Successful treatment of prediabetes in clinical practice using physiological assessment (STOP DIABETES).

BACKGROUND: Of the 84 million American adults with prediabetes, over 5 to 7 years, about 28 million progress to type 2 diabetes. We aimed to assess whether a real-world, pathophysiology-based, therapeutic approach could prevent development of type 2 diabetes in high-risk individuals. METHODS: We did a retrospective observational study of people at increased risk of type 2 diabetes from a community practice in southern California, USA. Participants had an oral glucose tolerance test and were assigned a risk stratification on the basis of presence and severity of insulin resistance, impaired ß-cell function, and glycaemia (ie, 1-h plasma glucose concentration of more than 8·6 mmol/L during an oral glucose tolerance test). Treatment was recommended on the basis of risk: metformin, pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonist, and lifestyle therapy for participants at high risk of diabetes, and metformin, pioglitazone, and lifestyle therapy for those at intermediate risk. Individuals who refused pharmacological therapy were assigned to lifestyle therapy only. Participants were followed up every 6 months and oral glucose tolerance tests were repeated at 6 months and subsequently every 2 years or sooner. The primary outcome of our analysis was incidence of type 2 diabetes according to the American Diabetes Association criteria, within the study period (2009-16). This study is registered with ClinicalTrials.gov, number NCT03308773. FINDINGS: Between Jan 1, 2009 and Dec 31, 2016, we assessed 1769 people at increased risk of diabetes, of which 747 (42%) were identified at high or intermediate risk and were recommended pharmacological treatment. Of 422 participants analysed, 28 (7%) progressed to type 2 diabetes (seven [5%] of 141 participants who received metformin, pioglitazone, and lifestyle therapy, none [0%] of 81 who received metformin, pioglitazone, GLP-1 receptor agonist, and lifestyle therapy, and 21 [11%] of 200 who received lifestyle therapy only) after mean follow-up of 32·09 months (SEM 1·24). Compared with participants who received lifestyle therapy only, the adjusted hazard ratio for progression to type 2 diabetes was 0·29 (95% CI 0·11-0·78, p=0·0009) in participants who received metformin and pioglitazone, and 0·12 (95% CI 0·02-0·94, p=0·04) in participants who received metformin, pioglitazone, and GLP-1 receptor agonist. Improved ß-cell function was the strongest predictor of type 2 diabetes prevention. INTERPRETATION: Progression to type 2 diabetes in people at high risk of diabetes can be markedly reduced with interventions designed to correct underlying pathophysiological disturbances (ie, impaired insulin secretion and resistance) in a real-world setting. FUNDING: None.

TRIGLYCERIDE/HIGH-DENSITY LIPOPROTEIN CHOLESTEROL CONCENTRATION RATIO IDENTIFIES ACCENTUATED CARDIOMETABOLIC RISK.

OBJECTIVE: Plasma triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratios have been shown to identify apparently healthy individuals at increased cardiometabolic risk. This study evaluated the utility of this approach in patients at risk of developing diabetes. METHODS: Individuals (n = 1,010) treated at a private practice identified as being at an increased risk of type 2 diabetes mellitus (T2DM) based on American Association of Clinical Endocrinologist criteria were evaluated. Subjects had measurements of body mass index (BMI); blood pressure; lipid/lipoprotein concentrations; high-sensitivity C-reactive protein (hs-CRP) levels and glucose, insulin, and C-peptide concentrations during a 75-g, glucose challenge. The TG/HDL-C ratio was used to stratify individuals into high (highest quartile) and low (lowest 3 quartiles) risk categories. RESULTS: The TG/HDL-C ratios identifying the highest quartile differed in males (≥3.0 mg/dL) and females (≥2.0 mg/dL). Using these cutpoints, the. high-risk groups for males and females had significantly higher blood pressure, more adverse lipid profiles, were more insulin resistant as assessed by the homeostatic model assessment-insulin resistance (HOMA-IR) or the Matsuda index, and had higher hs-CRP concentrations. Combined, approximately 25% of highest quartile patients expressed values ≥3.0 mg/dL. CONCLUSION: The TG/HDL-C ratio provides a simple approach to identify individuals at higher cardiometabolic risk within a population of perceived increased risk of T2DM. This was especially true for insulin resistance. Given the many syndromes associated with insulin resistance, including T2DM and coronary heart disease, an elevated TG/HDL-C ratio supports more aggressive efforts to enhance insulin sensitivity.

Successful treatment of prediabetes in clinical practice: targeting insulin resistance and ß-cell dysfunction.

OBJECTIVE: To determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes. METHODS: Patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing-derived indices of insulin resistance and impaired ß-cell function. Patients who declined pharmacologic therapy received lifestyle modification only. RESULTS: One hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or ß-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and ß-cell function improved by 42% and 50%, respectively (all P<.001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and ß-cell function improved by 52% and 109%, respectively (all P<.001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes. CONCLUSIONS: Targeted pathophysiologic therapy based on oral glucose tolerance test-derived measures of insulin sensitivity and ß-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients.