Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes.

BACKGROUND: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes. METHODS: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. RESULTS: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group. CONCLUSIONS: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes.

BACKGROUND: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain. METHODS: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%. RESULTS: A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups. CONCLUSIONS: All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Intensive blood pressure control, falls, and fractures in patients with type 2 diabetes: the ACCORD trial.

BACKGROUND: There are few rigorous studies to confirm or refute the commonly cited concern that control of blood pressure to lower thresholds may result in an increased risk of falls and fractures. OBJECTIVE: To compare falls and fractures in participants with type 2 diabetes in the intensive (targeting a systolic blood pressure of < 120 mmHg) and standard (targeting a systolic blood pressure of < 140 mmHg) blood pressure control arms of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized trial (N = 4,733). PARTICIPANTS: A subset of 3,099 participants self-reported annually on the occurrence of falls and non-spine fractures. Fractures were centrally adjudicated. MAIN MEASURES: The incidence of falls in the two treatment groups was compared using a random-effects negative binomial model, and fracture risk was compared using Cox proportional hazards models. KEY RESULTS: At enrollment in both groups, the mean age was 62 years, 44% were women, 25% were Black, and mean blood pressure was 138/75 mmHg. During follow-up, all classes of medications, particularly thiazide diuretics, were more commonly prescribed in the intensive group. After 1 year of follow-up, the mean systolic blood pressure was 133 ± 15 mmHg in the standard group and 119 ± 14 mmHg in the intensive group. The adjusted rate of falls did not differ in the intensive and standard groups (62.2/100 person-years vs. 74.1/100 person-years, RR = 0.84, 95% CI 0.54-1.29, p = 0.43). The risk of non-spine fractures was nonsignificantly lower in the intensive than in the standard blood pressure group (HR 0.79, 95% CI 0.62-1.01, p = 0.06). CONCLUSIONS: We conclude that intensive antihypertensive treatment that lowered mean systolic blood pressure to below 120 mmHg was not associated with an increased risk of falls or non-spine fractures in patients age 40 to 79 years with type 2 diabetes.

The renal transcriptome of db/db mice identifies putative urinary biomarker proteins in patients with type 2 diabetes: a pilot study.

We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: 31 upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-ß, growth and differentiation factor-15, interleukin-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and interleukin-6 were associated with a marker of proximal tubule damage, N-acetyl-ß-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.

Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials.

One of the first steps in the management of patients with type 2 diabetes mellitus is setting glycemic goals. Professional organizations advise setting specific hemoglobin A(1c) (HbA(1c)) targets for patients, and individualization of these goals has more recently been emphasized. However, the operational meaning of glycemic goals, and specific methods for individualizing them, have not been well-described. Choosing a specific HbA(1c) target range for a given patient requires taking several factors into consideration, including an assessment of the patient's risk for hyperglycemia-related complications versus the risks of therapy, all in the context of the overall clinical setting. Comorbid conditions, psychological status, capacity for self-care, economic considerations, and family and social support systems also play a key role in the intensity of therapy. The individualization of HbA(1c) targets has gained more traction after recent clinical trials in older patients with established type 2 diabetes mellitus failed to show a benefit from intensive glucose-lowering therapy on cardiovascular disease (CVD) outcomes. The limited available evidence suggests that near-normal glycemic targets should be the standard for younger patients with relatively recent onset of type 2 diabetes mellitus and little or no micro- or macrovascular complications, with the aim of preventing complications over the many years of life. However, somewhat higher targets should be considered for older patients with long-standing type 2 diabetes mellitus and evidence of CVD (or multiple CVD risk factors). This review explores these issues further and proposes a framework for considering an appropriate and safe HbA(1c) target range for each patient.

Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight.

OBJECTIVE: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for <10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in. RESULTS: Adjusted for duration of run-in, the mean ± SD change in HbA1c was -0.65 ± 0.02% (-7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, -0.48 ± 0.02% (-5.2 ± 0.2 mmol/mol) when the dose was unchanged, and -0.23 ± 0.07% (-2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P < 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894). CONCLUSIONS: Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control.

Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring.

Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.

Assessment of a National Diabetes Education Program diabetes management booklet: The GRADE experience.

BACKGROUND AND PURPOSE: The National Diabetes Education Program created the 4 Steps to Manage Your Diabetes for Life (4 Steps) booklet to help patients with diabetes learn the basics of self-management and care recommendations. The purpose of this study is to explore the impact of 4 Steps on participants' diabetes management knowledge and self-efficacy in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). METHODS: A sample of 348 adults with type 2 diabetes enrolled in GRADE was included in this analysis. Participants took a pretest, were sent home with 4 Steps, then took a posttest at their next visit. The Wilcoxon signed rank test was used to detect differences in knowledge and self-efficacy between scale scores pre- and posttest. CONCLUSIONS: Analyses revealed increases in participants' diabetes management knowledge (p < .001) and self-efficacy (p < .001) from pre- to posttest. Participants who reported no formal previous diabetes education showed a statistically significant increase in knowledge scores compared to those with previous diabetes education (p < .05). IMPLICATIONS FOR PRACTICE: Appropriate, relevant diabetes education materials may improve self-management knowledge and self-efficacy among adults with type 2 diabetes. Providers should feel confident using 4 Steps as a resource for clinical practice.

Understanding adherence to medications in type 2 diabetes care and clinical trials to overcome barriers: a narrative review.

AIM: To identify factors affecting adherence to medications in type 2 diabetes (T2D) care and clinical trials. BACKGROUND: Adherence to medication is associated with better patient outcomes, lower healthcare costs, and improved quality and robustness of trial data. In T2D, non-adherence to regimens may compromise glycemic, blood pressure and lipid control, which can, in turn, increase morbidity and mortality rates. DESIGN: A literature search was performed to identify studies reporting adherence to medications and highlighting specific adherence challenges/approaches in T2D. The search was limited to clinical trials, comparative studies or meta-analyses, reported in English with a freely available abstract. DATA SOURCE: MEDLINE (31 December 2008 to 31 December 2013). REVIEW METHODS: Studies not reporting adherence to medications or highlighting adherence challenges/approaches in T2D, presenting only self-reported adherence or including fewer than 100 patients were excluded. Eligible reports are discussed narratively. RESULTS: Factors identified as having a detrimental impact on adherence were smoking, depression and polypharmacy. Conversely, increased convenience (e.g. pen compared with vial and syringe; medication supplied by mail order vs. retail pharmacy) was associated with better patient adherence, as were interventions that increased patient motivation (e.g. individualized, nurse-led consultation) and education. CONCLUSIONS: Medication adherence is influenced by complex and multifactorial issues, which can include smoking, depression, polypharmacy, convenience of obtaining and administering the medication, patient motivation and education. We recommend simplifying treatment regimens, where possible, improving provider-patient communication, and providing support and education to increase medication adherence, with a view to improving patient outcomes and clinical trial data quality.