Overview of Data Concerning the Safe Use of Antihyperglycemic Medications in Type 2 Diabetes Mellitus and Chronic Kidney Disease.

INTRODUCTION: It can be a challenge to manage glycemic control in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), due to both patient and medication issues. Although most antihyperglycemic medications can be used in mild kidney disease, many medications are either not advised or require dose adjustments in more advanced CKD. This review summarizes product label information, pharmacokinetic and clinical studies, and clinical guidelines relevant to use of antihyperglycemic medications in CKD. METHODS: Product labels and guidelines from North America and Europe, as well as pharmacokinetic and clinical studies of diabetes medication use in CKD were identified through Medline and PubMed searches, up to February 2015. Available data are summarized and correlations between treatment recommendations and available research are discussed, as are glycemic targets for patients with CKD. RESULTS: Newer medications have significantly more data available than older medications regarding use in CKD, although larger clinical studies are still lacking for some drugs. As CKD advances, dose adjustment is needed for many medications [numerous dipeptidyl peptidase-4 inhibitors, some insulins, sodium glucose co-transporter 2 (SGLT2) inhibitors], although not for others (thiazolidinediones, meglitinides). Some medications are not recommended for use in more advanced CKD (metformin, SGLT2 inhibitors, some glucagon-like protein-1 receptor agonists) for safety or efficacy reasons. There is not always good alignment between label recommendations, pharmacokinetic or clinical studies, and guideline recommendations for use of these drugs in CKD. In particular, controversy remains about the use of metformin in moderate CKD and appropriate use of liraglutide and sulfonylureas in advanced CKD. CONCLUSION: Considerable variability exists with respect to recommendations and clinical data for the many antihyperglycemic drugs used in patients with T2DM and CKD. FUNDING: Eli Lilly and Company.

Early discontinuation and restart of insulin in the treatment of type 2 diabetes mellitus.

INTRODUCTION: Although the largest improvement in glycemic control occurs within the first 90 days of insulin therapy, little is known about early persistence on insulin therapy. This research aimed to identify predictors of early discontinuation and of subsequent restart of basal or mixture insulin among patients with type 2 diabetes mellitus (T2DM) and to assess the economic cost associated with such behaviors over a 1-year period. METHODS: Truven's Health Analytics Commercial Claims and Encounters database was utilized for the study. Logistic regressions were used to examine factors associated with early discontinuation of insulin (basal or mixture) and, among patients who discontinued early, the factors associated with restarting. Cost regressions were estimated using generalized linear models with a gamma distribution and logistic link. Kaplan-Meier survival curves were used to examine time to discontinuation and time to restart among those who discontinued. RESULTS: Multivariate analyses revealed that patient characteristics, prior healthcare resource utilization, comorbid diagnoses, and type of initiated insulin were associated with early discontinuation of insulin and of restarting among patients who discontinued early. Acute care (hospitalization and emergency room) costs were 9.6% higher among patients who discontinued early (P < 0.001), although outpatient, drug, and total costs were significantly lower among individuals who discontinued early. Among the early discontinuation subgroup, restarting insulin was associated with higher costs. Specifically: 11.3% higher acute care costs (P < 0.001), 24.0% higher outpatient costs (P < 0.001), 80.2% higher drug costs (P < 0.001), and 30.3% higher total costs (P < 0.001), compared to patients who discontinued early but did not restart insulin therapy in the 1-year post-period. CONCLUSION: Among patients with T2DM who were initiated on insulin therapy, early discontinuation of insulin and its subsequent restart were associated with significantly higher acute care costs, which may signal a more complex and challenging subgroup of patients who tend to be less engaged in outpatient care and may have poorer long-term outcomes.

Effect of protein kinase Cbeta inhibition on renal hemodynamic function and urinary biomarkers in humans with type 1 diabetes: a pilot study.

OBJECTIVE: The aim of this study was to examine the effect of protein kinase Cbeta inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Albuminuric subjects were randomized (2:1) to ruboxistaurin (32 mg daily; n = 13) or placebo (n = 7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia or hyperglycemia and before and after ruboxistaurin or placebo. RESULTS: Ruboxistaurin was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post hoc analysis comparing hyperfilterers with normofilterers during euglycemia, glomerular filtration rate and MCP-1 decreased, whereas the epidermal growth factor-to-MCP-1 ratio increased in hyperfilterers versus normofilterers (all P < 0.05). CONCLUSIONS: The effect of ruboxistaurin is modest and dependent, at least in part, on the level of ambient glycemia and baseline glomerular filtration rate.

Assessing compliance, acceptance, and tolerability of teriparatide in patients with osteoporosis who fractured while on antiresorptive treatment or were intolerant to previous antiresorptive treatment: an 18-month, multicenter, open-label, prospective study.

BACKGROUND: Teriparatide (parathyroid hormone [1-34] [ribosomal DNA origin]) stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. It has been found to significantly reduce vertebral fractures by 65%, and nonvertebral fragility fractures by 53% in treatment-naive postmenopausal women who have previously suffered a vertebral fracture. OBJECTIVE: This study examined the compliance, acceptance, and adherance of SC teriparatide 20 pg QD. METHODS: In this 18-month, multicenter, openlabel, prospective study, women with postmenopausal osteoporosis, and men >30 years of age with either idiopathic or hypogonadal osteoporosis (with low bone mass [T-score of -1 or worse] and > or =1 fragility fracture), who had experienced a treatment-related adverse event (AE) or an inadequate response while receiving antiresorptive treatment, and who were willing to receive open-label teriparatide for > or =18 months were eligible. Compliance was defined as self-reported use of > or =80% of study medication. Acceptance of the injection pen was determined by scores obtained from questionnaires and rating scales measuring patients' perception. Patients self-reported on injection discomfort, ease of use, and the overall injection administration. Acceptance was assessed at baseline, and 3, 6, and 18 months. AEs were recorded at each clinical visit from the patients' self-reports. At the 3-month visit, a serum calcium level was drawn > or =16 hours after the previous teriparatide dose. RESULTS: In this study, 116 patients-102 women with postmenopausal osteoporosis and 14 men (12 with idiopathic osteoporosis and 2 with hypogonadal osteoporosis)-were assessed for inclusion in the study. The mean (SD) age was 68.8 (11.1) years (range, 40-89 years) and the mean (SD) weight was 60.5 (11.7) kg (range, 37-87 kg). Seventy-three percent of the patients in this study had baseline spinal T-scores < or =-2.5, and 72% had fractured during treatment with an osteoporosis medication. Reported compliance was 89% at 6 months and 82% at 18 months. At baseline, 42% of patients were concerned about injection discomfort, and 43% were somewhat concerned with daily injections, while 7% were quite concerned. At 6 months, most patients reported much less concern (49%) or no concern (42%). Patient perceptions associated with learning how to use the pen injection, attaching the needle, holding the pen, and injecting the dose, improved during the first 6 months of the study. The most commonly reported AEs were dizziness, 12 (10.3%); nausea, 12 (10.3%); back pain, 9 (7.8%); and muscle cramps, 9 (7.8%). No AEs were believed to be associated with the use of the pen injection or teriparatide. Five patients had mildly elevated serum calcium concentrations (maximum value 2.8 mmol/L) at 3 months. However, all were normal on repeat testing approximately 4 weeks thereafter. CONCLUSIONS: This study found that teriparatide pen injection was well accepted in these patients, and acceptance rates improved during the first 6 months of treatment and, thereafter, improved slightly for approximately 18 months. Reported compliance remained high throughout the study (82%-89%). Teriparatide pen injection was a viable treatment in these osteopenic or osteoporotic patients with fragility fractures.

Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass.

UNLABELLED: The double-blind, randomized raloxifene alendronate comparison trial was the first study designed to compare two osteoporosis therapies head-to-head for fracture risk reduction. The original protocol planned to treat 3000 postmenopausal women with alendronate 10 mg/day (ALN) or raloxifene 60 mg/day (RLX) for 5 years, and to recruit women (50-80 years old) with a femoral neck bone mineral density (BMD) T-score between -2.5 and -4.0, inclusive, no prevalent vertebral fractures, and no prior bone-active agent use. The trial was stopped early, due to difficulty in finding treatment-naïve women to meet enrollment goals within the planned timeline, resulting in insufficient power to show non-inferiority between therapies in the primary endpoint (number of women with >or=1 new osteoporotic vertebral or nonvertebral fracture). Except for vertebral fractures, fracture analyses were based upon 1412 of the 1423 women randomized (mean age of 66 years). After 312+/-254 days (mean+/-SD), 22 women in the ALN group and 20 in the RLX group had new vertebral or nonvertebral fractures. Four women in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04). Lumbar spine, femoral neck, and total hip BMD were increased from baseline at 2 years in each group (P<0.001), with greater increases in the ALN group (each P<0.05). Similar numbers of women in each group had >or=1 adverse event and discontinued due to an adverse event. The only adverse events with an incidence that differed between groups were colonoscopy, diarrhea, and nausea; each was more common with ALN treatment (each P<0.05). One woman in each group had a venous thromboembolic event. One case of breast cancer occurred in each group. In summary, as this trial was terminated early, there was insufficient power to compare the fracture risks between alendronate and raloxifene. Safety profiles were as expected from clinical trial and post-marketing reports. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00035971.

A Canadian observational study of the optimal method of transition from postmenopausal hormone therapy to raloxifene.

OBJECTIVE: To determine the optimal method of transition from postmenopausal hormone therapy (HT) to raloxifene (RLX) therapy in order to minimize hot flashes and night sweats. METHODS: Postmenopausal women in Canada who had discontinued HT (estrogen with or without progestogen) in the preceding nine months and who were starting RLX were followed for approximately nine months in this observational study. The method of transition from HT to RLX therapy (method and duration of tapering HT, duration of washout) and the frequency and severity of hot flashes during the transition and RLX treatment periods were recorded. RESULTS: There were 373 women who participated in this study. Most women (86.3%) had a washout period between HT and RLX, and 55.2% had tapered their HT in some fashion. After beginning RLX, women who had had a washout duration of more than one week were found to be more likely to have an improvement in the severity of hot flashes (odds ratio [OR] = 6.3), and in the frequency of hot flashes (OR = 4.6), than women with a shorter washout or no washout period at all. The method of tapering of HT did not seem to affect either the severity or the frequency of hot flashes once on RLX. Women who had undergone a tapering period of more than one week's duration were more likely (OR = 2.6) to experience an improvement in the frequency (but not the severity) of hot flashes on RLX. CONCLUSION: Women who had a washout period following HT had better amelioration of hot flashes on RLX therapy.