Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis.

IMPORTANCE: Numerous glucose-lowering drugs are used to treat type 2 diabetes. OBJECTIVE: To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. DATA SOURCES: Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. STUDY SELECTION: Randomized clinical trials of 24 weeks' or longer duration. DATA EXTRACTION AND SYNTHESIS: Random-effects network meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A1c (HbA1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. RESULTS: A total of 301 clinical trials (1,417,367 patient-months) were included; 177 trials (56,598 patients) of drugs given as monotherapy; 109 trials (53,030 patients) of drugs added to metformin (dual therapy); and 29 trials (10,598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]). CONCLUSIONS AND RELEVANCE: Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.

Design and implementation of the Canadian Kidney Disease Cohort Study (CKDCS): A prospective observational study of incident hemodialysis patients.

BACKGROUND: Many nephrology observational studies use renal registries, which have well known limitations. The Canadian Kidney Disease Cohort Study (CKDCS) is a large prospective observational study of patients commencing hemodialysis in five Canadian centers. This study focuses on delineating potentially reversible determinants of adverse outcomes that occur in patients receiving dialysis for end-stage renal disease (ESRD). METHODS/DESIGN: The CKDCS collects information on risk factors and outcomes, and stores specimens (blood, dialysate, hair and fingernails) at baseline and in long-term follow-up. Such specimens will permit measurements of biochemical markers, proteomic and genetic parameters (proteins and DNA) not measured in routine care. To avoid selection bias, all consenting incident hemodialysis patients at participating centers are enrolled, the large sample size (target of 1500 patients), large number of exposures, and high event rates will permit the exploration of multiple potential research questions. PRELIMINARY RESULTS: Data on the baseline characteristics from the first 1074 subjects showed that the average age of patients was 62 (range; 50-73) years. The leading cause of ESRD was diabetic nephropathy (41.9%), and the majority of the patients were white (80.0%). Only 18.7% of the subjects received dialysis in a satellite unit, and over 80% lived within a 50 km radius of the nearest nephrologist's practice. DISCUSSION: The prospective design, detailed clinical information, and stored biological specimens provide a wealth of information with potential to greatly enhance our understanding of risk factors for adverse outcomes in dialysis patients. The scientific value of the stored patient tissue will grow as new genetic and biochemical markers are discovered in the future.

Diagnostic Yield of Population-Based Screening for Chronic Kidney Disease in Low-Income, Middle-Income, and High-Income Countries.

Importance: Population-based screening for chronic kidney disease (CKD) is sometimes recommended based on the assumption that detecting CKD is associated with beneficial changes in treatment. However, the treatment of CKD is often similar to the treatment of hypertension or diabetes, which commonly coexist with CKD. Objective: To determine the frequency with which population-based screening for CKD is associated with a change in recommended treatment compared with a strategy of measuring blood pressure and assessing glycemia. Design, Setting, and Participants: This cohort study was conducted using data obtained from studies that evaluated CKD in population-based samples from China (2007-2010), India (2010-2014), Mexico (2007-2008), Senegal (2012), and the United States (2009-2014), including a total of 126 242 adults screened for CKD. Data were analyzed from January 2020 to March 2021. Main Outcomes and Measures: The primary definition of CKD was estimated glomerular filtration rate less than 60 mL/min/1.73 m2. For individuals with CKD, the need for a treatment change was defined as not taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker or having blood pressure levels of 140/90 mm Hg or greater. For individuals with CKD who also had diabetes, the need for a treatment change was also defined as having hemoglobin A1c levels of 8% or greater or fasting glucose levels of 178.4 mg/dL (9.9 mmol/L) or greater. Case finding was defined as testing for CKD only in adults with hypertension or diabetes. Results: Among 126 242 adults screened for CKD, there were 47 204 patients in the China cohort, 9817 patients in the India cohort, 51 137 patients in the Mexico cohort, 2441 patients in the Senegal cohort, and 15 643 patients in the US cohort. The mean age of participants was 49.6 years (95% CI, 49.5-49.7 years) in the China cohort, 42.9 years (95% CI, 42.6-43.2 years) in the India cohort, 51.6 years (95% CI, 51.5-51.7 years) in the Mexico cohort, 48.2 years (95% CI, 47.5-48.9 years) in the Senegal cohort, and 47.3 years (95% CI, 46.6-48.0 years) in the US cohort. The proportion of women was 57.3% (95% CI, 56.9%-57.7%) in the China cohort, 53.4% (95% CI, 52.4%-54.4%) in the India cohort, 68.8% (95% CI, 68.4%-69.2%) in the Mexico cohort, 56.0% (95% CI, 54.0%-58.0%) in the Senegal cohort, and 51.9% (51.0%-52.7%) in the US cohort. The prevalence of CKD was 2.5% (95% CI, 2.4%-2.7%) in the China cohort, 2.3% (95% CI, 2.0%-2.6%) in the India cohort, 10.6% (95% CI, 10.3%-10.9%) in the Mexico cohort, 13.1% (95% CI, 11.7%-14.4%) in the Senegal cohort, and 6.8% (95% CI, 6.2%-7.5%) in the US cohort. Screening for CKD was associated with the identification of additional adults whose treatment would change (beyond those identified by measuring blood pressure and glycemia) per 1000 adults: China: 8 adults (95% CI, 8-9 adults); India: 5 adults (95% CI, 4-7 adults); Mexico: 26 adults (95% CI, 24-27 adults); Senegal: 59 adults (95% CI, 50-69 adults); and the US: 19 adults (95% CI, 16-23 adults). Case finding was associated with the identification of 46.2% (95% CI, 45.1%-47.4%) to 86.4% (95% CI, 85.4%-87.3%) of individuals with CKD depending on the country, an increase in the proportion of individuals requiring a treatment change by as much 89.6% (95% CI, 80.4%-99.3%) in the US, and a decrease in the proportion of individuals needing GFR measurements by as much as 57.8% (95% CI, 56.3%-59.3%) in the US. Conclusions and Relevance: This study found that most additional individuals with CKD identified by population-based screening programs did not need a change in treatment compared with a strategy of measuring blood pressure and assessing glycemia and that case finding was more efficient than screening for early detection of CKD.

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.