Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)

OBJECTIVE

To compare the efficacy and safety of two doses of once-weekly dulaglutide, a glucagon-like peptide 1 receptor agonist, to sitagliptin in uncontrolled, metformin-treated patients with type 2 diabetes. The primary objective was to compare (for noninferiority and then superiority) dulaglutide 1.5 mg versus sitagliptin in change from baseline in glycosylated hemoglobin A_1c (HbA_1c) at 52 weeks.

RESEARCH DESIGN AND METHODS

This multicenter, adaptive, double-blind, parallel-arm study randomized patients (N = 1,098; mean baseline age 54 years; HbA_1c 8.1% [65 mmol/mol]; weight 86.4 kg; diabetes duration 7 years) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, sitagliptin 100 mg, or placebo (placebo-controlled period up to 26 weeks). The treatment period lasted 104 weeks, with 52-week primary end point data presented.

RESULTS

The mean HbA_1c changes to 52 weeks were (least squares mean ± SE): −1.10 ± 0.06% (−12.0 ± 0.7 mmol/mol), −0.87 ± 0.06% (9.5 ± 0.7 mmol/mol), and −0.39 ± 0.06% (4.3 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg, and sitagliptin, respectively. Both dulaglutide doses were superior to sitagliptin (P < 0.001, both comparisons). No events of severe hypoglycemia were reported. Mean weight changes to 52 weeks were greater with dulaglutide 1.5 mg (−3.03 ± 0.22 kg) and dulaglutide 0.75 mg (−2.60 ± 0.23 kg) compared with sitagliptin (−1.53 ± 0.22 kg) (P < 0.001, both comparisons). The most common gastrointestinal treatment-emergent adverse events in dulaglutide 1.5- and 0.75-mg arms were nausea, diarrhea, and vomiting.

CONCLUSIONS

Both dulaglutide doses demonstrated superior glycemic control versus sitagliptin at 52 weeks with an acceptable tolerability and safety profile.     

Morning Cortisol Levels and Cognitive Abilities in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.

RESULTS

In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).

CONCLUSIONS

High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.Type 2 diabetes is associated with cognitive impairments, including deficits in processing speed, executive function and declarative memory, and with structural changes in the brain including reductions in hippocampal and amygdalar volumes, which are key areas influencing learning and long-term memory (1,2). Hyperglycemia, cerebral microvascular disease, and recurrent severe hypoglycemic episodes have all been implicated as potential causative factors of cognitive decline (3) but are unlikely to explain the entire effect of diabetes on cognition.Increasing evidence supports a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and elevated endogenous glucocorticoids (as occurs in Cushing''s syndrome) are associated with cognitive impairment in animals and humans. More subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function have also been linked with cognitive function, with higher plasma cortisol levels at 0900 h being associated with poorer age-related cognitive ability in a small group of elderly, healthy male volunteers (4). Conversely, manipulations that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing in rodents (5,6). Elevated glucocorticoid levels have widespread effects within the central nervous system, including deleterious effects on the structure and function of the hippocampus, a key locus for cognitive function, which also highly expresses glucocorticoid receptors (7,8).Several studies have demonstrated that people with type 2 diabetes have activation of the HPA axis, manifested by elevated basal plasma cortisol levels (9,10), higher late-night salivary cortisol levels (11), elevated ACTH levels (12), increased cortisol levels following overnight dexamethasone suppression (13,14), and impaired habituation of cortisol levels to repeated stress (15). These findings are consistent with a central dysregulation of the HPA axis in type 2 diabetes. The elevated plasma cortisol levels are associated with metabolic abnormalities in diabetes (16) and with complications of diabetes, including retinopathy, neuropathy, and nephropathy (17).Investigators have started to explore whether altered HPA axis activity contributes to cognitive impairment in diabetes. Impaired central negative feedback control of the HPA axis, as indicated by higher cortisol levels after 1.5 mg dexamethasone administration, was related to declarative memory impairments, possibly reflecting hippocampal dysfunction, in 30 individuals with type 2 diabetes compared with age-, sex-, and education-matched control subjects (18). However, the association between cortisol and cognitive function disappeared after adjustment for glycemic control (A1C). The same investigators reported similarly impaired HPA axis feedback control in association with verbal declarative memory deficits in 41 subjects with type 2 diabetes (1). In the latter study, the subjects with type 2 diabetes also had reduced hippocampal and prefrontal volumes, but there were no significant associations between the cortisol measurements and magnetic resonance image findings (1).Despite these findings from animal and human studies, information from large-scale epidemiological studies of representative populations is lacking, which could confirm or refute an association between circulating plasma cortisol levels and age-related cognitive impairment. We therefore examined the relationship between fasting cortisol and both late-life cognitive ability and estimated lifetime cognitive change in a large, representative study population of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). The ET2DS has the advantage over many previous epidemiological studies of having detailed cognitive testing in a range of cognitive domains and very extensive phenotyping for potential confounding or mediating factors.     

Metabolic Effects of Exercise Training Among Fitness-Nonresponsive Patients With Type 2 Diabetes: The HART-D Study

OBJECTIVETo evaluate the impact of exercise training (ET) on metabolic parameters among participants with type 2 diabetes mellitus (T2DM) who do not improve their cardiorespiratory fitness (CRF) with training.RESULTSA total of 202 participants (mean age 57.1 ± 7.9 years, 63% women) were included. Among the exercise groups (n = 161), there was substantial heterogeneity in ΔVO_2peak; 57% had some improvement in CRF (ΔVO_2peak >0), with only 36.6% having a ≥5% increase in VO_2peak. Both fitness responders and nonresponders (respectively) had significant improvements in hemoglobin A_1c and measures of adiposity (ΔHbA_1c: −0.26% [95% CI −0.5 to −0.01] and −0.26% [−0.45 to −0.08]; Δwaist circumference: −2.6 cm [−3.7 to −1.5] and −1.8 cm [−2.6 to −1.0]; Δbody fat: −1.07% [−1.5 to −0.62] and −0.75% [−1.09 to −0.41]). No significant differences were observed in the degree of change of these metabolic parameters between fitness responders and nonresponders. Control group participants had no significant changes in any of these metabolic parameters.CONCLUSIONSET is associated with significant improvements in metabolic parameters irrespective of improvement in cardiorespiratory fitness.     

Incidence of Remission in Adults With Type 2 Diabetes: The Diabetes & Aging Study

OBJECTIVETo estimate the incidence of remission in adults with type 2 diabetes not treated with bariatric surgery and to identify variables associated with remission.RESULTSThe incidence density (remissions per 1,000 person-years; 95% CI) of partial, complete, or prolonged remission was 2.8 (2.6–2.9), 0.24 (0.20–0.28), and 0.04 (0.01–0.06), respectively. The 7-year cumulative incidence of partial, complete, or prolonged remission was 1.47% (1.40–1.54%), 0.14% (0.12–0.16%), and 0.007% (0.003–0.020%), respectively. The 7-year cumulative incidence of achieving any remission was 1.60% in the whole cohort (1.53–1.68%) and 4.6% in the subgroup with new-onset diabetes (<2 years since diagnosis) (4.3–4.9%). After adjusting for demographic and clinical characteristics, correlates of remission included age >65 years, African American race, <2 years since diagnosis, baseline HbA_1c level <5.7% (<39 mmol/mol), and no diabetes medication at baseline.CONCLUSIONSIn community settings, remission of type 2 diabetes does occur without bariatric surgery, but it is very rare.     

Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation.

RESEARCH DESIGN AND METHODS

People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia.

RESULTS

Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA_1c, BMI, and treatment type.

CONCLUSIONS

Daytime sleepiness may be a novel risk factor for hypoglycemia.Hypoglycemia is an adverse side effect of insulin and sulfonylurea treatment for type 2 diabetes. Factors influencing risk of severe hypoglycemia (requiring external assistance) include duration of diabetes (1), duration of insulin treatment (2), renal impairment (2), age (1), comorbidities (3), and impaired awareness of hypoglycemia (4). Sleep-disordered breathing with associated daytime somnolence is reported in up to 75% of people with type 2 diabetes (5) and is linked to a range of cardiovascular and metabolic morbidities (6). We hypothesized that sleep disorder and increased daytime sleepiness would be associated with increased frequency of severe hypoglycemia in people with diabetes.     

Change in Sleep Duration and Type 2 Diabetes: The Whitehall II Study

OBJECTIVEEvidence suggests that short and long sleep durations are associated with a higher risk of type 2 diabetes. Using successive data waves spanning >20 years, we examined whether a change in sleep duration is associated with incident diabetes.RESULTSCompared with the reference group of persistent 7-h sleepers, an increase of ≥2 h sleep per night was associated with a higher risk of incident diabetes (odds ratio 1.65 [95% CI 1.15, 2.37]) in analyses adjusted for age, sex, employment grade, and ethnic group. This association was partially attenuated by adjustment for BMI and change in weight (1.50 [1.04, 2.16]). An increased risk of incident diabetes was also seen in persistent short sleepers (average ≤5.5 h/night; 1.35 [1.04, 1.76]), but this evidence weakened on adjustment for BMI and change in weight (1.25 [0.96, 1.63]).CONCLUSIONSThis study suggests that individuals whose sleep duration increases are at an increased risk of type 2 diabetes. Greater weight and weight gain in this group partly explain the association.     

Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience

OBJECTIVE

We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

RESEARCH DESIGN AND METHODS

The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother’s prenatal care and delivery and the infant’s health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed.

RESULTS

Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly.

CONCLUSIONS

Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity.     

Dose-Response Effects of Insulin Glargine in Type 2 Diabetes

OBJECTIVE

To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m² and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.

RESULTS

Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.

CONCLUSION

A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.Type 2 diabetes is a condition of relative or absolute insulin deficiency. Consequently, insulin replacement becomes a common and essential therapy in these individuals. Insulin therapy in type 2 diabetes can range from a single injection to basal-bolus replacement regimens with multiple daily injections. Insulin glargine is a soluble long-acting insulin analog that is widely used in clinical practice for basal insulin replacement.Numerous studies have investigated the clinical efficacy of insulin glargine in both type 1 and type 2 diabetes (1–3). Glargine has been found to lower A1C, provide effective basal insulin replacement, and reduce the risk of hypoglycemia (1–3). Despite the widespread use of glargine in clinical practice, there have been relatively few studies investigating the pharmacokinetic and pharmacodynamic characteristics of the insulin. Two studies have investigated subcutaneous doses of 0.3 and 0.35 U glargine in type 1 diabetic individuals (4,5). Other studies also using a 24-h glucose clamp technique have compared the pharmacokinetics and pharmacodynamics of single doses of glargine (0.5 and 0.8 units/kg) in patients with type 2 diabetes (6,7). These studies provide valuable information about single doses of glargine in patients with diabetes. Klein et al. (8) have also compared three doses of glargine (0.4, 0.8, and 1.4 units/kg) in type 2 diabetes during 24-h clamp studies using the Biostator. However, because the Biostator has been reported to limit maximal glucose infusions during a glucose clamp and also produce a wide variation of blood glucose concentrations around the target glucose value (9), we reasoned that further information regarding the dose-response characteristics of insulin glargine in patients with type 2 diabetes would also be useful. The aim of the present study was to use the 24-h euglycemic clamp technique to determine the pharmacokinetics and pharmacodynamics of differing large, single subcutaneous doses of glargine (similar to those used in clinical practice in treatment of obese insulin-resistant type 2 diabetic individuals). Isotope dilution methods were used to determine the effects of glargine on endogenous glucose production and glucose disappearance.     

Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes: A randomized, open-label trial

OBJECTIVE To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA(1c)) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8 mg/day, -1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA(1c) <7% (from ～30% to ～50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA(1c) (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7 mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia. CONCLUSIONS Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.     

Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Eight hundred thirty-one men and women (aged 60–75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change.

RESULTS

Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, −0.12) and of subclinical markers with actual 4-year decline (standardized β, −0.12, 0.12, and −0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors.

CONCLUSIONS

Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.Cognitive abilities are essential for independent living in later life, and some domains of cognitive functioning decline in mean level from relatively early adulthood (1). Age-related cognitive decline is accompanied by pathological changes in the brain, including cerebral microvascular changes, and although individual differences exist in the severity of age-related microvascular damage in the brain, this is difficult to investigate noninvasively. Systemic atherosclerotic changes in the body may serve as a marker of vascular-related changes in the brain (2) that, in turn, lead to cognitive deficits (3,4). However, the potential of large vessel changes distant from the brain itself to function as markers of cognitive decline remains unclear. We aimed to study a range of measures of clinical and subclinical macrovascular disease that focus on different areas of the vasculature or different underlying pathophysiological mechanisms to assess which of these might function as proxies of cognitive decline.Understanding the role of macrovascular disease in age-related cognitive impairment is particularly important in diabetes, given the higher prevalence of atherosclerotic large vessel disease as well as the accelerated cognitive decline and increased risk of cognitive impairment (5,6) associated with this condition, and the potentially modifiable nature of macrovascular disease (7). The prevalence of stroke, of transient ischemic attack (TIA) (8), and of coronary heart disease (9) are higher in diabetic populations than in nondiabetic populations, and average natriuretic peptide levels, a marker of cardiac stress, are increased (10). Markers of subclinical atherosclerosis also are altered, with increased average carotid intima-media thickness (cIMT) (11) and reduced mean ankle brachial index (ABI) (12). Despite this, investigation into the role of macrovascular disease in age-related cognitive impairment in people with diabetes is limited compared with investigation into this issue in the general (predominantly nondiabetic) population. We set out to determine the association of a variety of measures of subclinical macrovascular disease and cardiovascular event categories with cognitive decline in a sample of older people, all of whom had diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). We did so using two cognitive outcomes, actual late-life cognitive change over a 4-year period and estimated lifetime cognitive change. These analyses are timely given the increasing prevalence of diabetes at younger ages (13) that, together with greater survival (14) and greater lifetime exposure to diabetes in current generations, is likely to contribute to increasing prevalence of cognitive impairment.     

HbA1c and Risk of Severe Hypoglycemia in Type 2 Diabetes: The Diabetes and Aging Study

OBJECTIVE

We examined the association between HbA_1c level and self-reported severe hypoglycemia in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Type 2 diabetic patients in a large, integrated healthcare system, who were 30–77 years of age and treated with glucose-lowering therapy, were asked about severe hypoglycemia requiring assistance in the year prior to the Diabetes Study of Northern California survey conducted in 2005–2006 (62% response rate). The main exposure of interest was the last HbA_1c level collected in the year preceding the observation period. Poisson regression models adjusted for selected demographic and clinical variables were specified to evaluate the relative risk (RR) of severe hypoglycemia across HbA_1c levels. We also tested whether the HbA_1c-hypoglycemia association differed across potential effect modifiers (age, diabetes duration, and category of diabetes medication).

RESULTS

Among 9,094 eligible survey respondents (mean age 59.5 ± 9.8 years, mean HbA_1c 7.5 ± 1.5%), 985 (10.8%) reported experiencing severe hypoglycemia. Across HbA_1c levels, rates of hypoglycemia were 9.3–13.8%. Compared with those with HbA_1c of 7–7.9%, the RR of hypoglycemia was 1.25 (95% CI 0.99–1.57), 1.01 (0.87–1.18), 0.99 (0.82–1.20), and 1.16 (0.97–1.38) among those with HbA_1c <6, 6–6.9, 8–8.9, and ≥9%, respectively, in a fully adjusted model. Age, diabetes duration, and category of diabetes medication did not significantly modify the HbA_1c-hypoglycemia relationship.

CONCLUSIONS

Severe hypoglycemia was common among patients with type 2 diabetes across all levels of glycemic control. Risk tended to be higher in patients with either near-normal glycemia or very poor glycemic control.The goals of glucose-lowering therapy in type 2 diabetes are to reduce the risk of diabetes complications while minimizing harms associated with therapy, and thus increase both longevity and health-related quality of life. Intensive glucose-lowering strategies modestly reduce the risk of surrogates for microvascular complications, but the benefits for macrovascular outcomes are less clear (1–5). A recent position statement from the American Diabetes Association (ADA) has called for individualized decision making in diabetes that integrates patient goals and preferences and takes into account the benefits and risks associated with therapy to set glycemic targets for care (6). The ADA and American Geriatrics Society have made similar recommendations for older patients with diabetes (7). However, data are lacking on how to individualize glycemic targets. Several analyses of observational data have focused on determining what levels of glycemic control maximize benefits (8,9), but less is known about the risks associated with various levels of glucose control. Hypoglycemia is the most common adverse effect of diabetes therapy and is associated with unfavorable health outcomes (higher risk of dementia [10], falls [11], fall-related fractures [12], cardiovascular events [13,14], poor health-related quality of life [15,16], and increased mortality [17]). Therefore, data on the relationship between glucose control and risk of severe hypoglycemia are critical for making informed decisions about type and intensity of therapy.Clinicians may assume that the risk of hypoglycemia is highest among patients with the lowest HbA_1c levels. Compelling evidence for this comes from the Diabetes Control and Complications Trial (DCCT), which reported an inverse relationship between HbA_1c levels and the occurrence of severe hypoglycemia in participants with type 1 diabetes (4). Additionally, intensive glucose control strategies implemented in randomized control trial settings in patients with both type 1 and type 2 diabetes resulted in lower HbA_1c and were associated with an increased risk of hypoglycemia (1–5). However, recent post hoc analyses of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicated an increased hypoglycemia risk in type 2 diabetic participants with poorer glycemic control compared with subjects with more desirable HbA_1c levels, irrespective of assigned treatment group (18). In ACCORD, the intensive treatment arm and poorer achieved glycemic control in both the treatment and control arms increased hypoglycemia risk. Less is known about the relationship between glycemic control and hypoglycemia in usual care settings, where clinical decision making about treatment intensity occurs and is modified over the patient’s life course. Prior observational studies have yielded conflicting results; some have indicated increased risk of hypoglycemia at lower HbA_1c levels (19), whereas others have shown increased risk of hypoglycemia at higher HbA_1c levels (16,17), but none of these prior analyses were specifically designed to test the association between HbA_1c and hypoglycemia. Moreover, most studies were based on hypoglycemic events that came to clinical attention (as ascertained from emergency department or hospital records) and thus may miss the majority of events that are treated outside of the medical system.To investigate the relationship between HbA_1c level and hypoglycemia among patients with type 2 diabetes treated with glucose-lowering medications in a usual care setting, we analyzed data from the Diabetes Study of Northern California (DISTANCE) survey. We hypothesized that the risk of severe hypoglycemia may be higher in type 2 diabetic patients with either very low or high HbA_1c levels compared with those with glycemic control similar to the standard arm in clinical trials (mean HbA_1c ∼7.5%). The current standards of care recommend less intensive glucose control strategies in older patients with limited life expectancy, advanced diabetes, cognitive impairment, or very poor health given the limited potential for future benefits and the need to reduce the risk of hypoglycemia in these high-risk patients (7,20). Therefore, we further hypothesized that lower HbA_1c levels may be more strongly associated with hypoglycemia risk in older (vs. younger) patients with longer (vs. shorter) diabetes duration. Since hypoglycemia occurs as a result of glucose-lowering therapy and is not directly due to HbA_1c level, we speculated that the relationship between HbA_1c and hypoglycemia may differ by type of glucose-lowering regimen.     

The Second-Meal Phenomenon in Type 2 Diabetes

OBJECTIVE

In health, the rise in glucose after lunch is less if breakfast is eaten. We evaluated the second-meal effect in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Metabolic changes after lunch in eight obese type 2 diabetic subjects were compared on 3 days: breakfast eaten, no breakfast, and no breakfast but intravenous arginine 1 h before lunch.

RESULTS

Despite comparable insulin levels, the rise in plasma glucose after lunch was considerably less if breakfast had been eaten (0.68 ± 1.49 vs. 12.32 ± 1.73 vs. 7.88 ± 1.03 mmol · h⁻¹ · l⁻¹; P < 0.0001). Arginine administration almost halved the lunch rise in plasma glucose (12.32 ± 1.73 vs. 7.88 ± 1.03 mmol · h⁻¹ · l⁻¹). The plasma free fatty acid concentration at lunchtime directly related to plasma glucose rise after lunch (r = 0.67, P = 0.0005).

CONCLUSIONS

The second-meal effect is preserved in type 2 diabetes. Premeal administration of a nonglucose insulin secretagogue results in halving the postprandial glucose rise and has therapeutic potential.The effect of a prior meal in decreasing the rise in blood glucose after a subsequent meal was first recognized almost a century ago (1). It has repeatedly been confirmed in healthy subjects, but tests with intravenous or oral glucose suggested that the second-meal effect does not occur in type 2 diabetes (2–4). We observed incidentally that a second meal in subjects with type 2 diabetes brought about a 70% lesser rise in blood glucose (5).This study was designed to determine whether the second-meal phenomenon is present in type 2 diabetes and, if so, whether this can artificially be induced as a possible therapeutic approach.     

Cognitive Function in Adolescents and Young Adults With Youth-Onset Type 1 Versus Type 2 Diabetes: The SEARCH for Diabetes in Youth Study

OBJECTIVEPoor cognition has been observed in children and adolescents with youth-onset type 1 (T1D) and type 2 diabetes (T2D) compared with control subjects without diabetes. Differences in cognition between youth-onset T1D and T2D, however, are not known. Thus, using data from SEARCH for Diabetes in Youth, a multicenter, observational cohort study, we tested the association between diabetes type and cognitive function in adolescents and young adults with T1D (n = 1,095) or T2D (n = 285).RESEARCH DESIGN AND METHODSCognition was assessed via the National Institutes of Health Toolbox Cognition Battery, and age-corrected composite Fluid Cognition scores were used as the primary outcome. Confounder-adjusted linear regression models were run. Model 1 included diabetes type and clinical site. Model 2 additionally included sex, race/ethnicity, waist-to-height ratio, diabetes duration, depressive symptoms, glycemic control, any hypoglycemic episode in the past year, parental education, and household income. Model 3 additionally included the Picture Vocabulary score, a measure of receptive language and crystallized cognition.RESULTSHaving T2D was significantly associated with lower fluid cognitive scores before adjustment for confounders (model 1; P < 0.001). This association was attenuated to nonsignificance with the addition of a priori confounders (model 2; P = 0.06) and Picture Vocabulary scores (model 3; P = 0.49). Receptive language, waist-to-height ratio, and depressive symptoms remained significant in the final model (P < 0.01 for all, respectively).CONCLUSIONSThese data suggest that while youth with T2D have worse fluid cognition than youth with T1D, these differences are accounted for by differences in crystallized cognition (receptive language), central adiposity, and mental health. These potentially modifiable factors are also independently associated with fluid cognitive health, regardless of diabetes type. Future studies of cognitive health in people with youth-onset diabetes should focus on investigating these significant factors.     

素食预防2型糖尿病的效果

目的探讨素食预防2型糖尿病的效果。方法采用便利抽样的方法从某社区居民中抽取信仰佛教的素食2年以上者55例及饮食结构以植物性食物和动物性食物混合为主者53例,调查108例研究对象的糖尿病史,并空腹检测血糖及总胆固醇。结果素食组和荤素食混合组的空腹血糖分别为（4.05±0.61）、（4.86±1.61）mmol/L,胆固醇分别为（4.32±1.04）、（5.08±0.85）mmol/L,差异有统计学意义（P〈0.01）;素食组无一例符合糖尿病诊断标准（空腹血糖≥7.0mmol/L）,荤素食混合组有4例空腹血糖≥7.0mmol/L,差异无统计学意义（P=0.055）。结论通过增加膳食中植物性食物的比例,能提高机体对胰岛素的敏感性,降低空腹血糖,而且素食成分有助于维持人体的酸碱平衡、降低体内胆固醇水平,从而控制心血管系统疾病的危险因素。     

Prognostic Impact of Aortic Stiffness in High-Risk Type 2 Diabetic Patients: The Rio de Janeiro Type 2 Diabetes Cohort Study

OBJECTIVE

The prognostic importance of carotid-femoral pulse wave velocity (PWV), the gold standard measure of aortic stiffness, has been scarcely investigated in type 2 diabetes and never after full adjustment for potential confounders. The aim was to evaluate the prognostic impact of carotid-femoral PWV for cardiovascular morbidity and all-cause mortality in a cohort of 565 high-risk type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

Clinical, laboratory, ambulatory blood pressure (BP) monitoring, and carotid-femoral PWV data were obtained at baseline. The primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause mortality. Multiple Cox survival analysis was used to assess the associations between carotid-femoral PWV, as a continuous variable and categorized at 10 m/s, and the end points.

RESULTS

After a median follow-up of 5.75 years, 88 total cardiovascular events and 72 all-cause deaths occurred. After adjustments for potential cardiovascular risk factors, including micro- and macrovascular complications, ambulatory BP, and metabolic control, carotid-femoral PWV was predictive of the composite end point but not of all-cause mortality both as a continuous variable (hazard ratio 1.13 [95% CI 1.03–1.23], P = 0.009 for increments of 1 m/s) and as categorized at 10 m/s (1.92 [1.16–3.18], P = 0.012). On sensitivity analysis, carotid-femoral PWV was a better predictor of cardiovascular events in younger patients (<65 years), in those with microvascular complications, and in those with poorer glycemic control (HbA_1c ≥7.5% [58.5 mmol/mol]).

CONCLUSIONS

Carotid-femoral PWV provides cardiovascular risk prediction independent of standard risk factors, glycemic control, and ambulatory BPs and improves cardiovascular risk stratification in high-risk type 2 diabetes.In the past decade, knowledge of the importance of arterial stiffness in the pathogenesis of cardiovascular diseases grew (1,2). Arterial stiffness depends on the structural and geometric properties of the arterial wall and on the distending pressure, and aging and blood pressure (BP) are its main determinants (1,2). The measurement of carotid-femoral pulse wave velocity (PWV) is considered the gold standard evaluation of central aortic stiffness (1). Furthermore, aortic stiffness has been demonstrated to predict cardiovascular morbidity and mortality above and beyond other traditional cardiovascular risk factors in patients with end-stage renal disease (3) and hypertension (4), elderly individuals (5), and general population-based samples (6,7). This prognostic importance has also been recently confirmed in a meta-analysis (8).Type 2 diabetic patients have increased arterial stiffness (9–11) and are at particular risk for augmented cardiovascular morbidity and mortality. This high cardiovascular risk is not completely explained by clustering of traditional risk factors, and increased arterial stiffness may be one pathophysiological mechanism that links diabetes to increased cardiovascular morbidity and mortality (12). Nevertheless, only one previous study investigated the prognostic impact of increased aortic stiffness for cardiovascular outcomes in type 2 diabetes (13), but because of a smaller sample size (397 diabetic individuals), the study could not completely adjust for traditional cardiovascular risk factors, chronic diabetes complications, or metabolic control parameters. Therefore, we aimed to investigate in a prospective follow-up cohort of high-risk type 2 diabetic patients the prognostic impact of increased aortic stiffness for cardiovascular morbidity and mortality and for all-cause mortality. In particular, we evaluated whether aortic stiffness was able to add prognostic information beyond traditional cardiovascular risk markers and whether there were interactions between aortic stiffness and other important covariates, such as age, sex, presence of diabetes complications, and glycemic control.     

2型糖尿病患者血清铁代谢相关指标检测意义

目的 探讨2型糖尿病患者血清铁调素(Hepcidin)、铁蛋白(SF)、转铁蛋白受体(sTfR)和血清铁(SI)的变化与临床意义。方法 130例2型糖尿病患者,分为两组,A组为微量蛋白尿组45例(mAlb30～300 mg/24 h),B组为正常蛋白尿组85例(mAlb＜30 mg/24 h),另选同期45例健康体检者为对照C组。各组均取空腹晨血5 ml离心取血清检测铁调素,SF,sTfR和SI含量。结果 A组患者血清铁调素和SF水平(42.27±32.12 ng/ml,211.6±107.2 ng/ml)均显著高于B组(26.12±18.36 ng/ml,179.1±109.7 ng/ml; P均＜0.05)和C组(9.47±1.65 ng/ml,84.41±47.10 ng/ml),(P均＜0.01); B组患者铁调素和SF水平显著高于C组(P均＜0.01)。各组之间SI水平(15.26 μmol/L,18.65 μmol/L,17.71 μmol/L)和sTfR水平(1.12 μg/L,1.05 μg/L,1.16 μg/L)差异均无统计学意义(t=0.469～1.176,P均＞0.05)。相关分析显示,2型糖尿病患者铁调素与SF呈显著正相关(r=0.329,P＜0.05),铁调素与sTfR,SI无显著相关性(r=0.169,P＞0.05; r=-0.149,P＞0.05)。结论 2型糖尿病患者体内存在以血清铁调素、SF增高为主的铁超负荷和铁代谢紊乱,并与尿微量清蛋白的排泄呈正相关。因此,检测血清铁调素和SF可作为糖尿病早期肾功能损伤的重要预测因子。     

The Reality of Type 2 Diabetes Prevention

Efforts to reduce the burden of type 2 diabetes include attempts to prevent or delay the onset of the disease. Landmark clinical trials have shown that lifestyle modification programs focused on weight loss can delay the onset of type 2 diabetes in subjects at high risk of developing the disease. Building on this knowledge, many community-based studies have attempted to replicate the trial results and, simultaneously, payers have begun to cover diabetes prevention services. This article focuses on the evidence supporting the premise that community prevention efforts will be successful. Unfortunately, no study has shown that diabetes can be delayed or prevented in a community setting, and efforts to replicate the weight loss achieved in the trials have been mostly disappointing. Furthermore, both the clinical trials and the community-based prevention studies have not shown a beneficial effect on any diabetes-related clinical outcome. While the goal of diabetes prevention is extremely important, the absence of any persuasive evidence for the effectiveness of community programs calls into question whether the use of public funds or national prevention initiatives should be supported at this time.     

Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D trial

OBJECTIVE—Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI).RESEARCH DESIGN AND METHODS—Patients (type 2 diabetes, aged 30–75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l).RESULTS—A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1–1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P < 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group.CONCLUSIONS—Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with diabetes, for which ∼65% of deaths are attributable to heart disease or stroke (1,2). Among individuals with type 2 diabetes, those with a previous myocardial infarction have a particularly high risk of additional cardiovascular events (3).The higher prevalence of classic cardiovascular risk factors in type 2 diabetes only partly explains the increased cardiovascular risk associated with diabetes (2,3). Chronic hyperglycemia increases this risk (4–7) and postchallenge/postprandial hyperglycemia has been associated with CVD independent of A1C or fasting blood glucose (FBG) (8,9). Increased oxidative stress has been suggested as a pathophysiologic mechanism to explain this relationship (10). Furthermore, acarbose, an α-glucosidase inhibitor that specifically reduces postprandial hyperglycemia, reduced cardiovascular mortality in a diabetes prevention trial (11).The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial (12) demonstrated a reduction in mortality in patients with type 2 diabetes and recent acute myocardial infarction (AMI) after intensive insulin treatment, and this study was developed to determine the impact of postprandial hyperglycemia on CVD in a similar high-risk population. Thus, the primary objective of the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) study was to demonstrate a difference between two insulin strategies, one targeting postprandial hyperglycemia and the other targeting fasting and interprandial hyperglycemia, on time until the first combined adjudicated cardiovascular event (primary outcome defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome).     

Angiopoietin-Like Protein 2 and Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study

OBJECTIVE

To examine, for the first time, the association between a novel inflammatory cytokine, angiopoietin-like protein (ANGPTL) 2, and the development of type 2 diabetes (T2DM).

RESEARCH DESIGN AND METHODS

A total of 2,164 community-dwelling Japanese individuals aged 40 to 79 years without diabetes were followed up for 7 years. Serum ANGPTL2 levels were divided into quartile categories at baseline: <2.15, 2.16–2.71, 2.72–3.40, and ≥3.41 ng/mL. During follow-up, 221 participants developed T2DM.

RESULTS

In multivariate analyses, after adjusting for comprehensive risk factors and high-sensitivity C-reactive protein (hs-CRP) levels, the risk of developing T2DM was significantly higher in the highest ANGPTL2 quartile than in the lowest quartile (hazard ratio, 1.80; 95% CI, 1.14–2.85; P = 0.01).

CONCLUSIONS

Elevated serum ANGPTL2 levels were positively associated with the development of T2DM in a general population, independent of other risk factors including hs-CRP levels.Angiopoietin-like proteins (ANGPTLs), which are structurally similar to angiopoietins, are characterized by a coiled-coil domain in the N-terminus and a fibrinogen-like domain in the C-terminus. Seven ANGPTLs have been identified to date (1–3); one of them, ANGPTL2, has been shown to be expressed abundantly in adipose tissues and to be a key mediator linking obesity to adipose tissue inflammation and systemic insulin resistance in mice (4,5). In humans, ANGPTL2 is also closely related to adiposity and inflammation (4). However, the association of serum ANGPTL2 levels with the risk of developing type 2 diabetes (T2DM) has not been investigated to date. The objective of this study was to examine this issue in a cohort of the general Japanese population, taking into account a comprehensive range of confounders.     

The Pharmacogenetics of Type 2 Diabetes: A Systematic Review

OBJECTIVE

We performed a systematic review to identify which genetic variants predict response to diabetes medications.

RESEARCH DESIGN AND METHODS

We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA_1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance.

RESULTS

Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis.

CONCLUSIONS

We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.