A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents.

AIMS: Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed-dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. METHODS: We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two-part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double-blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. RESULTS: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: -2.3% and -1.8% (p < 0.001 for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. CONCLUSIONS: A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated.

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus.

AIMS: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed-dose combination of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes. METHODS: This double-blind study (18-week Phase A and 26-week Phase B) randomized 1250 drug-naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. RESULTS: At week 18, mean change from baseline HbA1c was -2.4% for sitagliptin/metformin FDC and -1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (-3.8 mmol/l) versus metformin monotherapy (-3.0 mmol/l; p < 0.001). Homeostasis model assessment of ß-cell function (HOMA-ß) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. CONCLUSION: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.

Use of cold iodine in patients with Graves' disease: observations from a clinical practice.

OBJECTIVE: To determine the efficacy and safety of cold iodine after radioactive iodine therapy (RAI) and the effects of prior antithyroid drug therapy in patients with Graves' disease. METHODS: We undertook a review of medical records of 280 consecutive patients with Graves' disease who were treated with RAI followed by cold iodine. Logistic regression methods were used to model treatment failure. RESULTS: Of the 280 patients, 246 (88%) were successfully treated with a single dose of RAI, whereas 34 patients (12%) required further therapy. The mean duration of time to achieve euthyroidism or hypothyroidism in successfully treated patients was 68 days. Of the 209 patients who were never given antithyroid drugs (ATDs), 190 (91%) were successfully treated with a single dose of RAI. No differences were found in patient age, thyroid gland size, or initial free thyroxine index between the successfully treated group and the treatment failure group among those who received RAI alone. Of the 71 patients who had been treated with ATDs before RAI administration, 56 (79%) were successfully treated with a single dose of RAI. The treatment failure rate of 21% in patients who had received ATDs was significantly higher than the 9% failure rate observed in those who were never given ATDs (P = 0.01). Multivariate analysis showed that larger gland size increased the likelihood of treatment failure [c2(2) = 11.76)] and prior treatment with ATDs doubled the risk of treatment failure after adjusting for gland size. No serious adverse events were noted after RAI or cold iodine therapy. CONCLUSION: Treatment of Graves' disease with RAI followed by cold iodine was safe and effective. The use of ATDs before 131I ablation resulted in a 2.3-fold higher treatment failure rate. ATDs need be used only in high-risk persons, and if such therapy is undertaken, higher doses of 131I should be administered to reduce the incidence of treatment failure.

Promising new approaches.

Insulin resistance in liver and muscle tissue, together with beta-cell secretory defects, leads to overt type 2 diabetes mellitus. In the early stages of this progressive disorder, glycaemic control can be established through diet and exercise alone. Indeed, in some patients, marked weight reduction can lead to normalized fasting blood glucose. As a consequence, pharmacological approaches to weight loss have been investigated as a new option for the management of type 2 diabetes in obese patients. The serotonin- and noradrenaline-reuptake inhibitor sibutramine has emerged as the most promising agent in the treatment of obesity, although it appears to be less effective in diabetic patients than in non-diabetic patients. Other weight-reducing agents of potential benefit include noradrenergic anorexiants, orlistat, leptin, and beta3-agonists. Insulin and insulin secretagogues, the oldest available antidiabetic drugs, have been used to compensate for beta-cell secretory defects in patients with type 2 diabetes. Repaglinide, a new, fast-acting insulin secretagogue with a short duration of action, reduces postprandial hyperglycaemia when taken shortly before meals. Other novel antidiabetic agents are currently under development, including pramlintide (an amylin analogue) and glucagon-like peptide. Pramlintide slows gastric emptying and delays glucose absorption, and glucagon-like peptide is the most potent endogenous stimulator of glucose-induced insulin release. Recent advances in type 2 diabetes therapy have seen the development of the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), which improve insulin resistance in patients whose diabetes is poorly controlled by diet and exercise therapy. Thiazolidinediones bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and act through a process involving gene regulation at a transcriptional level. Troglitazone, the first approved drug in the class, has been shown to decrease plasma glucose levels as monotherapy but is more effective in combination with sulphonylureas, metformin, or insulin. However, despite its generally good safety profile, troglitazone has been associated with severe idiosyncratic hepatocellular injury. There have been more than 150 spontaneous reports of serious hepatic events, including at least 25 instances in which patients died or required a liver transplant. Rosiglitazone, the most potent thiazolidinedione, is still in clinical development, as is pioglitazone. To date, rosiglitazone has been shown to have no reported cases of idiosyncratic drug reactions leading to jaundice or liver failure and no clinically significant drug interactions with cytochrome P450 3A4-metabolized drugs such as nifedipine. Although the available data for pioglitazone are limited to the results of short-term studies, it is reported to be safe and well tolerated. Combination therapy is increasingly important in type 2 diabetes management following failure of monotherapy because complementary mechanisms of action of the different classes of oral agents demonstrate synergistic effects when used in combination. Oral agents may also be used as adjuncts to insulin for achieving glycaemic control.

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.

Endocrine emergencies. Recognizing clues to classic problems.

Although the possibility of an endocrine emergency occurring in a primary care setting may seem remote, awareness of such emergencies is crucial for appropriate management. While some symptoms are specific to classic endocrine disorders, other symptoms, such as nausea, vomiting, and diarrhea, are so general that the diagnosis may not be considered initially. In these situations, careful and thoughtful diagnostic studies can be lifesaving.

Pattern of recovery of the hypothalamic-pituitary-thyroid axis following radioactive iodine therapy in patients with Graves' disease.

PURPOSE: To characterize the time course of recovery of the hypothalamic-pituitary-thyroid (HPT) axis by determining the frequency, onset, duration, and clinical attributes of the central hypothyroid phase following 131I therapy for Graves' disease and to examine whether the central hypothyroid phase is due to direct pituitary thyrotroph suppression or to hypothalamic thyrotropin-releasing hormone (TRH) deficiency. PATIENTS AND METHODS: Twenty-one hyperthyroid patients with Graves' disease evaluated at a university endocrine clinic and treated with radioactive iodine were prospectively studied. Serial thyroid function levels (serum thyroxine [T4], free thyroxine [free T4], triiodothyronine [T3], and thyroid-stimulating hormone [TSH]) were measured and TRH stimulation tests were performed at 2 to 4 week intervals for all subjects following 131I treatment. None of the patients was treated with thionamides after receiving 131I therapy. RESULTS: Nineteen (90%) of the patients with Graves' disease experienced a transient central hypothyroid phase defined as the presence of a suppressed or inappropriately normal TSH level despite a low free T4 level following 131I treatment. This phase occurred a mean of 62.8 +/- 5.1 days following 131I treatment, persisted for an average of 24.7 +/- 2.4 days, and was not predictive of eventual treatment outcome. All patients had concordantly low T4 and T3 levels during this period and exhibited a blunted TSH response to TRH compared to 29 euthyroid control subjects, suggesting primary feedback suppression at the level of the pituitary thyrotrophs. The suppressed thyrotrophs required a minimum of 2 weeks to recover once patients became hypothyroid. The length of preexisting hyperthyroidism, basal free T4 elevation, and administered dose of 131I failed to predict the duration of the central hypothyroid phase, although a higher dose of 131I was associated with an earlier onset of central hypothyroidism (r = -.51, P < 0.05). CONCLUSIONS: Clinicians should be aware of the delay in the recovery of the HPT axis that occurs in the majority of patients with Graves' disease treated with 131I and is manifested by a transient central hypothyroid phase. The blunted TSH response to TRH stimulation during this period suggests that suppression occurs primarily at the level of the pituitary thyrotrophs. The use of sensitive TSH measurements alone to monitor these patients during this period is not helpful and may be misleading.

Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM.

OBJECTIVE: To investigate the effect of chromium picolinate supplementation on the lipid profile of the predominantly Hispanic population of non-insulin-dependent diabetes mellitus (NIDDM) patients in San Antonio, Texas. RESEARCH DESIGN AND METHODS: A prospective, double-blind, placebo-controlled, crossover study was performed on 14 men and 16 women. Initially, each patient was randomly assigned to receive either chromium picolinate or placebo for 2 months. This initial treatment phase was followed by a 2-month washout period. Subjects were then crossed-over and received the alternate capsule for an additional 2 months. Fasting blood glucose, HbA1c, and serum lipids were compared at the end of each treatment phase. RESULTS: Twenty-eight of the originally enrolled 30 patients completed the study. There were no adverse reactions to chromium reported. There were no differences noted between the control and chromium-treated subjects in glucose control, high-density lipoprotein cholesterol levels, or low-density lipoprotein cholesterol levels. Triglyceride (TG) levels were reduced significantly (17.4%; P < 0.05) during the 2 months of chromium supplementation. CONCLUSIONS: Ours is the first report of a significant reduction in serum TGs in a group of NIDDM patients treated with chromium. The low cost and excellent safety profile of chromium make it an attractive lipid-lowering agent for this population. Long-term studies are needed to determine if the short-term changes in plasma lipids can be sustained.

The Diabetes Control and Complications Trial Study: implications for the diabetic foot.

The pathogenesis of foot problems in patients with diabetes mellitus involves multiple factors including macrovascular disease, microvascular disease, abnormalities in blood flow distribution, peripheral neuropathy, autonomic neuropathy, physical stress, and infection. Surprisingly, the role of poor glycemic control in the development of diabetic foot complications has not been well studied. Recently, the Diabetes Control and Complications Trial has provided conclusive evidence that hyperglycemia plays a major role in the development of microvascular complications. Because the etiologic factors that contribute to microvascular complications also play an important role in foot complications, one would expect that tight glycemic control, however achieved, would be effective in both the primary and secondary prevention of diabetic foot problems.

Elevated thyroxine levels in a euthyroid patient. A search for the cause of euthyroid hyperthyroxinemia.

A clinically euthyroid man with a family history of hyperthyroidism presented for evaluation of an elevated thyroxine (T4) level and an increased free T4 index with a normal thyrotropin (TSH) level. Results of thyroid hormone-binding protein tests confirmed the diagnosis of familial dysalbuminemic hyperthyroxinemia. This disorder should be considered in patients who have a normal serum TSH level, despite an elevated total T4 concentration. Accurate diagnosis is essential to avoid inappropriate treatment. Affected family members also should be identified. No treatment is required, because patients remain euthyroid and maintain a normal free T4 level.

Diabetic nephropathy: pathogenetic basis for treatment.

For maximal effectiveness, interventions to prevent diabetic nephropathy are initiated prior to clinically detectable proteinuria--during the microalbuminuria stage. Effects of therapy in relation to pathologic processes are described.

Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate.

We administered risedronate, a potent oral bisphosphonate, to patients with mild primary hyperparathyroidism in order to 1) determine if we could normalize the serum calcium concentration in the short term, and 2) analyze changes in the homeostatic mechanisms responsible for maintaining hypercalcemia in this patient population. When administered for 7 days, risedronate reduced fasting serum calcium concentrations without significant toxicity in patients with primary hyperparathyroidism. The decrease in serum calcium was accompanied by evidence of inhibition of bone resorption, as assessed by measurement of urinary hydroxyproline, increased serum immunoreactive PTH concentrations, enhanced renal tubular reabsorption of calcium, and a progressive decrease in serum alkaline phosphatase. Serum PTH was partially suppressed by an oral calcium load in untreated patients as well as in patients treated with risedronate. Although patients treated with risedronate had normal fasting serum calcium levels, serum calcium values in these normocalcemic patients were labile after oral ingestion of calcium. After daily calcium intake of 2 g, serum calcium levels in risedronate-treated patients were similar to those in untreated patients with primary hyperparathyroidism, suggesting that there are likely to be fluctuations in serum calcium in risedronate-treated patients with normal fasting serum calcium during postprandial periods. These studies show that risedronate lowers fasting serum calcium during short term treatment. However, further studies are required to determine whether the lability in serum calcium in these patients after an oral calcium load has clinical significance, and whether longer term treatment would maintain serum calcium in the normal range.

Multiple endocrine neoplasia type III.

The multiple endocrine neoplasia (MEN) syndromes are autosomally dominant inherited disorders in which hyperplastic or neoplastic changes occur in a wide variety of tissues. The specific syndromes are classified according to the endocrine glands affected. MEN type I consists of an aggregation of tumors of parathyroid, pancreatic, and pituitary glands. The association of medullary carcinoma of the thyroid (MCT) and pheochromocytoma is called MEN type II or type IIA, and if combined with mucosal neuromas, intestinal ganglioneuromatosis, and prominent corneal nerves, is named MEN type III or type IIB. Individuals afflicted with MEN type III are characterized by a marfanoid habitus, mucosal neuromas involving oral and ocular tissues, and a number of ophthalmologic findings including prominent corneal nerves, thickened eyelids, and subconjunctival neuromas. These features are easily recognized during the ocular exam, allowing the ophthalmologist to make an early diagnosis of this syndrome prior to the onset of life-threatening manifestations like medullary thyroid carcinoma and pheochromocytoma.

Thyrotoxicosis in the critically ill.

The thyrotoxic patient offers a considerable challenge to the critical care physician because the "obvious" diagnosis often will be a cardiac (or other nonthyroidal) problem, but the "correct" diagnosis will be an endocrinologic one. The importance of considering the diagnosis of thyrotoxicosis in any patient with tachyarrhythmias, new-onset congestive heart failure, weight loss, or change in mental status cannot be overstated. Treatment for presumed thyroid disease sometimes will have to be initiated prior to the availability of the results of diagnostic tests. Timely and appropriate treatment of the thyroid problem is vital for a successful outcome in treating patients with thyrotoxicosis.