Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. Design, Setting, and Participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Main Outcomes and Measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. Conclusions and Relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. Trial Registration: ClinicalTrials.gov Identifier: NCT01794143.

Evaluation of polygenic risk scores to differentiate between type 1 and type 2 diabetes.

Polygenic risk scores (PRS) quantify the genetic liability to disease and are calculated using an individual's genotype profile and disease-specific genome-wide association study (GWAS) summary statistics. Type 1 (T1D) and type 2 (T2D) diabetes both are determined in part by genetic loci. Correctly differentiating between types of diabetes is crucial for accurate diagnosis and treatment. PRS have the potential to address possible misclassification of T1D and T2D. Here we evaluated PRS models for T1D and T2D in European genetic ancestry participants from the UK Biobank (UKB) and then in the Michigan Genomics Initiative (MGI). Specifically, we investigated the utility of T1D and T2D PRS to discriminate between T1D, T2D, and controls in unrelated UKB individuals of European ancestry. We derived PRS models using external non-UKB GWAS. The T1D PRS model with the best discrimination between T1D cases and controls (area under the receiver operator curve [AUC] = 0.805) also yielded the best discrimination of T1D from T2D cases in the UKB (AUC = 0.792) and separation in MGI (AUC = 0.686). In contrast, the best T2D model did not discriminate between T1D and T2D cases (AUC = 0.527). Our analysis suggests that a T1D PRS model based on independent single nucleotide polymorphisms may help differentiate between T1D, T2D, and controls in individuals of European genetic ancestry.

Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports.

BACKGROUND: Since 2011 six immune checkpoint inhibitors (ICI) have been approved to treat patients with many advanced solid tumor and hematological malignancies to improve their prognosis. Case reports of their endocrine immune-related adverse events [irAEs]) are increasingly published as more real-world patients with these malignancies are treated with these drugs. They alert physicians of a drug's AEs (which may change during a drug's life cycle) and contribute to post-marketing safety surveillance. Using a modified framework of Arksey and O'Malley, we conducted a scoping review of the spectrum and characteristics of ICI-induced endocrinopathies case reports before and after ICIs are marketed. METHODS: In July 2017, we searched, without date and language restrictions, 4 citation databases for ICI-induced endocrinopathies. We also hand-searched articles' references, contents of relevant journals, and ran supplemental searches to capture recent reports through January 2018. For this study, a case should have information on type of cancer, type of ICI, clinical presentation, biochemical tests, treatment plus temporal association of ICI initiation with endocrinopathies. Two endocrinologists independently extracted the data which were then summarized and categorized. RESULTS: One hundred seventy nine articles reported 451 cases of ICI-induced endocrinopathies - 222 hypopituitarism, 152 thyroid disorders, 66 diabetes mellitus, 6 primary adrenal insufficiencies, 1 ACTH-dependent Cushing's syndrome, 1 hypoparathyroidism and 3 diabetes insipidus cases. Their clinical presentations reflect hormone excess or deficiency. Some were asymptomatic and others life-threatening. One or more endocrine glands could be affected. Polyglandular endocrinopathies could present simultaneously or in sequence. Many occur within 5 months of therapy initiation; a few occurred after ICI was stopped. Mostly irreversible, they required long-term hormone replacement. High dose steroids were used when non-endocrine AEs coexisted or as therapy in adrenal insufficiency. There was variability of information in the case reports but all met the study criteria to make a diagnosis. CONCLUSIONS: The spectrum of ICI-induced endocrinopathies is wide (5 glands affected) and their presentation varied (12 endocrinopathies). Clinical reasoning integrating clinical, biochemical and treatment information is needed to properly diagnose and manage them. Physicians should be vigilant for their occurrence and be able to diagnose, investigate and manage them appropriately at onset and follow-up.

Laboratory and Benchtop Performance of a Mealtime Insulin-Delivery System.

BACKGROUND: A basal bolus insulin regimen requires multiple daily insulin injections, which might discourage patient adherence. As a potential solution, a mealtime insulin-delivery system-a 3-day wearable bolus-only patch-was designed to manually administer mealtime insulin discreetly by actuating buttons through clothing, without the need for multiple needle sticks. METHOD: Extensive functional testing of the patch included dose accuracy (from initial fill of the device to empty), pressure-vacuum leak testing, last-dose lockout and occlusion detection (safety alert features that lock the dosing buttons when no insulin is delivered), assessments of insulin drug stability, toxicological risk (including chemical testing), and system biocompatibility. RESULTS: Dosing accuracy was 2 units ±10% (with U-100 insulin) over a range of environmental conditions, with ≥95% reliability and confidence. The fluid seal performance and the safety alert features performed with ≥95% reliability and ≥95% confidence. The system met acceptable standards for insulin (U-100 lispro and aspart) stability for its intended 3-day use, in addition to the operational requirements. The toxicological risk assessment and demonstrated biocompatibility suggested that the patch is safe for human use. CONCLUSIONS: Benchtop performance showed that the bolus-only patch is a safe, accurate, and reliable device for mealtime insulin delivery.

Patient Perceptions and Preferences for a Mealtime Insulin Delivery Patch.

INTRODUCTION: A basal-bolus insulin regimen is needed to achieve glycated hemoglobin A1c (HbA1c) below 7.0% in people with type 1 (T1D) or type 2 (T2D) diabetes who have significant loss of beta-cell function. Nonadherence to therapy is common and negatively affects the ability to reach treatment goals. We examined patient assessment of a new, wearable mealtime insulin-delivery system (patch) relative to their current mealtime insulin-delivery system (syringe, pen, or pump). The patch is designed to deliver only boluses of fast-acting insulin (no basal insulin), mechanically controlled by the patient. METHODS: Adults (n = 101) with T1D or T2D assessed their current mealtime insulin-delivery system and then assessed simulated (no active medication) patch use over a 3-day period. Participants evaluated mealtime insulin-delivery systems using eight measures from five domains (convenience, interference with daily activities, diabetes-related worry, psychological well-being, and overall satisfaction/preference) on the self-administered Insulin Delivery System Rating Questionnaire. User ratings of their current insulin-delivery systems (syringe, pen, pump) were compared with those for the patch by repeated measure analysis of variance and one-sample t tests. RESULTS: Participants had significant (p < 0.05) preference for patch over syringe in all eight comparisons, and over pen in five out of eight comparisons, with no significant preference for pen. Although there was a preference for patch over pump in six out of eight comparisons, only one showed a significant preference for patch, and one for pump. Significantly more participants reported that they would like to switch to the patch than continue using a syringe (78% vs 22%) or pen (76% vs 24%) but this difference was not significant for the group using a pump (52% vs 48%). CONCLUSIONS: Participants preferred using the patch over pens and syringes. Its ease of use and discreet method of insulin delivery may contribute to improved patient adherence to mealtime insulin regimens among people currently using injection devices. FUNDING: Calibra Medical.

Diabetes Care Program of Nova Scotia: Celebrating 25 Years of Improving Diabetes Care in Nova Scotia.

The Diabetes Care Program of Nova Scotia (DCPNS)'s mission is "to improve, through leadership and partnerships, the health of Nova Scotians living with, affected by, or at risk of developing diabetes." Working together with local, provincial and national partners, the DCPNS has improved and standardized diabetes care in Nova Scotia over the past 25 years by developing and deploying a resourceful and collaborative program model. This article describes the model and highlights its key achievements. With balanced representation from frontline providers through to senior decision makers in health care, the DCPNS works across the age continuum, supporting the implementation of national clinical practice guidelines and, when necessary, developing provincial guidelines to meet local needs. The development and implementation of standardized documentation and data collection tools in all diabetes centres created a robust opportunity for the development and expansion of the DCPNS registry. This registry provides useful clinical and statistical information to staff, providers within the circle of care, management and senior leadership. Data are used to support individual care, program planning, quality improvement and business planning at both the local and the provincial levels. The DCPNS supports the sharing of new knowledge and advances through continuous education for providers. The DCPNS's ability to engage diabetes educators and key physician champions has ensured balanced perspectives in the creation of tools and resources that can be effective in real-world practice. The DCPNS has evolved to become an illustrative example of the chronic care model in action.

Metformin: From Research to Clinical Practice.

Metformin is the recommended first-line oral glucose-lowering drug initiated to control hyperglycemia in type 2 diabetes mellitus. It acts in the liver, small intestines, and skeletal muscles with its major effect on decreasing hepatic gluconeogenesis. It is safe, inexpensive, and weight neutral and can be associated with weight loss. It can reduce microvascular complication risk and its use is associated with a lower cardiovascular mortality compared with sulfonylurea therapy. It is also used to delay the onset of type 2 diabetes mellitus, in treating gestational diabetes, and in women with polycystic ovary syndrome.

Design, development and deployment of a Diabetes Research Registry to facilitate recruitment in clinical research.

BACKGROUND AND AIM: A major challenge in conducting clinical trials/studies is the timely recruitment of eligible subjects. Our aim is to develop a Diabetes Research Registry (DRR) to facilitate recruitment by matching potential subjects interested in research with approved clinical studies using study entry criteria abstracted from their electronic health records (EHR). METHOD: A committee with expertise in diabetes, quality improvement, information technology, and informatics designed and developed the DRR. Using a hybrid approach, we identified and consented patients interested in research, abstracted their EHRs to assess common eligibility criteria, and contacted them about their interest in participating in specific studies. Investigators submit their requests with study entry criteria to the DRR which then provides a list of potential subjects who may be directly contacted for their study. The DRR meets all local, regional and federal regulatory requirements. RESULTS: After 5 years, the DRR has over 5000 registrants. About 30% have type 1 diabetes and 70% have type 2 diabetes. There are almost equal proportions of men and women. During this period, 31 unique clinical studies from 19 unique investigators requested lists of potential subjects for their studies. Eleven grant applications from 10 unique investigators used aggregated counts of potentially eligible subjects in their applications. CONCLUSION: The DRR matches potential subjects interested in research with approved clinical studies using study entry criteria abstracted from their EHR. By providing large lists of potentially eligible study subjects quickly, the DRR facilitated recruitment in 31 clinical studies.

Using registries to recruit subjects for clinical trials.

AIM: We studied the use of patient/disease registries to recruit potential subjects for prospective clinical trials - describing the number, types and major benefits of using this approach. METHODS: In December 2013, we conducted a focused database search in PubMed, EMBASE, and Web of Science for studies (English language only) that used registries to recruit subjects for clinical trials published in 2004-2013. Of the 233 unique citations identified, 21 used registries to recruit subjects - 10 papers and 11 abstracts. Pearling and search for subsequent full papers of the abstracts identified 4 more papers. RESULTS: Our analysis, based on these 25 citations, showed that 14 are related to cancer, 3 to diabetes mellitus, 1 each to stroke, asthma, and celiac disease and 5 are disease neutral. Many types of registries (population-based cancer, quality improvement, disease-specific, web-based disease-neutral registries, local general practice registers, and national health database) are used to recruit subjects for clinical trials and uncover new knowledge. Overall, 16 registries are in the US, 4 in UK, 1 each in Canada, Spain, and Australia and 1 involved in many countries. Registries can identify very large number of subjects for screening for eligibility for clinical trials, especially in very large trials, rare disease trials, and trials involving minority patients. CONCLUSIONS: Registries can retrospectively identify very large numbers of potential subjects for screening for eligibility and enrollment in prospective clinical trials. This matching can lead to more timely recruitment and help solve a major problem in conducting clinical trials.

Detemir plus aspart and glulisine induced lipoatrophy: 2015 literature review and report of a new case.

BACKGROUND: In the first and only literature review, conducted in 2009, of human insulin analog- induced lipoatrophy, there were 12 published cases, including 1 with aspart, 1 with detemir, 1 with NovoMix 30 and none with detemir plus aspart. It is perceived that insulin analog induced-lipoatrophy is increasing. We conducted a 2015 literature review of published reports of lipoatrophy induced by aspart, detemir, detemir plus aspart, and NovoMix30. We also report a new case of detemir plus aspart and glulisine induced lipoatrophy. METHODS: Our focused literature searches (limited to 1995-2014) in PubMed, Embase, and Web of Science, using a combination of insulin analog and lipoatrophy terminology, was conducted in early January 2015. RESULTS: From the 520 unique citations there were 33 (from 13 papers and 9 abstracts) lipoatrophy cases induced by detemir (n = 5), aspart (n = 21), detemir plus aspart (n = 4) and NovoMix 30 (n = 3), representing 30 new cases since 2009. Many of these reported cases were females (76 %), had type 1 diabetes mellitus (T1DM) (94 %) and were in young persons (61 %). A 41-year-old T1DM woman developed lipoatrophy on her upper thighs, arms and abdomen 14 months after injecting detemir plus aspart at the same sites. Later on, after a year on continuous subcutaneous insulin infusion (CSII) using aspart and then glulisine, she developed lipoatrophy at the infusion sites. When CSII insulin was switched to lispro she did not develop lipoatrophy after 10 months. Meanwhile, the original lipoatrophy sites significantly improved. CONCLUSIONS: Our literature review uncovered 30 new published cases of aspart, detemir, aspart plus detemir and NovoMix 30-induced lipoatrophy since 2009. The largest increase in cases was in aspart- induced lipoatrophy. Recent surveys showed most rapid acting insulin analog-induced lipoatrophy were associated with CSII. In our review of the reported cases, 85.7 % cases of aspart-induced lipoatrophy were associated with CSII. As in previous reports, we showed lipoatrophy was more common in females, T1DM and young persons. Our patient may be the 5th published case of detemir plus aspart-induced lipoatrophy and possibly the first case report of glulisine induced lipoatrophy. She believed both detemir plus aspart and glulisine induced the lipoatrophy.

Maternally and zygotically provided Cdx2 have novel and critical roles for early development of the mouse embryo.

Divisions of polarised blastomeres that allocate polar cells to outer and apolar cells to inner positions initiate the first cell fate decision in the mouse embryo. Subsequently, outer cells differentiate into trophectoderm while inner cells retain pluripotency to become inner cell mass (ICM) of the blastocyst. Elimination of zygotic expression of trophectoderm-specific transcription factor Cdx2 leads to defects in the maintenance of the blastocyst cavity, suggesting that it participates only in the late stage of trophectoderm formation. However, we now find that mouse embryos also have a maternally provided pool of Cdx2 mRNA. Moreover, depletion of both maternal and zygotic Cdx2 from immediately after fertilization by three independent approaches, dsRNAi, siRNAi and morpholino oligonucleotides, leads to developmental arrest at much earlier stages than expected from elimination of only zygotic Cdx2. This developmental arrest is associated with defects in cell polarisation, reflected by expression and localisation of cell polarity molecules such as Par3 and aPKC and cell compaction at the 8- and 16-cell stages. Cells deprived of Cdx2 show delayed development with increased cell cycle length, irregular cell division and increased incidence of apoptosis. Although some Cdx2-depleted embryos initiate cavitation, the cavity cannot be maintained. Furthermore, expression of trophectoderm-specific genes, Gata3 and Eomes, and also the trophectoderm-specific cytokeratin intermediate filament, recognised by Troma1, are greatly reduced or undetectable. Taken together, our results indicate that Cdx2 participates in two steps leading to trophectoderm specification: appropriate polarisation of blastomeres at the 8- and 16-cell stage and then the maintenance of trophectoderm lineage-specific differentiation.

Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14).

Studies have shown that pioglitazone treatment in patients with type 2 diabetes mellitus can improve parameters of diabetic dyslipidemia. The aim of this study was to examine the effect of pioglitazone on triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels in patients from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) to determine whether pioglitazone-induced lipid effects were altered by different baseline antihyperglycemia medication or statin use. PROactive was a long-term, randomized, double-blind, cardiovascular outcomes study in patients with type 2 diabetes at high cardiovascular risk who had pioglitazone or placebo added to existing treatment. The present post hoc study analyzed lipid results from patients who received different baseline antihyperglycemia regimens and the presence or absence of baseline statin use. Independent of antihyperglycemia medication and statin use, triglyceride levels decreased in all subgroups treated with pioglitazone (-9.9% to -12.3%), whereas little change was observed in placebo groups. High-density lipoprotein cholesterol increased nearly twice as much with pioglitazone (18.1% to 20.3%) as with placebo (8.1% to 11.8%) across all subgroups. Low-density lipoprotein cholesterol increased moderately with pioglitazone (5.2% to 9.6%) compared with placebo (3.3% to 7.6%) (placebo-adjusted range 1.11% to 4.37%). In conclusion, long-term pioglitazone therapy led to durable improvements in triglyceride and high-density lipoprotein cholesterol levels, irrespective of baseline antihyperglycemia therapy or statin use.

Impact of prandial plus basal vs basal insulin on glycemic variability in type 2 diabetic patients.

OBJECTIVE: To determine whether metformin-treated patients with type 2 diabetes given an analogue mixture of basal and rapid-acting insulins (insulin lispro protamine suspension plus insulin lispro) would have less glycemic variability than patients given basal insulin glargine. METHODS: Two post hoc analyses were used to compare 7-point blood glucose profiles from 3 published studies comparing basal plus prandial premixed insulin lispro mixtures with insulin glargine in metformin-treated patients with type 2 diabetes. Glycemic variability indices used included standard deviation of mean daily blood glucose, coefficient of variation, M-value, mean amplitude of glycemic excursion, and J-index. RESULTS: Patients on the twice-daily insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro) plus metformin regimen had significantly lower standard deviation, M-value, and J-index than patients on the insulin glargine plus metformin regimen, but not lower coefficient of variation or mean amplitude of glycemic excursion. Patients on the 3 times daily insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin insulin lispro) plus metformin regimen had significantly lower values for all 5 indices than patients on the insulin glargine plus metformin regimen. CONCLUSION: Use of basal plus prandial insulin lispro mixtures at 2 or 3 meals was associated with lower glycemic variability in metformin-treated patients with type 2 diabetes.

Relationship between HbA1c and hypoglycaemia in patients with type 2 diabetes treated with different insulin regimens in combination with metformin.

BACKGROUND: To examine the relationship between glycaemic control and hypoglycaemia in patients with type 2 diabetes treated with metformin (Met) and either insulin lispro mixtures, given twice or thrice daily (LM + Met), or insulin glargine, given once daily (G + Met). METHODS: Data from three randomized clinical trials were pooled to compare effects of LM + Met with G + Met. RESULTS: The LM + Met group achieved lower mean HbA(1c) (mean+/-SE, 7.2+/-0.1 vs. 7.7+/-0.1%, p<0.0001) and all meals combined post-prandial blood glucose (BG) (8.9+/-0.1 vs. 10.2+/-0.1 mmol/L, p<0.0001) compared with the G + Met group, but had higher fasting blood glucose (8.1+/-0.1 vs. 6.8+/-0.1 mmol/L, p<0.0001) and insulin requirement (0.7+/-0.01 vs. 0.6+/-0.01 U/kg, p<0.0001). Over the entire study period, daytime hypoglycaemia was higher for the LM + Met group (10.3 vs. 3.5 episodes/patient/year, p<0.0001) than for the G + Met group; however, nocturnal hypoglycaemia was lower (3.4 vs. 6.6 episodes/patient/year, p=0.003). At endpoint, daytime hypoglycaemia was higher for the LM + Met group (6.2 vs. 1.4 episodes/patient/year, p<0.0001); however, nocturnal hypoglycaemia was similar in both groups (1.9 vs. 3.0 episodes/patient/year). An inverse relationship was observed between all confirmed hypoglycaemia and HbA(1c) at endpoint; for every 1% reduction in HbA(1c), the increase (in slope) was 1.4 episodes/patient/year (p=0.04). Patients with confirmed hypoglycaemia had lower HbA(1c) than patients without hypoglycaemia (7.39 vs. 7.64%, respectively; decrement=0.26%, p=0.026). CONCLUSIONS: These studies demonstrated an inverse relationship between HbA(1c) and 24-h and daytime hypoglycaemia. Lispro insulin mixtures provided lower HbA(1c) and post-prandial blood glucose values than glargine, but caused more daytime hypoglycaemia. Frequency of nocturnal hypoglycaemia was similar and severe hypoglycaemia was rare with both insulin regimens.

Pioglitazone versus Rosiglitazone: Effects on Lipids, Lipoproteins, and Apolipoproteins in Head-to-Head Randomized Clinical Studies.

Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPARgamma and PPARgamma have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPARgamma agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPARgamma agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agents.

Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison.

BACKGROUND: In people without diabetes, approximately 50% of daily insulin secretion is basal and the remainder is postprandial. Hence, it would be expected that insulin replacement therapy in a 50/50 ratio with each meal would mimic physiologic insulin secretion better than treatment with once-daily basal insulin in patients with diabetes mellitus. Using lispro mix (LM) 50/50 before meals may be a logical approach to achieving glycemic targets (glycosylated hemoglobin [HbA(lc)] and pre- and postprandial blood glucose [BG] concentrations) in these patients. OBJECTIVE: The aim of this study was to test the hypothesis that treatment with a premixed insulin analogue containing 50/50 basal + prandial insulins administered before each meal would achieve lower overall and mealtime glycemic control than once-daily basal insulin analogue, both plus metformin (Met), in patients with type 2 diabetes mellitus. METHODS: This 24-week, randomized, open-label, parallel-group trial was conducted at 38 sites across Australia, Greece, India, The Netherlands, Poland, Puerto Rico, and the United States. Male and female patients aged 35 to 75 years with type 2 diabetes mellitus and an HbA(1c) level of 6.5% to 11.0%, who were receiving metformin and/or a sulfonylurea with a stable dose of 0 to 2 daily insulin injections over the previous 3 months were eligible. Patients were randomly assigned to receive LM50/50 (50% insulin lispro protamine suspension [ILPS] and 50% lispro) TID plus metformin (to a maximally tolerated daily dosage of 500-1000 mg BID) (LM50/50 + Met) or insulin glargine QD at bedtime plus metformin (500-1000 mg BID) (G + Met) for 24 weeks. With LM50/50 + Met, the insulin dose was titrated to target a fasting BG (FBG) level of <6.7 mmol/L (<120 mg/dL) and a 2-hour post-prandial BG (PPBG) level of <8.0 mmol/L (<144 mg/dL); those who did not reach the FBG target would be switched from presupper LM50/50 to LM75/25 (75% ILPS, 25% lispro). RESULTS: A total of 315 patients were randomized and received treatment (158 women, 157 men; mean age, 57.7 years; mean body mass index, 32.1 kg/m2; LM50/50 + Met, 157 patients; G + Met, 158 patients). At 24 weeks, the mean (SD)HbA(1c) level was significantly lower in the LM50/50 + Met group than in the G + Met group (7.1% [0.9%] vs 7.5% [1.0%]; P<0.001), and the proportion who reached an HbA(1c) target of < or = 7.0% was greater (88 [56.1%] vs 63 [39.9%]; P = 0.005). The G + Met group had a lower mean (SD)FBG value (6.5 [1.6] vs 8.1 [1.8] mmol/L; P<0.001). The LM50/50 + Met group had lower mean preprandial BG levels prelunch (7.4 [1.9] vs 7.9 [2.1] mmol/L; P=0.03) and presupper (8.3 [2.0] vs 8.9 [2.8] mmol/L; P=0.04). The LM50/50 + Met group also had lower mean 2-hour PPBG values postbreakfast (8.7 [2.2] vs 9.2 [2.5] mmol/L; P=0.03), postlunch (8.4 [1.9] vs 9.8 [2.6], mmol/L; p<0.001), and postsupper (8.7 [2.2] vs 10.7 [3.2], mmol/L; P<0.001). The mean (SD) total insulin doses at study end point were 0.7 (0.3) U/kg in the LM50/50 + Met group and 0.6 (0.3) U/kg in the G + Met group (P<0.001). The mean (SD)M-value (an expression of mean glycemia and the effect of glucose swings) was statistically similar between the 2 groups at baseline but significantly lower in the LM50/50 + Met group at end point (17.3 [13.8] vs 25.1 [24.8] mmol/L; P<0.001). During the entire treatment period, mean (SD) overall and nocturnal hypoglycemia rates (episodes per patient for 30 days) were statistically similar between the 2 groups (overall, 0.8 [1.4] vs 0.5 [1.0]; nocturnal, 0.2 [0.7] vs 0.3 [0.6]). At end point, the mean (SD) nocturnal hypoglycemia rates were similar between the 2 groups (0.2 [0.9] vs 0.2 [0.6]), but the overall and non-nocturnal hypoglycemia rates were higher with LM50/50 + Met (overall, 0.7 [1.7] vs 0.3 [0.8]; P=0.02; non-nocturnal, 0.5 [1.2] vs 0.1 [0.4]; P=0.002). CONCLUSION: In these patients with type 2 diabetes, mealtime LM50/50 + Met was associated with lower overall (HbA(1c)) and preprandial BG and PPBG levels (except for FBG), with similar nocturnal hypoglycemia and less glycemic variability, compared with G + Met.

Prandial premixed insulin analogue regimens versus basal insulin analogue regimens in the management of type 2 diabetes: an evidence-based comparison.

BACKGROUND: Insulin is an effective treatment for type 2 diabetes (T2D), a progressive condition in which insulin deficiency is one of the core defects. When patients with T2D are unable to achieve glycemic goals with diet and oral antihyperglycemic medications, a common starting insulin regimen consists of basal or premixed insulin added to oral antihyperglycemic medications. When glycemic goals are not achieved with the initial insulin regimen, a basal-bolus regimen is necessary. OBJECTIVE: This article reviews clinical-trial data on the efficacy and safety profile of prandial premixed insulin analogues (insulin aspart and insulin lispro) compared with basal insulin analogues (insulin glargine, insulin detemir, and insulin lispro protamine suspension), with or without a prandial insulin analogue, in the management of T2D. METHODS: A systematic search of Ovid, MEDLINE, and EMBASE (1995-2007) was performed to identify published randomized controlled trials comparing prandial premixed insulin analogues with basal insulin analogues, with or without prandial insulin, in patients with T2D. The search terms were premixed insulin analogues, premixed insulin, biphasic insulin aspart, insulin aspart 70/30, insulin aspart 50/50, premixed insulin lispro, insulin lispro 75/25, insulin lispro 50/50, glargine, and detemir. Abstracts presented at the 2005 and 2006 meetings of the American Diabetes Association and the European Association for the Study of Diabetes and bibliographies of the identified studies were also reviewed. Predetermined criteria for study inclusion were treatment duration of at least 12 weeks, T2D diagnosed using valid criteria, use of a basal insulin analogue (with or without rapid-acting insulin) as a study comparator, and use of well-accepted end points (eg, glycosylated hemoglobin [HbA1c], hypoglycemia, preprandial and postprandial blood glucose). RESULTS: Of the identified randomized controlled trials, 3 studies compared premixed insulin analogues containing 70% or 75% basal and 30% or 25% rapid-acting insulin analogue with basal insulin analogues only, and 3 studies evaluated premixed insulin analogues containing 50% basal and 50% rapid-acting insulin analogue with basal insulin analogues only. Use of prandial premixed insulin analogues was associated with better overall and postprandial glycemic control. In the studies that compared twice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA1c ranged from -1.00% to -2.79% and from -0.42% to -2.36%, respectively (P < 0.01). In the studies that compared thrice-daily premixed insulin analogues with a basal insulin analogue, changes in HbA1c ranged from -0.72% to -1.2% and from -0.3% to -0.75%, respectively (P < 0.01). These results were achieved with some increase in overall hypoglycemia, but not in nocturnal or severe hypoglycemia. Doses of the premixed insulin analogues were adjusted during the titration period to achieve glycemic goals. CONCLUSIONS: The results of this systematic review suggest that regimens consisting of prandial premixed insulin analogues, which provide both basal and prandial insulin coverage, may be used as an initial insulin regimen in patients with T2D to enable better overall, preprandial, and postprandial glycemic control compared with a basal insulin analogue regimen alone. Premixed insulin analogues are an effective option for initiating and intensifying insulin therapy in patients with T2D.