Pleiotropic Effects of Atorvastatin and Fenofibrate in Metabolic Syndrome and Different Types of Pre-Diabetes

OBJECTIVE

To compare extra-lipid effects of statins and fibrates in relation to the baseline metabolic status of patients.

RESEARCH DESIGN AND METHODS

The study involved a group of 242 metabolic syndrome patients with or without pre-diabetes and randomized to atorvastatin, fenofibrate, or placebo.

RESULTS

Compared with matched healthy subjects, metabolic syndrome patients exhibited higher plasma levels/activities of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, factor VII, plasminogen activator inhibitor 1, and enhanced monocyte cytokine release. These abnormalities were alleviated by both atorvastatin and fenofibrate treatment. CRP-lowering and monocyte-suppressing actions were more pronounced for atorvastatin in subjects with impaired fasting glucose and for fenofibrate in patients with impaired glucose tolerance.

CONCLUSIONS

The presence of pre-diabetes potentiates metabolic syndrome–induced abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function. Both atorvastatin and fenofibrate exhibit multidirectional pleiotropic effects in subjects with metabolic syndrome, the strength of which seem to be partially determined by the type of pre-diabetes.The anti-inflammatory, endothelial-protective, antioxidant, and anti-thrombotic actions of statins and fibrates are observed not only in patients with dyslipidemia (1–5) but also in subjects with early and late glucose metabolism abnormalities (6–8). This suggests that metabolic syndrome (MS) patients may receive more benefits from statin or fibrate treatment than individuals suffering from isolated lipid or glucose metabolism disturbances. No previous study has examined whether the presence and type of pre-diabetes determines cardiovascular risk factor concentrations and the extra-lipid effects of lipid-lowering agents in MS patients.     

Long-Term Safety and Efficacy of Empagliflozin,Sitagliptin, and Metformin: An active-controlled,parallel-group,randomized, 78-week open-label extension study in patients with type 2 diabetes

OBJECTIVE

To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.

RESULTS

Changes from baseline in HbA_1c at week 90 were −0.34 to −0.63% (−3.7 to −6.9 mmol/mol) with empagliflozin, −0.56% (−6.1 mmol/mol) with metformin, and −0.40% (−4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin, −1.3 kg with metformin, and −0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2–74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0–5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8–12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.

CONCLUSIONS

Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.Type 2 diabetes is characterized by insulin resistance and progressive deterioration of β-cell function (1). Metformin is the recommended first-line antidiabetes agent for patients with type 2 diabetes (2). However, in order to achieve and maintain glycemic control as the disease progresses, patients often require therapies in addition to metformin (2,3).Despite the availability of a number of antihyperglycemic agents, the side effects associated with existing treatments and their gradual loss of efficacy over time (2,3) mean that many patients with type 2 diabetes do not reach therapeutic goals (3,4). In addition, treatment is often complicated by common comorbidities of type 2 diabetes such as obesity and hypertension, which are not addressed by existing oral antidiabetes agents (5–7).Inhibition of sodium glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, represents an approach for the treatment of type 2 diabetes that is independent of β-cell function and insulin resistance (8,9). SGLT2 mediates most of renal glucose reabsorption, and inhibition of this transporter leads to reduced reabsorption of filtered glucose and increased urinary glucose excretion (8,10), resulting in reduced plasma glucose levels in patients with type 2 diabetes (8–10). In addition, this mechanism leads to weight loss owing to the loss of calories via urinary glucose excretion (8,11).Empagliflozin is a potent and selective inhibitor of SGLT2 (12), which in patients with type 2 diabetes causes urinary glucose excretion of up to 90 g/day (13). In two placebo- and active-controlled, dose-finding trials, treatment with empagliflozin for 12 weeks in patients with type 2 diabetes was generally well tolerated and resulted in placebo-corrected reductions in HbA_1c of up to 0.72% (7.9 mmol/mol) and placebo-corrected reductions in weight of up to 1.7 kg (14,15). In these studies, reductions in HbA_1c were comparable to those of the active comparators metformin and sitagliptin (14,15). The objective of this study was to assess the long-term safety and efficacy of empagliflozin, sitagliptin, and metformin in a 78-week, open-label extension study of two dose-finding trials.     

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.     

A Single Nucleotide Polymorphism in STK11 Influences Insulin Sensitivity and Metformin Efficacy in Hyperinsulinemic Girls With Androgen Excess

OBJECTIVE

Serine-threonine kinase STK11 catalyzes the AMP-activated protein kinase complex. We tested the hypothesis that a gene variant in STK11 contributes to variation in insulin sensitivity and metformin efficacy.

RESEARCH DESIGN AND METHODS

We studied the effects of a single nucleotide polymorphism (SNP) (rs8111699) in STK11 on endocrine-metabolic and body composition indexes before and after 1 year of metformin in 85 hyperinsulinemic girls with androgen excess, representing a continuum from prepuberal girls with a combined history of low birth weight and precocious pubarche over to postmenarchial girls with hyperinsulinemic ovarian hyperandrogenism. Metformin was dosed at 425 mg/day in younger girls and 850 mg/day in older girls. STK11 rs8111699 was genotyped. Endocrine-metabolic features were assessed in the fasting state; body composition was estimated by absorptiometry.

RESULTS

Genotype effects were similar in younger and older girls. At baseline, the mutated G allele in STK11 rs8111699 was associated with higher insulin and IGF-I levels (both P < 0.005). The response to metformin differed by STK11 genotype: GG homozygotes (n = 24) had robust metabolic improvements, GC heterozygotes (n = 38) had intermediate responses, and CC homozygotes (n = 23) had almost no response. Such differences were found for 1-year changes in body composition, circulating insulin, IGF-I, free androgen index, and lipids (all P < 0.005).

CONCLUSIONS

In hyperinsulinemic girls with androgen excess, the STK11 rs8111699 SNP influences insulin sensitivity and metformin efficacy, so that the girls with the least favorable endocrine-metabolic profile improve most with metformin therapy.Genetic variation in enzymes and transporters mediating the actions and metabolism of medications contribute to interindividual variation in therapeutic response, on the efficacy as well as on the safety side (1).Polycystic ovary syndrome (PCOS) is a common endocrinopathy that affects ∼5–10% of young women; PCOS is characterized by androgen excess plus either anovulation or polycystic ovaries (2,3). A majority of patients with PCOS are insulin resistant, and, accordingly, metformin is often prescribed for this condition, also in adolescents (4,5). In selected girls at high risk for developing hyperinsulinemic ovarian androgen excess, metformin is even under exploration as a potentially preventive treatment; among these high-risk girls are those with a combined history of low birth weight (LBW) and precocious pubarche (6–9).The actions of metformin seem to be largely exerted through activation of AMP-activated protein kinase (AMPK), a conserved regulator of the cellular response to low energy, in many organs, including liver and skeletal muscle (10,11). The activation of AMPK in the liver is catalyzed by serine-threonine kinase (STK11, formerly known as LKB1), a tumor suppressor gene defective in Peutz-Jeghers syndrome (12); deletion of hepatic STK11 in mice results in a nearly complete loss of AMPK activity, leading to adipogenesis and lipogenic gene expression (13). STK11 serves as a mediator of metformin effects, rather than as a direct target of metformin (14).Recently, the C allele of a single nucleotide polymorphism (SNP) (rs8111699) in STK11 has been associated with a reduced ovulatory response to metformin in women with PCOS (15). In a pilot study, we have tested the hypothesis that the same SNP in STK11 also influences the endocrine-metabolic and body composition changes after metformin therapy in girls with hyperinsulinemic androgen excess.     

Pediatric Endocrinologists' Management of Children With Type 2 Diabetes

OBJECTIVE

To understand physician behaviors and attitudes in managing children with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A survey was mailed to a nationwide sample of pediatric endocrinologists (PEs).

RESULTS

A total of 40% of PEs surveyed responded (211 of 527). Concordance with current monitoring guidelines varied widely, ranging from 36% (foot care) to 93% (blood pressure monitoring). Given clinical vignettes addressing hyperlipidemia, hypertension, and microalbuminuria, only 34% of PEs were fully concordant with current treatment guidelines. Reported barriers included concerns about patient adherence, insufficient scientific evidence about treatment, and lack of familiarity with current recommendations. Providers aged ≤45 years or in clinical practice <10 years reported significantly more aggressive management behaviors and had higher concordance with guidelines.

CONCLUSIONS

Screening and management of pediatric type 2 diabetes varied widely among PEs, suggesting opportunities for quality improvement. More aggressive management of type 2 diabetes among younger providers may be related to recent training when type 2 diabetes was more common.The incidence of type 2 diabetes in children is increasing (1), and children with type 2 diabetes are at high risk to develop diabetes-related complications, including hyperlipidemia, hypertension, and microalbuminuria (2–4). Despite limited scientific evidence, several consensus statements on the assessment and management of pediatric type 2 diabetes have been developed (4–6). Current understanding of physician management of pediatric type 2 diabetes is limited (7–10). We conducted a survey to better understand pediatric endocrinologists'' (PEs'') behaviors and attitudes related to the management of pediatric type 2 diabetes.     

Peri-Conceptional A1C and Risk of Serious Adverse Pregnancy Outcome in 933 Women With Type 1 Diabetes

OBJECTIVE

To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality).

RESEARCH DESIGN AND METHODS

Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes.

RESULTS

The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%.

CONCLUSIONS

These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.Recently, guidelines for management of pregnancy in women with pregestational diabetes have recommended pregestational A1C values <7.0% (1,2) and <6.1% (3). Previous studies have reported information of early A1C including 116–691 pregnancies (4–10). We aimed to study whether there is a threshold value for peri-conceptional A1C in women with type 1 diabetes below which the risk of serious adverse pregnancy outcome (congenital malformation and perinatal mortality) is not increased.     

Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin: A proof-of-concept study

OBJECTIVE

To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

RESEARCH DESIGN AND METHODS

This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl).

RESULTS

The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

CONCLUSIONS

EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.The UK Prospective Diabetes Study (UKPDS) demonstrated that good glycemic control in type 2 diabetes is associated with a reduced risk of diabetes complications (1). After lifestyle modifications (diet and exercise) and oral hypoglycemic agents (OHAs) the addition of basal insulin to OHAs is common practice (2), because this kind of regimen requires only a single injection in most cases and can improve glycemic control. Its use, however, may not adequately control postprandial hyperglycemia or may be associated with hypoglycemia and/or weight gain (3,4). Because obesity is frequently present in subjects with type 2 diabetes (5) and represents a factor contributing to insulin resistance (5) and cardiovascular risk (5), weight gain may be particularly undesirable.A significant advance in basal insulin therapy was the introduction of insulin glargine, a long-acting insulin analog with an extended duration of action of ∼24 h without exhibiting a pronounced peak (6,7). In subjects with type 2 diabetes, insulin glargine was shown to confer glycemic control at least equivalent to that of NHP insulin with a lower incidence of hypoglycemia (3,8,9). However, insulin glargine still has the drawbacks of insulin treatment such as weight gain (3,8,9) and a lower effect on postprandial glucose excursions (8) than on fasting glucose values.Exenatide is the first-in-class glucagon-like peptide 1 (GLP-1) receptor agonist (or incretin mimetic) approved in the U.S. and Europe (10). Compared with placebo, exenatide statistically reduced A1C, whereas there was no difference in A1C improvement between exenatide and insulin glargine or biphasic insulin aspart (11–14). However, postprandial glycemia as well as weight was further reduced with exenatide compared with insulin glargine or biphasic insulin, with a similar risk of hypoglycemia (12,13).Sitagliptin is an approved once-daily, potent, and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor (15). When added to metformin, sitagliptin, given at a dose of 100 mg once daily over 24 weeks, led to significant reductions in A1C, fasting, and 2-h postprandial plasma glucose and was weight-neutral (16).With this background, a therapy controlling both fasting blood glucose (FBG) and postprandial glucose excursions seems to be a promising approach for subjects with type 2 diabetes (17–21). Therefore, in the present study we investigated the influence of a 4-week adjunctive therapy of either a GLP-1 receptor agonist (exenatide) or a DPP-4 inhibitor (sitagliptin) to titrated basal insulin (insulin glargine) plus metformin versus the continuation with titrated insulin glargine plus metformin alone as active comparator in subjects with type 2 diabetes.     

Determinants of Maternal Triglycerides in Women With Gestational Diabetes Mellitus in the Metformin in Gestational Diabetes (MiG) Study

OBJECTIVE

Factors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preeclampsia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women.

RESEARCH DESIGN AND METHODS

Of the 733 women randomized to metformin or insulin in the MiG trial, 432 (219 metformin and 213 insulin) had fasting plasma triglycerides measured at enrollment and at 36 weeks. Factors associated with maternal triglycerides were assessed using general linear modeling.

RESULTS

Mean plasma triglyceride concentrations were 2.43 (95% CI 2.35–2.51) mmol/L at enrollment. Triglycerides were higher at 36 weeks in women randomized to metformin (2.94 [2.80–3.08] mmol/L; +23.13% [18.72–27.53%]) than insulin (2.65 [2.54–2.77] mmol/L, P = 0.002; +14.36% [10.91–17.82%], P = 0.002). At 36 weeks, triglycerides were associated with HbA_1c (P = 0.03), ethnicity (P = 0.001), and treatment allocation (P = 0.005). In insulin-treated women, 36-week triglycerides were associated with 36-week HbA_1c (P = 0.02), and in metformin-treated women, they were related to ethnicity.

CONCLUSIONS

At 36 weeks, maternal triglycerides were related to glucose control in women treated with insulin and ethnicity in women treated with metformin. Whether there are ethnicity-related dietary changes or differences in metformin response that alter the relationship between glucose control and triglycerides requires further study.Maternal metabolism in late pregnancy is catabolic, with increasing insulin resistance, decreased adipose tissue lipoprotein lipase (LPL) activity, and increased lipolysis (1). These processes combine to ensure the availability of maternal fuels such as glucose, fatty acids, and ketone bodies for fetal use (1). It is recognized that gestational age, maternal obesity (2), and preeclampsia (3) are associated with increases in lipids during pregnancy. Gestational diabetes mellitus (GDM) is also associated with abnormalities in maternal lipid metabolism (4–6), which may contribute to the elevated fat mass seen at birth in infants of women with GDM (7–10).Maternal glucose control and the pharmacological therapies used for treatment of GDM have the potential to influence these changes in maternal lipids (11). Insulin suppresses adipose tissue lipolysis and might be expected to reduce circulating triglycerides (12). Metformin reduces insulin resistance, but it has also been suggested to influence lipid metabolism (13), independent of glycemic control. In type 2 diabetes, metformin treatment is associated with a reduction in plasma triglyceride, total cholesterol, LDL cholesterol (13), and VLDL cholesterol concentrations (14). Metformin treatment in type 2 diabetes is also associated with increases in LPL mass level and LDL cholesterol particle size (15) and with a reduction in the release of free fatty acids from adipose tissue (16).We have recently examined maternal lipids in the Metformin in Gestational Diabetes (MiG) trial and found that maternal fasting plasma triglycerides and measures of glucose control at 36 weeks were the strongest predictors of customized birth weight >90th percentile (17). Interestingly, triglycerides increased more from randomization to 36 weeks'' gestation in women allocated to metformin than in those allocated to treatment with insulin, but there was no difference in customized birth weights or other neonatal anthropometry measures between the groups; there were also no differences in cord blood triglycerides (17). The aim of this study was to examine the known and putative determinants of maternal triglyceride concentrations and determine whether the difference seen in maternal plasma triglycerides at 36 weeks was due to treatment or other factors that may have differed between treatment groups.     

Effect of Pharmacological Treatment of Depression on A1C and Quality of Life in Low-Income Hispanics and African Americans With Diabetes: A randomized, double-blind, placebo-controlled trial

OBJECTIVE

To determine whether pharmacological treatment of depression in low-income minorities with diabetes improves A1C and quality of life (QOL).

RESEARCH DESIGN AND METHODS

This was a 6-month, randomized, double-blind, placebo-controlled trial. Patients were screened for depression using Whooley''s two-question tool at a county diabetes clinic. Depression was confirmed (or not) with the Computerized Diagnostic Interview Survey (CDIS) software program, and the severity of depression was assessed monthly by the Hamilton Depression Scale (HAM-D). Depressed subjects with A1C levels ≥8.0% were randomly assigned to receive either sertraline or placebo. Diabetes care was provided by nurses following detailed treatment algorithms who were unaware of therapy for depression.

RESULTS

A total of 150 subjects answered positively to at least one question on Whooley''s questionnaire. The positive predictive value for depression diagnosed by CDIS was 69, 67, and 84% for positive answers to question 1 only, question 2 only, or both, respectively. Of the 89 subjects who entered the study, 75 completed. An intention-to-treat analysis revealed significant differences between baseline and 6 months in HAM-D and pain scores, QOL, and A1C and systolic blood pressure levels in both groups, with no differences between groups for the first three but a significantly greater decrease with sertraline in A1C and systolic blood pressure levels. Changes in HAM-D scores and A1C levels were significantly correlated in all subjects (P = 0.45 [P < 10⁻⁶]).

CONCLUSIONS

In this low-income minority population, pharmacological treatment of depression significantly improved A1C and systolic blood pressure levels compared with placebo.The prevalence of depression among people with diabetes is more than twice that of the general population (1). Coexistence of depression in persons with diabetes is associated with worse glycemic control (2), which may be due to less adherence to self-care behaviors and medications (3). Eventually, there is increased morbidity (4) and mortality (5) and higher medical costs (6).The prevalence of untreated depression in people with diabetes is higher in minorities (1). Yet, screening for and treating depression are less common in this population (7). Very little research has been published on diabetes and depression with a focus on minority populations, who have significant disparities in outcomes (8), such as higher A1C levels (9), increased rates of complications (10), and more severe depression (8).Depression is associated with worse glycemic control (2). Some studies have evaluated whether treatment of depression will improve A1C levels (11–20). However, these drug studies were open label, were of short duration, and/or were conducted in highly educated (more than high school education) Caucasian populations. Most showed that although depression was improved, A1C levels were not. We sought to determine whether use of antidepressants in a minority population with uncontrolled diabetes improved their A1C levels, quality of life (QOL), and depression compared with placebo.     

Metformin and cancer occurrence in insulin-treated type 2 diabetic patients

OBJECTIVE

Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients.

RESEARCH DESIGN AND METHODS

A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort.

RESULTS

During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25–0.85], P = 0.014 and 0.75 [0.39–1.45], P = 0.40, respectively).

CONCLUSIONS

The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.Several studies have shown that metformin is associated with reduced cancer-related morbidity and mortality (1–4), due to improvement in insulin sensitivity (5) or to the activation of AMP-activated protein kinase (6). In insulin-treated patients, the reduction in insulin doses determined by metformin (7) could theoretically produce a decrease in cancer incidence.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

Poor Glycemic Control Is an Independent Risk Factor for Low HDL Cholesterol in Patients With Type 2 Diabetes

OBJECTIVE

To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors.

RESULTS

A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1–1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1–1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05–1.18], P = 0.00017).

CONCLUSIONS

Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes (1,2). Several studies have shown that aggressive comprehensive management of the mixed dyslipidemia associated with the metabolic syndrome and type 2 diabetes is needed to reduce the increased cardiovascular risk (3,4). Despite this evidence, treatments do not completely address all the components of diabetic dyslipidemia and therapeutic targets are still not achieved (5). Nearly half of type 2 diabetic patients have low levels of HDL cholesterol (5), a key component of diabetes-related dyslipidemia and a strong independent risk factor for CVD. HDL cholesterol is inversely correlated with cardiovascular risk, even when LDL cholesterol has been reduced with statin therapy (6–7).An inverse relationship between HDL cholesterol and A1C levels has been described in type 2 diabetic patients (8,9). It is unclear, however, whether this relationship is partly dependent on obesity and/or hypertriglyceridemia, which are known determinants of low HDL cholesterol and frequently found in patients with poorly controlled diabetes. This study was designed to test the hypothesis that glycemic control is independently associated with HDL cholesterol in patients with type 2 diabetes.     

Association of Metformin, Elevated Homocysteine, and Methylmalonic Acid Levels and Clinically Worsened Diabetic Peripheral Neuropathy

OBJECTIVE

The severity of peripheral neuropathy in diabetic patients varies for unclear reasons. Long-term use of metformin is associated with malabsorption of vitamin B¹² (cobalamin [Cbl]) and elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, which may have deleterious effects on peripheral nerves. The intent of this study was to clarify the relationship among metformin exposure, levels of Cbl, Hcy, and MMA, and severity of peripheral neuropathy in diabetic patients. We hypothesized that metformin exposure would be associated with lower Cbl levels, elevated Hcy and MMA levels, and more severe peripheral neuropathy.

RESEARCH DESIGN AND METHODS

This was a prospective case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy, comparing those who had received >6 months of metformin therapy (n = 59) with those without metformin exposure (n = 63). Comparisons were made using clinical (Toronto Clinical Scoring System and Neuropathy Impairment Score), laboratory (serum Cbl, fasting Hcy, and fasting MMA), and electrophysiological measures (nerve conduction studies).

RESULTS

Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences.

CONCLUSIONS

Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of, as well as during, metformin therapy to detect potential secondary causes of worsening peripheral neuropathy.Diabetes is an increasingly prevalent disorder with a range of systemic complications including diabetic peripheral neuropathy (DPN), which occurs in up to 50% of diabetic patients and causes sensory, motor, and/or autonomic dysfunction (1). Several pathogenic mechanisms contribute to DPN severity, including microangiopathy, oxidative stress, polyol flux, mitochondrial dysfunction, insulin deficiency, and advanced glycation end products and ligand activation of their receptor (2–5). The course and severity of DPN are further affected by a wide range of comorbid conditions.Vitamin B₁₂ (cobalamin [Cbl]) deficiency may co-occur with diabetes. Although it is most classically associated with subacute combined degeneration, an exclusive peripheral neuropathy presentation can occur, typically manifesting as axonal neuropathy based on electrophysiology and pathology (6–8). Accumulating evidence suggests that Cbl-associated metabolites methylmalonic acid (MMA) and homocysteine (Hcy) are more sensitive (MMA and Hcy) and specific (MMA) indicators of early symptomatic Cbl deficiency than serum Cbl itself (9,10).Metformin, a biguanide, is perennially reported as a pharmacological cause of Cbl deficiency (11–13). The responsible mechanism has been controversial; proposed contributors have included competitive inhibition or inactivation of Cbl absorption, alterations in intrinsic factor levels, bacterial flora, gastrointestinal motility, or ileal morphological structure, and interaction with the cubulin endocytic receptor (11,14,15). Biguanides have recently been shown to impair calcium-dependent membrane activity in the ileum, including uptake of the Cbl-intrinsic factor complex (16).Metformin is recommended by the American Diabetes Association and the European Association for the Study of Diabetes as initial medical therapy for type 2 diabetes at diagnosis (17). Despite its wide use and its known effects on Cbl, metformin has not been systematically studied as a potential iatrogenic cause of or contributor to DPN. The potentially reversible effect of cobalamin deficiency may increase the clinical burden for a population of patients with DPN whose sensory function, gait, and balance frequently are already compromised.We designed a prospective case-control study to assess the effects of prolonged metformin intake in patients with type 2 diabetes matched for disease duration and disease control. We specifically examined the relationship among metformin use, levels of Cbl and its metabolites, and clinical and electrophysiological markers of peripheral neuropathy severity. We hypothesized first that metformin use would be associated with biochemical evidence of Cbl deficiency (lower serum Cbl levels and elevated MMA and Hcy) and second that metformin use would be associated with more severe peripheral neuropathy. Decreases in Cbl have been shown to depend on the dose and duration of metformin therapy in a previous case-control study (18); this finding led us to further hypothesize that biochemical abnormalities and severity of neuropathy would correlate with cumulative lifetime metformin dose.     

Adverse Outcomes After Noncardiac Surgery in Patients With Diabetes: A nationwide population-based retrospective cohort study

OBJECTIVE

To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries.

RESEARCH DESIGN AND METHODS

With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes.

RESULTS

Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]).

CONCLUSIONS

Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.Diabetes is a common chronic disease that causes widespread disability and death, with a global prevalence of 2.8% in 2000 and an estimated prevalence of 4.4% in 2030 (1). In the U.S., the national burden of diabetes was estimated to be $245 billion in 2012 (2). The epidemiology, pathogenesis, prevention, and treatment of diabetes have been well established over the past 2 centuries (3).Diabetes is an independent determinant of increased risk of perioperative complications and mortality in cardiovascular surgeries (4,5), yet how extensively diabetes affects postoperative mortality and complications in noncardiac surgeries has not been determined. Some studies indicated that survival outcomes and perioperative complications in noncardiac surgeries do not differ between patients with and without diabetes (6,7), whereas other research showed conflicting data about whether diabetes increased perioperative complications, mortality, hospital stay, and health care expenditures (8–16).Previous studies were limited by several factors, including a focus on a single type of noncardiac surgery (6,8,10,12,14), small sample size (6,7,9,13), inappropriate selection of nondiabetes control subjects (6–16), inadequate adjustment for potential confounders (7,9–12,15), and reporting of a single outcome after surgery (10,16). It remains unclear whether coexisting medical conditions, types of diabetes, glycemic control, and diabetes-related comorbidities affect postoperative outcomes in patients with diabetes.This study used Taiwan National Health Insurance Program reimbursement claims to investigate postoperative complications, 30-day mortality, length of hospital stay, and medical expenditures after adjustment by propensity score-matched pair method in patients with diabetes undergoing noncardiac surgeries. We also investigated the impact of coexisting medical conditions and diabetes-related comorbidities on postoperative 30-day mortality among patients with diabetes.     

Rosiglitazone Decreases C-Reactive Protein to a Greater Extent Relative to Glyburide and Metformin Over 4 Years Despite Greater Weight Gain: Observations from A Diabetes Outcome Progression Trial (ADOPT)

OBJECTIVE

C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.

RESEARCH DESIGN AND METHODS

In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.

RESULTS

Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by −47.6% relative to glyburide and by −30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and −2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = −0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.

CONCLUSIONS

Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.C-reactive protein (CRP) has been traditionally viewed as one of the acute-phase reactants and is a sensitive systemic marker of inflammation and tissue damage. This acute-phase inflammatory protein is predominantly secreted in hepatocytes, its release being regulated by interleukin-6 and other inflammatory cytokines (1). Other studies have shown that extrahepatic sources of CRP production from adipocytes could point to a more systemic generation of CRP in the body after stimulation by inflammatory cytokines and more specifically, by the adipokine, resistin (1).Both population-based and prospective studies have demonstrated a clear association between CRP and an increased risk of cardiovascular disease (CVD) and stroke (2). The magnitude of the CRP prediction for future CVD events is similar to that of other traditional CVD risk factors (cholesterol, hypertension, and smoking status) (2). CRP also may be a mediator of atherosclerosis (1,3–6). However, there is no available evidence from clinical trials that a reduction in CRP directly reduces or prevents further CVD events.The production of CRP by adipocytes may partially explain why CRP levels are elevated in patients with the metabolic syndrome (1), in whom CVD risk is increased. The strong association between CRP and body adiposity has been observed in both diabetic (7) and nondiabetic subjects (8–11) and was only moderately attenuated by adjustment of insulin sensitivity. These results suggest that obesity, insulin resistance, and the metabolic syndrome are interconnected in a proinflammatory state that may be mediated by cytokines and subsequently cause elevated levels of CRP. Elevated CRP concentrations have been shown to predict an increased risk of diabetes (9,12,13). Therefore, CRP may play an active role in the causal relationship among obesity, diabetes, and the high risk of future CVD events. Statins (14) and weight loss (15–17), which can reduce CRP levels and improve other CVD risk factors, also show benefits in reducing CVD events.Glucose-lowering agents have different effects on CRP, weight, insulin sensitivity, and glycemic control in the treatment of type 2 diabetes. The thiazolidinediones (TZDs) rosiglitazone and pioglitazone, insulin-sensitizing oral antidiabetic agents, have been shown to be effective in reducing CRP in several short-term (≤6 months) studies (18–21). However, it is not clear whether the weight gain associated with TZDs could attenuate the effect on CRP reduction over larger periods of time. In short-term studies, metformin moderately decreases CRP (16,18), increases insulin sensitivity, and produces weight loss (16). The longer-term relationships among the three commonly used oral antidiabetic agents (TZDs, sulfonylureas, and metformin) with CRP, insulin sensitivity, weight, and glycemic control have not been investigated previously.A Diabetes Outcome Progression Trial (ADOPT) provided the opportunity to evaluate the effects of members of these three classes of oral agents in a randomized, double-blind, controlled trial involving >4,000 patients, treated for a median time of 4 years (22,23). This study compared the efficacy and safety of rosiglitazone, glyburide, and metformin in drug-naive patients with newly diagnosed (≤3 years) type 2 diabetes. We have previously reported the association of CRP, obesity, and insulin resistance in the baseline examination of the ADOPT study (7). We discuss here a subgroup analysis of ADOPT, in which we examined prospectively the long-term effects of rosiglitazone, glyburide, and metformin on CRP reduction and the relationship among CRP, insulin sensitivity, weight, and glycemic variables.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Impact of Metabolic Syndrome Compared With Impaired Fasting Glucose on the Development of Type 2 Diabetes in a General Japanese Population: The Hisayama study

OBJECTIVE

We examined whether metabolic syndrome predicts incident type 2 diabetes more effectively than impaired fasting glucose (IFG) in a general Japanese population.

RESEARCH DESIGN AND METHODS

A total of 1,935 nondiabetic subjects aged 40–79 years were followed-up prospectively for a mean of 11.8 years.

RESULTS

During the follow-up, 286 subjects developed type 2 diabetes. Compared with those without metabolic syndrome, the multivariate-adjusted hazard ratio (HR) for incident type 2 diabetes was significantly higher in subjects of both sexes with metabolic syndrome, even after adjustment for confounding factors, age, family history of diabetes, total cholesterol, alcohol intake, smoking habits, and regular exercise (men: HR 2.58 [95% CI 1.85–3.59]; women: 3.69 [2.58–5.27]). The multivariate-adjusted HR of metabolic syndrome for type 2 diabetes was slightly lower in men and similar in women compared with that of IFG. The multivariate-adjusted HR for type 2 diabetes rose progressively as the number of metabolic syndrome components increased in both subjects with and without IFG. In stratified analysis, the multivariate-adjusted risk of type 2 diabetes was significantly higher in subjects with metabolic syndrome alone (2.37 [1.45–3.88]) or IFG alone (3.49 [2.57–4.74]) and markedly increased in subjects with both metabolic syndrome and IFG (6.76 [4.75–9.61]) than in subjects with neither metabolic syndrome nor IFG. Furthermore, the multivariate-adjusted risk for type 2 diabetes was also significantly higher in subjects with both metabolic syndrome and IFG than in those with either one alone (both P < 0.001).

CONCLUSIONS

Our findings suggest that metabolic syndrome significantly increases the risk of incident type 2 diabetes, independent of IFG, and is therefore a valuable tool to identify individuals at high risk of type 2 diabetes.Metabolic syndrome consists of a clustering of cardiovascular risk factors, such as central obesity, elevated blood pressure, glucose intolerance, and dyslipidemia, and individuals with this condition have an elevated risk of developing cardiovascular diseases (1–5) and type 2 diabetes in different ethnic populations (1–4,6–11). Thus, the concept of metabolic syndrome could be used to reduce the incidence of these diseases worldwide. However, a number of experts in the field of diabetes have questioned whether the idea of metabolic syndrome is useful and valuable (12–14). Because all of the criteria sets for metabolic syndrome have included the component of impaired fasting glucose (IFG), which is a powerful predictor of type 2 diabetes, detractors have questioned whether the more complex definition of metabolic syndrome is better than a simple measurement of fasting plasma glucose (FPG). However, reported findings concerning this issue are controversial: a cohort study has shown that the ability of metabolic syndrome to predict type 2 diabetes was superior to that of IFG alone (3), whereas in other studies, the value of metabolic syndrome was comparable or inferior to that of IFG alone (2,6,7). Furthermore, most of these epidemiological studies were performed in Western populations, and this subject has not been assessed sufficiently in Asian populations.The purpose of the present study was to investigate the association between metabolic syndrome and the development of type 2 diabetes in a prospective study of a defined Japanese population, taking into account comprehensive risk factors. In addition, we compared which of the two measures, metabolic syndrome or IFG, better predicted incident type 2 diabetes.     

Pioglitazone Decreases Plasma Cholesteryl Ester Transfer Protein Mass, Associated With a Decrease in Hepatic Triglyceride Content, in Patients With Type 2 Diabetes

OBJECTIVE

Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We included 78 men with type 2 diabetes (aged 56.5 ± 0.6 years; HbA1c 7.1 ± 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy.

RESULTS

Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range 2.6–17.4] versus 4.1 [1.9–12.3]%, P < 0.05), decreased plasma CETP mass (2.33 ± 0.10 vs. 2.06 ± 0.10 μg/ml, P < 0.05), and increased plasma HDL cholesterol level (1.22 ± 0.05 vs. 1.34 ± 0.05 mmol/l, P < 0.05). Metformin did not significantly change any of these parameters.

CONCLUSIONS

A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mice.Hepatic steatosis is a prevalent condition in patients with type 2 diabetes and is associated with an increased cardiovascular risk (1,2). Furthermore, many patients with type 2 diabetes display dyslipidemia characterized by high plasma levels of apolipoprotein (apo) B-lipoproteins and triglycerides and low plasma levels of HDL cholesterol. Recently, Toledo et al. (3) showed that hepatic steatosis is associated with more severe hyperlipidemia in type 2 diabetes, which might contribute to the increased risk of cardiovascular disease.To reduce this increased cardiovascular risk in type 2 diabetes, regular treatment algorithms include lipid-lowering drugs. Our previous studies in APOE*3-Leiden.CETP transgenic mice, a well-established model for human-like lipoprotein metabolism, showed that treatment with either statins (4), fibrates (5), or niacin (6) resulted in a reduction in plasma apoB-lipoproteins and triglyceride levels and an increase in HDL cholesterol. Moreover, these treatments reduced hepatic lipid content (i.e., both triglycerides and cholesterol) as well as the hepatic expression and plasma levels of cholesteryl ester transfer protein (CETP) (4–6). CETP is a protein that mediates the heteroexchange of cholesteryl esters from HDL to (V)LDL with a simultaneous exchange of triglycerides from (V)LDL to HDL. These studies thus suggest that lowering of hepatic lipid content in APOE*3-Leiden.CETP mice increased HDL cholesterol levels by reduction of plasma CETP mass.Because the correlation between hepatic triglyceride content and plasma CETP mass has not been studied in humans, the aim of this study was to evaluate whether the relationship between lowering of hepatic triglyceride content and decreased plasma CETP mass also exists in humans. Hepatic triglyceride content can be lowered by thiazolidinediones, including pioglitazone (7). Indeed, in a previous study, we reported that both antidiabetic drugs pioglitazone and metformin improved insulin sensitivity in men with type 2 diabetes whereas only pioglitazone reduced hepatic triglyceride content (8). Therefore, we used pioglitazone treatment as a model to study the effects of a change in hepatic triglyceride content on CETP mass in patients with type 2 diabetes and used metformin treatment as a negative control.