi-institution strategy for improving enrolment in a trial of secondary stroke prevention. METHODS: We invited 11 Connecticut hospitals to participate in a project named the Local Identification and Outreach Network (LION). Each hospital provided the names of patients with stroke or TIA, identified from electronic admission or discharge logs, to researchers at a central coordinating center. After obtaining permission from personal physicians, researchers contacted each patient to describe the study, screen for eligibility, and set up a home visit for consent. Researchers traveled throughout the state to enroll and follow participants. Outside the LION, investigators identified trial participants using conventional recruitment strategies. We compared recruitment success for the LION and other sites using data from January 1, 2005, through June 30, 2007. RESULTS: The average monthly randomization rate from the LION was 4.0 participants, compared with 0.46 at 104 other Insulin Resistance Intervention after Stroke (IRIS) sites. The LION randomized on average 1.52/1,000 beds/month, compared with 0.76/1,000 beds/month at other IRIS sites (p = 0.03). The average cost to randomize and follow one participant was $8,697 for the LION, compared with $7,198 for other sites. CONCLUSION: A geographically based network of institutions, served by a central coordinating center, randomized substantially more patients per month compared with sites outside of the network. The high enrollment rate was a result of surveillance at multiple institutions and greater productivity at each institution. Although the cost per patient was higher for the network, compared with nonnetwork sites, cost savings could result from more rapid completion of research.