Although all types of diabetes result in hyperglycemia, the pathophysiology of each type of diabetes is different. These guidelines summarize available data specific to the comprehensive care of ...youth with type 2 diabetes. The objective is to enrich the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology, its management, and the prevention of associated complications.
A clinical trial assessed the efficacy of three treatments, all involving metformin, on glycemic control in youth-onset type 2 diabetes. This follow-up study shows that the risk of complications ...increased steadily over time, and complications developed in most participants by young adulthood.
Context:
Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use.
Objective:
To assess the risk of B12 deficiency with metformin use in the ...Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS).
Design:
Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years.
Setting:
Twenty-seven study centers in the United States.
Patients:
DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively.
Interventions:
Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS).
Main Outcome Measures:
B12 deficiency, anemia, and peripheral neuropathy.
Results:
Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels.
Conclusions:
Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.
Participants from DPP/DPPOS were assigned to placebo (n=1082) or metformin (n=1073) for 3.2 years, followed by metformin in the metformin group for 9 years. Metformin use was associated with increased risk of vitamin B12 deficiency.
To examine whether cardiovascular autonomic neuropathy (CAN) is an independent risk factor of cardiovascular disease (CVD) events during DCCT/EDIC.
Standardized cardiovascular autonomic reflex tests ...(R-R response to paced breathing, Valsalva maneuver, postural changes in blood pressure) were performed at DCCT baseline, every 2 years throughout DCCT, and at two time points in EDIC. CVD events were ascertained throughout the study and adjudicated by a review committee. Cox proportional hazards models were used to estimate the effect of CAN at DCCT closeout on subsequent CVD risk.
There were 299 adjudicated CVD events in 165 participants following the DCCT closeout assessment: 132 of 1,262 subjects (10%) without CAN at DCCT closeout who experienced 244 CVD events versus 33 of 131 subjects (25%) with CAN at DCCT closeout who experienced 55 events (hazard ratio 2.79, 95% CI 1.91-4.09 for time to first CVD event). The cumulative incidence of the first occurrence of any CVD event during EDIC was significantly higher in participants with CAN at DCCT closeout compared with those without CAN. The association remained marginally significant after adjustment for multiple risk factors, including the EDIC updated mean HbA
. When analyzed as a continuous variable, R-R variation was significantly lower at DCCT closeout in participants who experienced a CVD event compared with those who did not (P = 0.0012).
In the DCCT/EDIC cohort, individuals diagnosed with CAN at DCCT closeout experienced a higher long-term risk of CVD events during follow-up in EDIC. This association was not independent of historic glycemic exposure and its metabolic memory effect, the principal determinant of both long-term CVD risk and CAN in type 1 diabetes.
The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional ...therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC.
The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models.
Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA
, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA
, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA
, older age, and longer duration of T1D.
Mean HbA
was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.
The Diabetes Control and Complications Trial (DCCT) demonstrated that a mean of 6.5 years of intensive therapy aimed at near-normal glucose levels reduced the risk of development and progression of ...retinopathy by as much as 76% compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications study (EDIC) observational follow-up showed that the risk of further progression of retinopathy 4 years after the DCCT ended was also greatly reduced in the former intensive group, despite nearly equivalent levels of HbA1c, a phenomenon termed metabolic memory. Metabolic memory was shown to persist through 10 years of follow-up. We now describe the risk of further progression of retinopathy, progression to proliferative diabetic retinopathy, clinically significant macular edema, and the need for intervention (photocoagulation or anti-VEGF) over 18 years of follow-up in EDIC. The cumulative incidence of each retinal outcome continues to be lower in the former intensive group. However, the year-to-year incidence of these outcomes is now similar, owing in large part to a reduction in risk in the former conventional treatment group.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing ...diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA
was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA
, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m
, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.
Aims/Introduction
Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, ...but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN.
Materials and Methods
Standardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN.
Results
Participants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut‐off points of ECG‐derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with CARTs‐defined CAN. Combining SDNN and rMSSD optimal cut‐off points does not provide additional predictive power for CAN.
Conclusions
These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care.
Participants with cardiovascular reflex tests‐defined cardiovascular autonomic neuropathy (CAN) had significantly lower standard deviation of normally conducted R‐R intervals and root mean square of successive differences between normal‐to‐normal R‐R intervals compared to those without CAN (P < 0.001). standard deviation of normally conducted R‐R intervals plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistics for standard deviation of normally conducted R‐R intervals was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut‐off point, showing fair agreement with cardiovascular reflex tests‐defined CAN.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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