Development and validation of QDiabetes-2018 risk prediction algorithm to estimate future risk of type 2 diabetes

Objectives To derive and validate updated QDiabetes-2018 prediction algorithms to estimate the 10 year risk of type 2 diabetes in men and women, taking account of potential new risk factors, and to compare their performance with current approaches.

Design Prospective open cohort study.

Setting Routinely collected data from 1457 general practices in England contributing to the QResearch database: 1094 were used to develop the scores and a separate set of 363 were used to validate the scores.

Participants 11.5 million people aged 25-84 and free of diabetes at baseline: 8.87 million in the derivation cohort and 2.63 million in the validation cohort.

Methods Cox proportional hazards models were used in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QDiabetes (age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids) and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, gestational diabetes, and polycystic ovary syndrome. Additional models included fasting blood glucose and glycated haemoglobin (HBA1c). Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.

Main outcome measure Incident type 2 diabetes recorded on the general practice record.

Results In the derivation cohort, 178 314 incident cases of type 2 diabetes were identified during follow-up arising from 42.72 million person years of observation. In the validation cohort, 62 326 incident cases of type 2 diabetes were identified from 14.32 million person years of observation. All new risk factors considered met our model inclusion criteria. Model A included age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids, and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, and gestational diabetes and polycystic ovary syndrome in women. Model B included the same variables as model A plus fasting blood glucose. Model C included HBA1c instead of fasting blood glucose. All three models had good calibration and high levels of explained variation and discrimination. In women, model B explained 63.3% of the variation in time to diagnosis of type 2 diabetes (R2), the D statistic was 2.69 and the Harrell’s C statistic value was 0.89. The corresponding values for men were 58.4%, 2.42, and 0.87. Model B also had the highest sensitivity compared with current recommended practice in the National Health Service based on bands of either fasting blood glucose or HBA1c. However, only 16% of patients had complete data for blood glucose measurements, smoking, and body mass index.

Conclusions Three updated QDiabetes risk models to quantify the absolute risk of type 2 diabetes were developed and validated: model A does not require a blood test and can be used to identify patients for fasting blood glucose (model B) or HBA1c (model C) testing. Model B had the best performance for predicting 10 year risk of type 2 diabetes to identify those who need interventions and more intensive follow-up, improving on current approaches. Additional external validation of models B and C in datasets with more completely collected data on blood glucose would be valuable before the models are used in clinical practice.

Reference: BMJ 2017;359:j5019

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Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes

Question  What is the effect of oral semaglutide on glycemic control in patients with type 2 diabetes?

Finding  In this randomized clinical trial of 632 patients with type 2 diabetes followed up for 31 weeks, oral semaglutide significantly reduced hemoglobin A1c level by up to 1.9% vs placebo (0.3%).

Meaning  Oral semaglutide resulted in better glycemic control than placebo over 26 weeks. Phase 3 studies are warranted to assess longer-term and clinical outcomes, as well as safety.

Reference: JAMA. 2017;318(15):1460-1470.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND

The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

METHODS

We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

RESULTS

In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.

CONCLUSIONS

Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338.)

Reference: N Engl J Med 2017; 377:1228-1239September 28, 2017

Liraglutide and Renal Outcomes in Type 2 Diabetes

BACKGROUND

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.

METHODS

We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed.

RESULTS

A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively).

CONCLUSIONS

This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.)

Reference: N Engl J Med 2017; 377:839-848 August 31, 2017

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes

BACKGROUND

Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.

METHODS

We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome.

RESULTS

Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups.

CONCLUSIONS

Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529.)

Reference: N Engl J Med 2017; 377:723-732 August 24, 2017

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

BACKGROUND

Canagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes.

METHODS

The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

RESULTS

The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal.

CONCLUSIONS

In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629and NCT01989754, respectively.)

Reference: N Engl J Med 2017; 377:644-657August 17, 2017

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes The SWITCH 2 Randomized Clinical Trial

Question  Is the rate of hypoglycemia lower with insulin degludec vs insulin glargine U100 in insulin-treated patients with type 2 diabetes?

Findings  In this randomized crossover clinical trial of 721 patients, insulin degludec resulted in a significantly lower rate of overall symptomatic hypoglycemic episodes over a 16-week maintenance period compared with insulin glargine U100 (186 vs 265 episodes per 100 patient-years of exposure, respectively).

Meaning  Patients with type 2 diabetes treated with insulin degludec compared with insulin glargine U100 had a reduced risk of overall symptomatic hypoglycemia.

Reference: JAMA. 2017;318(1):45-56.