Renal Structure in Normoalbuminuric and Albuminuric Patients With Type 2 Diabetes and Impaired Renal Function

OBJECTIVE

The structural basis of normoalbuminuric renal insufficiency in patients with type 2 diabetes remains to be elucidated. We compared renal biopsy findings in patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) and measured GFR of <60 mL/min/1.73 m², associated with either normo-, micro-, or macroalbuminuria.

RESEARCH DESIGN AND METHODS

In patients with normo- (n = 8) or microalbuminuria (n = 6), renal biopsies were performed according to a research protocol. In patients with macroalbuminuria (n = 17), biopsies were performed according to clinical indication. Findings were categorized according to the Fioretto classification: category 1 (C1), normal/near normal; category 2 (C2), typical diabetic nephropathy (DN) with predominantly glomerular changes; and category 3 (C3), atypical with disproportionately severe interstitial/tubular/vascular damage and with no/mild diabetic glomerular changes.

RESULTS

In our study population (mean eGFR 35 mL/min/1.73 m²), typical glomerular changes (C2) of DN were observed in 22 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 subjects with normoalbuminuria (P = 0.002). By contrast, predominantly interstitial or vascular changes (C3) were seen in only 1 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 normoalbuminuric subjects (P = 0.08). Mesangial area increased progressively from normal controls to patients with type 2 diabetes and normo-, micro-, and macroalbuminuria. Varying degrees of arteriosclerosis, although not necessarily the predominant pattern, were seen in seven of eight subjects with normoalbuminuria.

CONCLUSIONS

Typical renal structural changes of DN were observed in patients with type 2 diabetes and elevated albuminuria. By contrast, in normoalbuminuric renal insufficiency, these changes were seen less frequently, likely reflecting greater contributions from aging, hypertension, and arteriosclerosis.In diabetic kidney disease (DKD), incipient diabetic nephropathy (DN) is classically defined by increasing albuminuria, heralding a decline in glomerular filtration rate (GFR) (1), which usually does not occur until the transition to macroalbuminuria (overt DN). However, a proportion of patients with either type 1 or type 2 diabetes does not follow this classical albuminuric pathway, instead showing declining renal function in the absence of an elevated albumin excretion rate (AER) (2,3). Previously, we have reported that up to 25% of patients with type 1 or type 2 diabetes have reduced renal function in the setting of a normal AER (<20 μg/min) (3). Others have also reported a reduction in GFR with normoalbuminuria in patients with type 1 diabetes (4). Subsequent studies have further demonstrated this dissociation between decreased GFR and increased albuminuria in patients with type 2 or type 1 diabetes (5–9).In patients with type 1 diabetes and reduced GFR, classic glomerular changes of DKD have been described regardless of albuminuria status (2,10). By contrast, in patients with type 2 diabetes and DKD, regardless of the level of GFR or urinary AER, renal biopsy findings are generally accepted to be more heterogeneous than in type 1 diabetes. One study by Fioretto et al. (11) of subjects with type 2 diabetes, microalbuminuria (AER 20–200 μg/min) and preserved GFR showed heterogeneous changes on renal biopsy. These changes were classifiable into three categories: category 1 (C1), defined by normal or near-normal renal structure, category2(C2), typical DN with predominantly glomerular changes, and category 3 (C3), defined by disproportionately severe interstitial, tubular, or vascular damage and few or no glomerular changes.To date, few studies have compared renal biopsy findings in subjects with type 2 diabetes, reduced GFR, and different degrees of albuminuria, and as a result, the histological basis of normoalbuminuric DKD remains poorly understood. The aim of this study, therefore, was to investigate renal biopsy findings in subjects with type 2 diabetes and impaired renal function (measured or estimated GFR [eGFR] <60 mL/min/1.73 m²) associated with normo-, micro-, or macroalbuminuria.     

Incidence of Bladder Cancer in Patients With Type 2 Diabetes Treated With Metformin or Sulfonylureas

OBJECTIVE

Previous studies evaluating the effect of metformin on cancer risk have been impacted by time-related biases. To avoid these biases, we examined the incidence of bladder cancer in new users of metformin and sulfonylureas (SUs).

RESEARCH DESIGN AND METHODS

This cohort study included 87,600 patients with type 2 diabetes in The Health Improvement Network database. Use of metformin or an SU was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared metformin use with SU use, adjusted for age, sex, smoking, obesity, and HbA_1c level.

RESULTS

We identified 196 incident bladder cancers in the metformin cohort and 66 cancers in the SU cohort. Use of metformin was not associated with decreased bladder cancer risk (HR 0.81 [95% CI 0.60–1.09]). This association did not differ by sex (P for interaction = 0.20). We observed no association with duration of metformin relative to SU use (3 to <4 years of use: 0.57 [0.25–1.34]; 4 to <5 years of use: 0.93 [0.30–2.85; ≥5 years of use: 1.18 [0.44–3.19]; P for trend = 0.26).

CONCLUSIONS

Use of metformin is not associated with a decreased incidence of bladder cancer. Similar methods should be used to study other cancers that have previously been identified as potentially preventable with metformin.     

Association Between Remission of Macroalbuminuria and Preservation of Renal Function in Patients With Type 2 Diabetes With Overt Proteinuria

OBJECTIVE

Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking.

RESEARCH DESIGN AND METHODS

A total of 211 T2DM patients with albuminuria ≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated.

RESULTS

During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12–0.76]).

CONCLUSIONS

Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.Diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM) is a leading cause of end-stage renal disease (ESRD) all over the world (1). The typical progressive course of diabetic nephropathy is initially developing an increase in albuminuria (known as microalbuminuria), progressing to macroalbuminuria, and, thereafter, a rapid decline in renal function (1). A few decades ago, diabetic nephropathy was considered to be a progressive and irreversible chronic complication. Moreover, the progression of macroalbuminuria was considered the “point of no return.” Thus, the main therapeutic target for T2DM patients with macroalbuminuria was the prevention of the progression to ESRD. Recently, growing evidence has contradicted this point of no return concept. Several clinical studies have reported that intensive intervention including inhibition of the renin-angiotensin system could induce a reduction in macroalbuminuria and improve renal prognosis (2–7). Thus, reduction of macroalbuminuria could be considered an important therapeutic target to improve renal outcomes in diabetic patients. However, how often remission from macroalbuminuria to microalbuminuria or normoalbuminuria occurs and its effect on the deterioration of renal function of T2DM patients remain unclear. In particular, there is almost no evidence from a primary care setting. Actually, in the clinical practice, we often encounter patients with T2DM that has already been complicated by macroalbuminuria at the time when they first consulted the hospital because they were unaware that they were suffering from diabetes. Moreover, a considerable number of T2DM patients progress to advanced nephropathy because of long-standing poor diabetes control. These patients must be at high risk for the progression to ESRD. However, it remains unclear whether their renal prognosis can be improved by later intensified diabetes treatment in primary care practice.Thus, the aim of this study was to clarify the clinical characteristics of T2DM patients who showed a reduction in macroalbuminuria in the primary care practice and to estimate the rate of reduction in macroalbuminuria and its effect on renal function. In particular, we focused on T2DM patients with macroalbuminuria who had not been treated for diabetes or had not received adequate intensified diabetes treatment according to clinical recommendations before they first consulted the clinic.     

Changes in Prandial Glucagon Levels After a 2-Year Treatment With Vildagliptin or Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE

To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal.

RESEARCH DESIGN AND METHODS

Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin b.i.d. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline A1C 7.3 ± 0.6%).

RESULTS

A1C and prandial glucose area under the curve (AUC)_{0–2 h} were reduced similarly in both groups, whereas prandial insulin AUC_{0–2 h} increased to a greater extent by glimepiride. Prandial glucagon AUC_{0–2 h} (baseline 66.6 ± 2.3 pmol · h⁻¹ · l⁻¹) decreased by 3.4 ± 1.6 pmol · h⁻¹ · l⁻¹ by vildagliptin (n = 137) and increased by 3.8 ± 1.7 pmol · h⁻¹ · l⁻¹ by glimepiride (n = 121). The between-group difference was 7.3 ± 2.1 pmol · h⁻¹ · l⁻¹ (P < 0.001).

CONCLUSIONS

Vildagliptin therapy but not glimepiride improves postprandial α-cell function, which persists for at least 2 years.Glucagon levels are increased in type 2 diabetes because of impaired glucose-mediated suppression of glucagon secretion resulting in increased hepatic glucose output with subsequent hyperglycemia (1). Improved glycemia by the dipeptidyl peptidase-4 inhibitor, vildagliptin (2), is mediated primarily by improved β- and α-cell sensitivity to glucose (3). As an add-on to metformin, vildagliptin displays equal efficacy as glimepiride, with the added benefits of a much lower risk of hypoglycemia and no weight gain (4). Here we report prandial assessments of glucagon levels and insulin secretion rates after up to ∼2 years of therapy with the two drugs.     

Plasma Copeptin and Renal Outcomes in Patients With Type 2 Diabetes and Albuminuria

OBJECTIVE

Plasma copeptin, a surrogate for vasopressin, was associated with albuminuria in population-based studies. These associations are consistent with the effect of vasopressin on albuminuria observed in humans and rodents. The objective of this study was to determine whether plasma copeptin is an independent marker of risk of renal events in people with type 2 diabetes and albuminuria.

RESEARCH DESIGN AND METHODS

We studied 3,101 participants of the DIABHYCAR trial (6-year follow-up) with type 2 diabetes and albuminuria. A renal event was defined as doubling of serum creatinine or development of end-stage renal disease.

RESULTS

During follow-up, 86 renal events occurred in 76 subjects (2.45%). Incidences by tertiles of baseline plasma copeptin were 1.06% (T1), 1.45% (T2), and 4.84% (T3). They were 2.43% (T1), 5.11% (T2), and 11.81% (T3) for the subset of subjects with macroalbuminuria at baseline (n = 729). Hazard ratio for plasma copeptin tertiles as a risk for renal events was 4.79 (95% CI, 2.48–9.24; P < 0.0001; for T3 vs. T1). In a stepwise regression analysis, urinary albumin excretion and plasma copeptin remained positively associated and HDL cholesterol and estimated glomerular filtration rate were inversely associated with the incidence of renal events. These independent predictors explained ∼18% of the variance of the outcome. The yearly variations of estimated glomerular filtration rate by copeptin tertiles were −1.43 ± 0.51 (T1), −2.29 ± 0.49 (T2), and −3.52 ± 0.44 mL/min/1.73 m² per year (T3) (P = 0.005) in subjects with macroalbuminuria.

CONCLUSIONS

Plasma copeptin may help to identify subjects with diabetic chronic kidney disease who are at high risk for renal function decline.Type 2 diabetes is a major cause of kidney and cardiovascular diseases, and screening for albuminuria and proteinuria is recommended for stratification of risk of these comorbidities (1). Care of patients with diabetes and albuminuria improved markedly in the past decades. However, as shown in recent randomized trials, even with optimal treatment up to 20% of patients with diabetes and proteinuria develop end-stage renal disease (ESRD) within a 3-year follow-up (2,3). There is still an important unmet therapeutic need and many innovative therapeutic options have been or are being evaluated. Some of these new strategies were disappointing because of severe side effects (4). Because not all patients with type 2 diabetes and proteinuria will progress to ESRD, the identification of those at higher risk would improve the benefit-to-risk ratio of intensification of treatment.Copeptin, the stable COOH-terminal portion of the precursor of vasopressin, is an easily measurable surrogate marker of vasopressin. Studies in healthy subjects have shown plasma copeptin and vasopressin concentrations to correlate strongly over a wide range of osmolalities (5,6). We hypothesized that vasopressin might contribute to the progression of kidney damage and, thus, that plasma copeptin could be a good candidate for the identification of subjects at high risk for progression of nephropathy. Vasopressin is elevated in diabetes (7), and copeptin was associated with albuminuria in a recent, cross-sectional, population-based study (8). Moreover, infusion of DDAVP (a selective vasopressin V2 receptor agonist) was shown to increase urinary albumin excretion (UAE) in healthy subjects and in normal rats (9), and treatment with a selective vasopressin V2-receptor antagonist prevented the increase in albuminuria in rats with streptozotocin-induced diabetes (10).The aim of the present investigation was to evaluate whether vasopressin could represent a risk factor for the decline of kidney function in patients with diabetic nephropathy. We examined the association of plasma copeptin with the risk of doubling plasma creatinine concentration and the risk of ESRD in subjects with type 2 diabetes and microalbuminuria or macroalbuminuria from the prospective DIABHYCAR study (11,12).     

Relationship Between Retinal Blood Flow and Renal Function in Patients With Type 2 Diabetes and Chronic Kidney Disease

OBJECTIVE

To study the relationship between retinal microcirculation and renal function in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Using a laser Doppler velocimetry system, we obtained the retinal blood flow (RBF) values by simultaneously measuring the retinal vessel diameter and blood velocity. To determine if the RBF is affected in the presence of renal dysfunction, we also evaluated the renal function using the estimated glomerular filtration rate calculated by age and serum creatinine level.

RESULTS

We recruited 169 eyes of 169 consecutive Japanese patients with type 2 diabetes, no or minimal diabetic retinopathy, and normo/microalbuminuria (mean age ± SD, 59.0 ± 11.1 years). We divided the patients into four groups based on the stage of chronic kidney disease (CKD) (non-CKD, n = 99; CKD stage 1, n = 22; stage 2, n = 27; stage 3, n = 21). We found significant (P = 0.035) decreases in RBF with decreased vessel diameter (P = 0.017) but no difference in blood velocity (P = 0.54) in stage 3 CKD compared with the non-CKD group. Multiple regression analysis showed that the CKD stage was significantly (P = 0.02) and independently associated with decreased RBF.

CONCLUSIONS

Our results indicated that the vessel diameter and RBF in the retinal arterioles decrease in patients with type 2 diabetes with stage 3 CKD, suggesting that impaired renal function might be associated with decreased RBF, probably via constriction of the retinal arterioles, in early-phase diabetic retinopathy.Although both retinopathy and nephropathy are major diabetic microvascular complications, few studies have examined the relationship between retinal structural changes and renal functions in patients with diabetes. Thickening of the basement membrane in the retinal and glomerular capillary vessels has been reported in late-stage diabetic retinopathy and nephropathy (1), suggesting that retinopathy and nephropathy share similar microvascular pathological pathways related to abnormal glucose metabolism and other processes, e.g., inflammation and endothelial dysfunction. Those findings support the clinical recommendation to monitor renal function in patients with diabetes who have signs of retinopathy. A growing body of evidence suggests that several cardiovascular risk factors are associated with the stage of chronic kidney disease (CKD) (2), which accelerates progression of atherosclerosis and increases the propensity to oxidative stress (3). Moreover, diabetes per se is the leading cause of the incidence and prevalence of CKD (4). Although we recently reported that retinal blood flow (RBF) decreases in patients with type 2 diabetes without retinopathy and with mild retinopathy using a retinal laser Doppler velocimetry (LDV) system (5), it is unclear whether renal dysfunction is associated with impaired retinal microcirculation in patients with diabetes.Recent ophthalmic epidemiologic studies have also reported that narrowing of the retinal arterioles is associated with CKD independent of diabetes and hypertension (6) and that patients with moderate CKD were three times more likely to develop early age-related macular degeneration compared with subjects with no or mild CKD (7), suggesting that renal dysfunction might have some effect on ocular disorders. However, no study has examined the relation between renal dysfunction and retinal microcirculation in type 2 diabetes. The current study examined the effect of renal dysfunction, evaluated by grading the CKD, on the retinal microcirculation in patients with type 2 diabetes, especially the early stages of retinopathy and nephropathy.     

The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone

OBJECTIVE

This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone.

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points.

RESULTS

Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P < 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo.

CONCLUSIONS

Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.Saxagliptin is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme (1,2). DPP-4 rapidly cleaves and inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1). GLP-1 and GIP regulate blood glucose homeostasis by stimulation of glucose-dependent insulin secretion (3). GLP-1 also delays gastric emptying and inhibits glucagon secretion (3,4). In rodents, GLP-1 has been shown to stimulate β-cell growth and differentiation and inhibit β-cell apoptosis (5). Such an approach is needed because the majority of patients with type 2 diabetes fail to achieve recommended glycemic targets with existing therapies, owing to safety and tolerability issues and loss of efficacy over time (6).Metformin is the most widely prescribed first-line agent for the management of type 2 diabetes and is standard first-line pharmacotherapy, along with diet and exercise (7). Mechanistically, metformin reduces hepatic glucose production and improves insulin sensitivity (8); however, metformin alone is frequently insufficient to maintain glycemic goals in the face of progressive β-cell failure and increasing insulin resistance (9). Consequently, many patients require multiple oral antihyperglycemic agents (9,10). Metformin works through pathways complementary to saxagliptin, and the combination of saxagliptin with metformin may improve glycemic control (11,12). Studies of other DPP-4 inhibitors in combination with metformin over 24 weeks have demonstrated increased efficacy versus placebo (13–15). The safety and efficacy of saxagliptin monotherapy in treatment-naive patients were established previously in a 12-week study across a dose range of 2.5 to 40 mg/day. Significant A1C reductions were demonstrated in all active treatment groups with maximal A1C efficacy observed with 5 mg saxagliptin. A test for log-linear trend across the treatment groups did not demonstrate a statistically significant dose response after 12 weeks of treatment. The overall frequency of adverse events was comparable across all treatment groups and placebo and did not appear to be dose related (16). The current trial (CV181-014) examined the efficacy and safety of saxagliptin in combination with metformin administered for up to 24 weeks in patients with type 2 diabetes inadequately controlled with metformin alone.     

The Efficacy and Safety of Imeglimin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE

A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone.

RESEARCH DESIGN AND METHODS

A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500–2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio.

RESULTS

After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was −0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (−0.91 mg/dL and −7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo.

CONCLUSIONS

Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. Imeglimin decreases hepatic glucose production, increases muscle glucose uptake, and improves pancreatic glucose-dependent insulin secretion (1).Previous studies have demonstrated imeglimin to be as effective as metformin in improving glycemia (2). Since metformin is the preferred first-line therapy for type 2 diabetes, the current study examined the efficacy, safety, and tolerability of imeglimin in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone.     

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.     

Renal Function Is Associated With Peak Exercise Capacity in Adolescents With Type 1 Diabetes

OBJECTIVE

Diabetic nephropathy and cardiovascular disease are strongly related in adults with type 1 diabetes, yet little is known about this relationship in adolescents prior to the onset of detectable clinical disease. We hypothesized that cardiopulmonary fitness would be directly associated with albumin-to-creatinine ratio (ACR) and inversely related to estimated glomerular filtration rate (eGFR) in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Sixty-nine adolescents with type 1 diabetes and 13 nondiabetic control subjects of similar pubertal stage and BMI had insulin sensitivity (glucose infusion rate [GIR]), measured by hyperinsulinemic-euglycemic clamp, and lean body mass, measured by DEXA. Cardiopulmonary fitness was measured by cycle ergometry to obtain peak volume of oxygen (VO₂peak), and renal function was measured by eGFR using the Bouvet equation (measuring creatinine and cystatin C levels) and ACR.

RESULTS

Adolescents (15.5 ± 2.2 years of age) with type 1 diabetes (6.3 ± 3.8 years diabetes duration) had reduced VO₂peak (31.5 ± 6.3 vs. 36.2 ± 7.9 mL/kg ⋅ min, P = 0.046) and VO₂peak/lean kg (43.7 ± 7.0 vs. 51.0 ± 8.6 mL/lean kg ⋅ min, P = 0.007) compared with nondiabetic control subjects. eGFR was inversely associated with VO₂peak and VO₂peak/lean kg after adjusting for sex, Tanner stage, GIR, HbA_1c level, systolic blood pressure, and LDL cholesterol level (β ± SE, VO₂peak: −0.19 ± 0.07, P = 0.02; VO₂peak/lean kg: −0.19 ± 0.09, P = 0.048). Moreover, participants in the highest tertile for eGFR had significantly lower sex- and Tanner-adjusted VO₂peak and VO₂peak/lean kg compared with participants in the lowest tertile.

CONCLUSIONS

Adolescents with type 1 diabetes had reduced exercise capacity, which was strongly associated with renal health, independent of insulin sensitivity. Future studies should examine the underlying interrelated pathophysiology in order to identify probable targets for treatment to reduce cardiovascular and renal complications.     

沙格列汀联合二甲双胍治疗2型糖尿病的疗效观察

目的探讨沙格列汀联合二甲双弧治疗2型糖尿病的疗效。方法选取2010年3月-2011年3月于我院治疗的2型糖尿病（T2DM）患者120例,随机分为对照组和治疗组,各60例。对照组仅予二甲双胍治疗。根据患者情况,用量在0.5-2mg。治疗组在二甲双胍治疗基础上,给予沙格列汀5mg/（次·d）。治疗12w后,比较两组空腹血糖、餐后2h血糖、糖化血红蛋白变化情况,低血糖发生事件及两组中二甲双胍用量。结果治疗12w后,两组指标均明显下降,组间比较,经t检验,P〈0.05,提示治疗组两药联合在控制血糖上优于单一药物。治疗组减少了二甲双胍的用量。两组在低血糖发生与不良事件发生率上无明显差异。结论沙格列汀联合二甲双胍治疗2型糖尿病能有效控制血糖,且未增加低血糖发生率,值得临床推广。     

Renal Effects of Aliskiren Compared With and in Combination With Irbesartan in Patients With Type 2 Diabetes, Hypertension, and Albuminuria

OBJECTIVE

We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.

RESEARCH DESIGN AND METHODS

This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).

RESULTS

Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m². Aliskiren treatment reduced albuminuria by 48% (95% CI 27–62) compared with placebo (P < 0.001), not significantly different from the 58% (42–79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59–79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3–8.8) ml/min per 1.73 m² by aliskiren, 8.0 (3.6–12.3) ml/min per 1.73 m² by irbesartan, and 11.7 (7.4–15.9) ml/min per 1.73 m² by the combination.

CONCLUSIONS

The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.Albuminuria is the best available surrogate parameter in the treatment of diabetic nephropathy. Degree of proteinuria is associated with risk of renal and cardiovascular events (1). Proteinuria reduction is associated with a slowing of the decline in renal function (2). Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of incipient and overt diabetic nephropathy, and in type 2 diabetes angiotensin II receptor blockers (ARBs) such as irbesartan are considered standard treatment after the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) 2 Study (3) and Irbesartan Diabetic Nephropathy Trial (IDNT) (1).Aliskiren represents a new principle of blocking the RAAS, inhibiting renin directly and acting at the rate-limiting step. The drug is approved for treatment of hypertension but has also shown renoprotective potential in patients with type 2 diabetes and albuminuria (4,5).Combining an ARB and a direct renin inhibitor could offer improved RAAS blockade by acting both at the receptor level and at the first step of the cascade. We compared the antiproteinuric effect of maximal recommended doses of aliskiren, irbesartan, and the combination in patients with type 2 diabetes and albuminuria. We also assessed the impact of the treatments on RAAS components and biomarkers of inflammation, endothelial dysfunction, and cardiovascular risk.     

Impact of Baseline Renal Function on the Efficacy and Safety of Aliskiren Added to Losartan in Patients With Type 2 Diabetes and Nephropathy

OBJECTIVE

Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1–3 chronic kidney disease [CKD]).

RESEARCH DESIGN AND METHODS

In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR <30 ml/min per 1.73 m² and serum potassium >5.1 mmol/l.

RESULTS

Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation >176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P = 0.032). Serum potassium elevations >5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.

CONCLUSIONS

Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.Renin inhibition is a new treatment modality that blocks the renin-angiotensin-aldosterone system (RAAS) at the first rate-limiting step of the cascade. Because the direct renin inhibitor aliskiren recently was approved for the treatment of hypertension, it seemed a reasonable assumption that this drug would also possess antiproteinuric qualities. In theory, renin inhibition will decrease plasma renin activity and levels of circulating angiotensin I and angiotensin II, leading to more efficient RAAS blockade. A previous study from our group has suggested a higher degree of RAAS blockade by the use of the combination of aliskiren and the angiotensin II receptor blocker irbesartan (1). Whereas this hypothesis was formerly proven only in small studies (1,2), the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study (3) was the first double-blind, randomized controlled trial to demonstrate the antiproteinuric ability of aliskiren (300 mg once daily) as an add-on to standard treatment, including the recommended dose of an angiotensin II receptor blocker (losartan), in patients with type 2 diabetes, hypertension, and nephropathy.There is an evident unmet need for improved renoprotective therapies because this patient group constitutes the majority of patients requiring dialysis in the western world (4). Reduction in proteinuria from RAAS blockade has been shown to be associated with improved renal and cardiovascular prognosis (5,6), and although its use remains controversial, albuminuria is the best available surrogate marker for renal protection. Combination treatment with renin inhibition and angiotensin II receptor blockade is evolving as a new antiproteinuric treatment, but not much is known about the impact of underlying renal function on the safety and efficacy of this treatment. The aim of this post hoc analysis was to investigate the efficacy and safety of add-on treatment with aliskiren in the AVOID study across different stages of estimated glomerular filtration rate (eGFR) at baseline.     

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.     

2型糖尿病肾病患者尿微量清蛋白/尿肌酐检测的临床价值

目的 探讨尿微量清蛋白/尿肌酐比(urinary albumin creatinine ratio,UACR)与2型糖尿病(type 2 diabetes mellitus,T2DM)肾病病变程度及尿微量清蛋白排泄率(urinary albumin excretion rate,UAER)相关性.方法 根据UAER将163例2型糖尿病患者分为单纯糖尿病(A)组(n=50)、早期糖尿病肾病(B)组(n=50)和临床糖尿病肾病(C)组(n=63),另选健康体检者作为对照(D)组(n=50),分别测定各组UACR,UAER和高敏C反应蛋白(high-sensieivity C-reactive protein,hs-CRP),并进行组间比较.结果 4组之间UACR和hs-CRP差异有统计学显著性意义(P<0.01),且UACR和hs-CRP与UAER正相关(r=0.83,P<0.05;r=0.79,P<0.01);在UAER正常范围时,有4.76%(3/63)患者UACR超出正常参考值;UACR和hs-CRP联合检测亦优于UACR单项检测.结论 尿微量清蛋白/尿肌酐比与糖尿病肾病的发生、发展密切相关,UACR可以代替UAER检查,联合hs-CRP检测具有更高的临床价值.     

Effect of Internet Therapeutic Intervention on A1C Levels in Patients With Type 2 Diabetes Treated With Insulin

OBJECTIVE

To assess the effect of an Internet-based glucose monitoring system (IBGMS) on A1C levels in patients with type 2 diabetes treated with insulin.

RESEARCH DESIGN AND METHODS

This trial involved 50 patients randomly assigned to receive either conventional treatment alone or with additional follow-up through an IBGMS for 6 months. Patients randomized to the intervention group uploaded blood glucose readings every 2 weeks to a secure Web site for review and receipt of feedback from their endocrinologist. A1C and laboratory test results were collected at 0, 3, and 6 months.

RESULTS

The baseline parameters were not significantly different. Over a 6-month follow-up, A1C dropped from 8.8 to 7.6% (P < 0.001) in the intervention group compared with 8.5 to 8.4% (P = 0.51) in the control group.

CONCLUSIONS

The use of IBGMS significantly improved A1C levels in patients with type 2 diabetes treated with insulin.In the management of diabetes, self-monitoring of blood glucose (SMBG) is performed as an adjunct to A1C measurements in order to assess and modify treatment (1–3); however, it often requires healthcare professionals to help interpret the results to refine treatment (4–6). The Internet provides a readily accessible platform for communication and remote health monitoring (7). In this study, we evaluated whether the use of an IBGMS would improve the outcome of treatment for patients with type 2 diabetes.