Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006

OBJECTIVE

To describe the prevalence of biochemical B₁₂ deficiency in adults with type 2 diabetes taking metformin compared with those not taking metformin and those without diabetes, and explore whether this relationship is modified by vitamin B₁₂ supplements.

RESEARCH DESIGN AND METHODS

Analysis of data on U.S. adults ≥50 years of age with (n = 1,621) or without type 2 diabetes (n = 6,867) from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Type 2 diabetes was defined as clinical diagnosis after age 30 without initiation of insulin therapy within 1 year. Those with diabetes were classified according to their current metformin use. Biochemical B₁₂ deficiency was defined as serum B₁₂ concentrations ≤148 pmol/L and borderline deficiency was defined as >148 to ≤221 pmol/L.

RESULTS

Biochemical B₁₂ deficiency was present in 5.8% of those with diabetes using metformin compared with 2.4% of those not using metformin (P = 0.0026) and 3.3% of those without diabetes (P = 0.0002). Among those with diabetes, metformin use was associated with biochemical B₁₂ deficiency (adjusted odds ratio 2.92; 95% CI 1.26–6.78). Consumption of any supplement containing B₁₂ was not associated with a reduction in the prevalence of biochemical B₁₂ deficiency among those with diabetes, whereas consumption of any supplement containing B₁₂ was associated with a two-thirds reduction among those without diabetes.

CONCLUSIONS

Metformin therapy is associated with a higher prevalence of biochemical B₁₂ deficiency. The amount of B₁₂ recommended by the Institute of Medicine (IOM) (2.4 μg/day) and the amount available in general multivitamins (6 μg) may not be enough to correct this deficiency among those with diabetes.It is well known that the risks of both type 2 diabetes and B₁₂ deficiency increase with age (1,2). Recent national data estimate a 21.2% prevalence of diagnosed diabetes among adults ≥65 years of age and a 6 and 20% prevalence of biochemical B₁₂ deficiency (serum B₁₂ <148 pmol/L) and borderline deficiency (serum B₁₂ ≥148–221 pmol/L) among adults ≥60 years of age (3,4).The diabetes drug metformin has been reported to cause a decrease in serum B₁₂ concentrations. In the first efficacy trial, DeFronzo and Goodman (5) demonstrated that although metformin offers superior control of glycosylated hemoglobin levels and fasting plasma glucose levels compared with glyburide, serum B₁₂ concentrations were lowered by 22% compared with placebo, and 29% compared with glyburide therapy after 29 weeks of treatment. A recent, randomized control trial designed to examine the temporal relationship between metformin and serum B₁₂ found a 19% reduction in serum B₁₂ levels compared with placebo after 4 years (6). Several other randomized control trials and cross-sectional surveys reported reductions in B₁₂ ranging from 9 to 52% (7–16). Although classical B₁₂ deficiency presents with clinical symptoms such as anemia, peripheral neuropathy, depression, and cognitive impairment, these symptoms are usually absent in those with biochemical B₁₂ deficiency (17).Several researchers have made recommendations to screen those with type 2 diabetes on metformin for serum B₁₂ levels (6,7,14–16,18–21). However, no formal recommendations have been provided by the medical community or the U.S. Prevention Services Task Force. High-dose B₁₂ injection therapy has been successfully used to correct the metformin-induced decline in serum B₁₂ (15,21,22). The use of B₁₂ supplements among those with type 2 diabetes on metformin in a nationally representative sample and their potentially protective effect against biochemical B₁₂ deficiency has not been reported. It is therefore the aim of the current study to use the nationally representative National Health and Nutrition Examination Survey (NHANES) population to determine the prevalence of biochemical B₁₂ deficiency among those with type 2 diabetes ≥50 years of age taking metformin compared with those with type 2 diabetes not taking metformin and those without diabetes, and to explore how these relationships are modified by B₁₂ supplement consumption.     

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.     

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.     

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.     

Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study

OBJECTIVE

Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.

RESEARCH DESIGN AND METHODS

Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.

RESULTS

Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.

CONCLUSIONS

In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.As the drug of first choice in type 2 diabetes, metformin is the most widely prescribed oral glucose-lowering drug (OGLD) (1,2). However, the decision to prescribe metformin also depends on patient characteristics: metformin use is contraindicated in those with renal failure, cardiac, or hepatic failure (2).A statistically nonsignificant relationship between use of metformin and the risk of colon cancer was described in 2004 (3). However, 1 year later, metformin was found to be associated with a decreased risk of cancer in general in a case-control study in a diabetic population (4). Numerous studies followed; among which studies confirming the association between use of metformin and a decreased risk of cancer in general (5–8) or in specific cancers (5,6,9–14). However, for breast cancer (5,6) and prostate cancer (5,14), the decreased risk was not consistently demonstrated; for other cancers, no association with use of metformin was found (6,12). Hence, there is heterogeneity among published studies on cancer in patients with diabetes on metformin (15), partly because different comparison groups were used, such as nonmetformin users, users of other OGLDs, or users of insulin. Higher endogenous insulin levels have been linked to an increased risk of certain cancers (16). Moreover, specifically for insulin glargine, the debate whether this specific insulin increases the risk of cancer is ongoing (17–21).Owing to factors such as different drugs used to attain metabolic control, the duration of diabetes, and the presence of other diseases, the assessment of cancer risk in diabetic patients remains difficult. Therefore, the objective of this study was to analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with use of sulfonylurea derivatives.     

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.     

Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes

OBJECTIVE

Physical activity or metformin enhances insulin sensitivity and opposes the progression from prediabetes to type 2 diabetes. The combination may be more effective because each treatment stimulates AMP-activated protein kinase activity in skeletal muscle. We evaluated the effects of exercise training plus metformin on insulin sensitivity in men and women with prediabetes, compared with each treatment alone.

RESEARCH DESIGN AND METHODS

For 12 weeks, men and women with prediabetes were assigned to the following groups: placebo (P), 2,000 mg/day metformin (M), exercise training with placebo (EP), or exercise training with metformin (EM) (n = 8 per group). Before and after the intervention, insulin sensitivity was measured by euglycemic hyperinsulinemic (80 mU/m²/min) clamp enriched with [6,6-²H]glucose. Changes due to intervention were compared across groups by repeated-measures ANOVA.

RESULTS

All three interventions increased insulin sensitivity (P < 0.05) relative to the control group. The mean rise was 25–30% higher after EP than after either EM or M, but this difference was not significant.

CONCLUSIONS

Insulin sensitivity was considerably higher after 12 weeks of exercise training and/or metformin in men and women with prediabetes. Subtle differences among condition means suggest that adding metformin blunted the full effect of exercise training.Before developing overt diabetes, most individuals spend years in an intermediate condition called prediabetes. Prediabetes is defined by impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or the combination of IGT plus IFG (1). Approximately 79 million individuals in the U.S. have prediabetes and are at risk to develop type 2 diabetes (2). The progression is not inevitable, however. The U.S. Diabetes Prevention Program (DPP) demonstrated that either lifestyle modification (i.e., low-fat diet and increased physical activity) or the antihyperglycemic medication metformin reduced the transition from prediabetes to type 2 diabetes (3).Habitual exercise and metformin each increase peripheral (mainly skeletal muscle) insulin sensitivity in part by stimulating AMP-activated protein kinase (AMPK) (4–8). Combining exercise plus metformin, compared with either treatment alone, may more effectively activate the key regulatory enzyme AMPK and oppose the transition from prediabetes to type 2 diabetes.The American Diabetes Association strongly recommends exercise as a cornerstone therapy for diabetes prevention and, recently, suggested that some individuals with prediabetes be considered for metformin treatment (9,10). The efficacy of combining lifestyle modification with metformin has been tested only a few times (11–15). Results suggest 2–5 kg more weight loss with the addition of metformin compared with lifestyle modification alone (11,12), but little (11,14) or no further (15,16) improvement to insulin sensitivity. However, the use of self-reports to estimate physical activity and surrogates (via fasting glucose and insulin concentrations or responses to oral carbohydrate) (11,13–15) rather than direct measurement of insulin sensitivity using the glucose clamp limits our understanding of the interaction between exercise and metformin. There is considerable need to better understand the potential for additive effects when physical activity and metformin are used concurrently because the scope of the public health problem is so pressing. Therefore, the purpose of this study was to determine the effect of combining exercise training with metformin (EM) on insulin sensitivity in individuals with prediabetes, compared with either treatment alone.     

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.     

Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose

OBJECTIVE

To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration.

RESEARCH DESIGN AND METHODS

A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7–8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations.

RESULTS

In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes.

CONCLUSIONS

An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.Impaired fasting glucose (IFG) was introduced in 1997 by the American Diabetes Association (ADA) (1), and, analogous with impaired glucose tolerance (IGT), it was meant to represent an intermediate stage in the transition from normal glucose tolerance (NGT) to overt type 2 diabetes. Both IFG and IGT indicate an increased risk for future type 2 diabetes (2–4). Previously (5–7), we have shown that the 1-h plasma glucose concentration has better predictive power than either fasting plasma glucose (FPG) or 2-h plasma glucose, suggesting that the 1-h plasma glucose concentration may have greater utility in identifying subjects at increased risk for type 2 diabetes in routine clinical practice.Previous studies have reported that IFG and IGT represent separate clinical entities, which are characterized by distinct metabolic abnormalities (8–13). Subjects with IGT manifest insulin resistance in skeletal muscle (9–12) and impaired β-cell function (both early and late phases of insulin secretion) (10,14–16), whereas subjects with IFG are characterized by increased hepatic insulin resistance (9,16), impaired early insulin response (12), and decreased non–insulin-dependent glucose clearance (15). Because of the prominent role of progressive β-cell failure in the development of hyperglycemia (17), the impairment in β-cell function in subjects with IGT represents a major pathogenic factor for their increased risk for future type 2 diabetes. Although the increase in fasting plasma glucose is associated with a decrease in first-phase insulin secretion (11–13,18), subjects with IFG have robust second-phase insulin secretion, and, when related to their prevailing level of insulin resistance, they have second-phase insulin secretion comparable with that of subjects with NGT (12,13). Thus, impaired β-cell function cannot fully explain the increased incidence of type 2 diabetes associated with the increase in FPG concentration, e.g., in subjects with isolated IFG.Previously we have shown a strong correlation between insulin resistance in skeletal muscle and liver (16). Thus, a strong correlation between FPG and postload plasma glucose concentrations is anticipated. Therefore, we hypothesized that the increased type 2 diabetes risk associated with the increase in FPG, at least in part, is due to the increased postprandial plasma glucose concentration associated with the increase in FPG and is not due to the increase in FPG per se. The aim of this study was to test this hypothesis.     

Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis

OBJECTIVE

Both in vitro and in vivo studies indicate that metformin inhibits cancer cell growth and reduces cancer risk. Recent epidemiological studies suggest that metformin therapy may reduce the risks of cancer and overall cancer mortality among patients with type 2 diabetes. However, data on its effect on colorectal cancer are limited and inconsistent. We therefore pooled data currently available to examine the association between metformin therapy and colorectal cancer among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

The PubMed and SciVerse Scopus databases were searched to identify studies that examined the effect of metformin therapy on colorectal cancer among patients with type 2 diabetes. Summary effect estimates were derived using a random-effects meta-analysis model.

RESULTS

The analysis included five studies comprising 108,161 patients with type 2 diabetes. Metformin treatment was associated with a significantly lower risk of colorectal neoplasm (relative risk [RR] 0.63 [95% CI 0.50–0.79]; P < 0.001). After exclusion of one study that investigated colorectal adenoma, the remaining four studies comprised 107,961 diabetic patients and 589 incident colorectal cancer cases during follow-up. Metformin treatment was associated with a significantly lower risk of colorectal cancer (0.63 [0.47–0.84]; P = 0.002). There was no evidence for the presence of significant heterogeneity between the five studies (Q = 4.86, P = 0.30; I² = 18%).

CONCLUSIONS

From observational studies, metformin therapy appears to be associated with a significantly lower risk of colorectal cancer in patients with type 2 diabetes. Further investigation is warranted.Colorectal cancer is one of the most frequent malignant tumors and a leading cause of cancer-related death worldwide (1). The incidence of colorectal cancer continues to increase in economically transitioning countries such as Asia, Eastern Europe, and selected countries in South America (2,3), whereas a declining trend has been noted in several developed countries in recent years (1).Type 2 diabetes is also a common disease, and it is well established that type 2 diabetes is associated with a higher risk of colorectal cancer (4–8). Metformin is a relative of isoamylene guanidine and has been recommended as the initial glucose-lowering therapy for diabetes. Emerging evidence from both in vitro and in vivo studies indicates that metformin may inhibit cancer cell growth and reduce cancer risks. Previous research suggests that metformin may be involved in the tumor suppressor pathway by indirectly activating AMP-activated protein kinase (9)—a key sensor of cellular ATP and AMP balance—and plays a role on activating tumor suppressor genes, e.g., LKB1. Subsequent in vitro studies have shown that metformin inhibits cancer cell proliferation (10,11) and selectively kills cancer stem cells (12). Animal experiments concur with these findings. Rodent models have shown that metformin suppresses colonic epithelial proliferation and colorectal aberrant crypt foci formation (13,14). Similarly, animal models of colon cancer have shown that metformin inhibits colon carcinoma growth (11,15). Given these encouraging findings, interest has arisen that metformin could potentially serve as a new antineoplasm drug to prevent colorectal cancer.Results from preliminary studies conducted in humans are encouraging. In a short-term randomized clinical trial among nondiabetic patients with rectal aberrant crypt foci, a significant decrease in the mean number of aberrant crypt foci was observed after metformin treatment for 1 month as compared with no significant changes in the control group (16). Findings from several epidemiological studies also support an antineoplastic role of metformin on cancer risks (17,18). If metformin therapy ultimately proves effective on reducing the risk of colorectal cancer, it would likely be recommended for the overwhelming majority of diabetes patients for both blood glucose control and cancer prevention. Nonetheless, despite accumulating evidence from population studies that indicate a lower risk of cancer at large with metformin therapy (17,19,20), data on its effect on colorectal cancer are limited and inconsistent. Accordingly, we performed a meta-analysis to pool studies currently available to examine the effect of metformin treatment on colorectal cancer risk among patients with type 2 diabetes.     

Dietary Phylloquinone and Menaquinones Intakes and Risk of Type 2 Diabetes

OBJECTIVE

To investigate whether dietary phylloquinone and menaquinones intakes are related to risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS

We used data from a prospective cohort study in 38,094 Dutch men and women, aged 20–70 years. Dietary phylloquinone and menaquinones intakes were assessed using a validated food frequency questionnaire. Diabetes case patients were ascertained mainly via self-report and verified against medical records.

RESULTS

During 10.3 years of follow-up, 918 incident cases of diabetes were documented. In a multivariate model adjusting for diabetes risk factors and dietary factors, phylloquinone intake tended to be associated (P = 0.08) with a reduced risk of type 2 diabetes with a hazard ratio (HR) of 0.81 (95% CI 0.66–0.99) for the highest versus the lowest quartile. For menaquinones intake, a linear, inverse association (P = 0.038) with risk of type 2 diabetes was observed with an HR of 0.93 (0.87–1.00) for each 10-μg increment in the multivariate model.

CONCLUSIONS

This study shows that both phylloquinone and menaquinones intakes may be associated with a reduced risk of type 2 diabetes.Vitamin K is a fat-soluble vitamin occurring in two biologically active forms; vitamin K₁ (phylloquinone) and vitamin K₂ (menaquinones). Phylloquinone, the most common form, is present in green, leafy vegetables and certain vegetable oils (1), whereas menaquinones occur in animal products such as meat, eggs, and cheese (2). However, strong regional differences in the amount and forms of menaquinones intake exist (2). Vitamin K functions as a cofactor in the γ-carboxylation of certain glutamic acid (Gla) residues of vitamin K-dependent proteins for their activation (3). Vitamin K was known mainly as a cofactor to carboxylate clotting factors such as prothrombin (3). More recently, it became apparent that vitamin K also carboxylates other proteins such as osteocalcin, a regulator of bone mineral maturation (3).A recent study showed that osteocalcin concentrations may also affect insulin sensitivity and type 2 diabetes by regulating the expression of insulin genes and β-cell proliferation markers (4). In mice, osteocalcin was shown to increase insulin secretion and insulin sensitivity and decrease the severity of type 2 diabetes (4). This animal study suggested a specific role for the uncarboxylated form of osteocalcin (4), contradicting a role for vitamin K. Subsequent human studies, however, observed relations between high total or carboxylated osteocalcin and improved insulin sensitivity (5,6). These latter studies suggest that vitamin K could reduce insulin resistance and risk of type 2 diabetes by carboxylating osteocalcin.To date, no studies have investigated the relation between vitamin K intake and risk of type 2 diabetes and only a few have explored relations with insulin sensitivity. In rats, vitamin K deficiency delayed the insulin response and decreased plasma glucose (7). Similar results have been shown in small-scale human studies among young men with a low risk of diabetes (8). Recently, two larger studies investigated the relation between dietary phylloquinone and insulin sensitivity. An observational study showed that high phylloquinone intake was associated with improved insulin sensitivity and glycemic control (9). A randomized controlled trial showed improved insulin sensitivity after phylloquinone supplementation among men (10). Whether dietary phylloquinone or menaquinones intakes are associated with a reduced risk of type 2 diabetes is unknown. Therefore, we investigated whether dietary phylloquinone and menaquinones intakes are inversely associated with type 2 diabetes in a prospective cohort of Dutch men and women. Because previous studies suggested relations between vitamin K and inflammatory factors or blood lipid profile (11–14), we explored relations between phylloquinone and menaquinones intakes and high-sensitivity C-reactive protein (CRP), blood lipid profile, and A1C as a marker of diabetes risk.     

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.     

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.     

Active Care Management Supported by Home Telemonitoring in Veterans With Type 2 Diabetes: The DiaTel randomized controlled trial

OBJECTIVE

We compared the short-term efficacy of home telemonitoring coupled with active medication management by a nurse practitioner with a monthly care coordination telephone call on glycemic control in veterans with type 2 diabetes and entry A1C ≥7.5%.

RESEARCH DESIGN AND METHODS

Veterans who received primary care at the VA Pittsburgh Healthcare System from June 2004 to December 2005, who were taking oral hypoglycemic agents and/or insulin for ≥1 year, and who had A1C ≥7.5% at enrollment were randomly assigned to either active care management with home telemonitoring (ACM+HT group, n = 73) or a monthly care coordination telephone call (CC group, n = 77). Both groups received monthly calls for diabetes education and self-management review. ACM+HT group participants transmitted blood glucose, blood pressure, and weight to a nurse practitioner using the Viterion 100 TeleHealth Monitor; the nurse practitioner adjusted medications for glucose, blood pressure, and lipid control based on established American Diabetes Association targets. Measures were obtained at baseline, 3-month, and 6-month visits.

RESULTS

Baseline characteristics were similar in both groups, with mean A1C of 9.4% (CC group) and 9.6% (ACM+HT group). Compared with the CC group, the ACM+HT group demonstrated significantly larger decreases in A1C at 3 months (1.7 vs. 0.7%) and 6 months (1.7 vs. 0.8%; P < 0.001 for each), with most improvement occurring by 3 months.

CONCLUSIONS

Compared with the CC group, the ACM+HT group demonstrated significantly greater reductions in A1C by 3 and 6 months. However, both interventions improved glycemic control in primary care patients with previously inadequate control.Within the Veterans Health Administration, ∼500,000 veterans receive care for diabetes annually; diabetes is a leading cause of morbidity and mortality and a major contributor to health care cost (1,2). Sampling data from 2009 indicate that ∼28% of veterans nationally have suboptimal glycemic control with A1C ≥8% (3). Increases in A1C levels above the normal range in patients with diabetes are associated with progressive increases in morbidity and mortality due to micro- and macrovascular disease (4). Intensive glycemic control can reduce microvascular complications in both type 1 and type 2 diabetes (5,6). However, recent studies have not demonstrated that intensive glycemic control for 3–6 years with achieved A1C targets from 6.4 to 6.9% reduces macrovascular complications in patients with long-standing type 2 diabetes (7–9). In contrast, intensive glycemic control initiated early in the course of either type 1 or type 2 diabetes appears to reduce the risk of subsequent macrovascular complications significantly even when glycemic control later deteriorates (10,11).Home-based telemedicine has been examined as a tool for management of chronic diseases (12), including diabetes (13–19). This approach can obviate geographic barriers; provide automated education, feedback, and data transmission; and facilitate provider-to-patient communication (12). However, outcomes with home telemonitoring in diabetes and other chronic diseases have been variable (12). Of several randomized controlled trials (RCTs) using home telemonitoring in diabetes care (13–19), only two have reported significant improvement in A1C (17,18). Neither of these trials included active medication management by a provider in response to real-time transmission of self-monitored blood glucose (SMBG) data or have specifically targeted patients not meeting glycemic control goals in response to pharmacological therapy under conditions of usual care.The present study compared the efficacy of home telemonitoring coupled with active medication management by a nurse practitioner (ACM+HT intervention) with a lower-intensity care coordination intervention (CC intervention) consisting of monthly telephone contact with a diabetes nurse educator. Our study specifically targeted veterans with A1C levels ≥8% after ≥1 year receiving pharmacological therapy under conditions of usual care.     

Maternal and Neonatal Circulating Markers of Metabolic and Cardiovascular Risk in the Metformin in Gestational Diabetes (MiG) Trial: Responses to maternal metformin versus insulin treatment

OBJECTIVE

This study was designed to compare glucose, lipids, and C-reactive protein (CRP) in women with gestational diabetes mellitus treated with metformin or insulin and in cord plasma of their offspring and to examine how these markers relate to infant size at birth.

RESEARCH DESIGN AND METHODS

Women with gestational diabetes mellitus were randomly assigned to metformin or insulin in the Metformin in Gestational Diabetes trial. Fasting maternal plasma glucose, lipids, and CRP were measured at randomization, 36 weeks’ gestation, and 6–8 weeks postpartum as well as in cord plasma. Women with available cord blood samples (metformin n = 236, insulin n = 242) were included.

RESULTS

Maternal plasma triglycerides increased more from randomization to 36 weeks’ gestation in women treated with metformin (21.93%) versus insulin (9.69%, P < 0.001). Maternal and cord plasma lipids, CRP, and neonatal anthropometry did not differ between treatments. In logistic regression analyses adjusted for confounders, the strongest associations with birth weight >90th centile were maternal triglycerides and measures of glucose control at 36 weeks.

CONCLUSIONS

There were few differences in circulating maternal and neonatal markers of metabolic status and no differences in measures of anthropometry between the offspring of women treated with metformin and the offspring of women treated with insulin. There may be subtle effects of metformin on maternal lipid function, but the findings suggest that treating gestational diabetes mellitus with metformin does not adversely affect lipids or CRP in cord plasma or neonatal anthropometric measures.Gestational diabetes mellitus is carbohydrate intolerance first diagnosed during pregnancy (1) and affects up to 18% of pregnancies. The prevalence varies depending on maternal demographics and diagnostic criteria (2). The prevalence of gestational diabetes mellitus is increasing, which is likely driven by the rising population prevalence of overweight and obesity and increasing maternal age at pregnancy (3). Gestational diabetes mellitus increases maternal and infant morbidity and mortality during pregnancy (4). Women with a history of gestational diabetes mellitus are at risk for metabolic syndrome, type 2 diabetes (5), and cardiovascular disease in later life (6). Children born to women with gestational diabetes mellitus have higher rates of type 2 diabetes and obesity (7).Treating gestational diabetes mellitus improves pregnancy outcomes for both mother and infant (8). Current therapies include modification of diet, increased physical activity, and drug therapy with insulin and oral hypoglycemic agents, including metformin. In addition to improving insulin sensitivity and hyperglycemia, metformin therapy in the setting of type 2 diabetes reduces triglycerides (9), total cholesterol, LDL cholesterol (10), and VLDL cholesterol; increases HDL cholesterol (9); and reduces markers of inflammation and thrombosis (11). Metformin therapy in gestational diabetes mellitus achieves maternal glucose control and pregnancy outcomes similar to insulin therapy (12,13).In contrast to insulin, metformin crosses the placenta (14) and, therefore, could directly influence fetal metabolism. Our recent follow-up studies in 2-year-old offspring of women enrolled in the Metformin in Gestational Diabetes (MiG) trial showed increased subcutaneous fat measurements with no increase in abdominal adiposity or total fat (15). Further assessments are required to determine whether metformin actually reduces visceral/ectopic fat. Therefore, we hypothesized that metformin would be more effective than insulin in improving markers of insulin sensitivity and cardiovascular risk during pregnancy and postpartum in women with gestational diabetes mellitus and in their newborns.     

Association of depressive symptoms with impaired glucose regulation, screen-detected, and previously known type 2 diabetes: findings from the Finnish D2D Survey

OBJECTIVE

To study the association between impaired glucose regulation (IGR), screen-detected type 2 diabetes, and previously known diabetes and depressive symptoms.

RESEARCH DESIGN AND METHODS

Altogether, 2,712 participants from three hospital districts in Finland attended a health examination. Cutoff scores ≥10 and ≥16 in the 21-item Beck Depression Inventory (BDI-21) were used for depressive symptoms. The participants were defined as having known diabetes if they reported diabetes. An oral glucose tolerance test was used to detect normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and screen-detected diabetes. The participants were defined as having IGR if they had IFG or IGT.

RESULTS

Prevalence of depressive symptoms, defined as a BDI-21 cutoff score ≥10, was 14.4% for those with NGR, 13.7% for those with IGR, 14.8% for those with screen-detected diabetes, and 26.4% for those with previously known diabetes. The corresponding prevalences for a cutoff score ≥16 were 3.4, 3.4, 4.2, and 7.5%, respectively. Compared with NGR and adjusted for demographic, lifestyle, and biological factors, the odds ratios for IGR, screen-detected diabetes, and previously known diabetes were 0.91 (95% CI 0.69–1.20), 0.70 (0.45–1.08), and 1.35 (0.84–2.15), respectively, for a cutoff score ≥10. For a cutoff score ≥16, the corresponding odds ratios were 1.05 (0.62–1.76), 0.87 (0.40–1.90), and 1.56 (0.69–3.50), respectively.

CONCLUSIONS

Participants with diagnosed diabetes had a higher prevalence of depressive symptoms than participants with NGR, IGR, and previously unknown diabetes. When potential confounding factors were included in the analysis, previously known diabetes was not significantly associated with depressive symptoms.It is widely recognized that depression is more common among people with diabetes than in the general population (1). However, previous studies (2–10) that have assessed the relationship between depressive symptoms and impaired glucose tolerance (IGT) or diabetes have been inconsistent. A German study (4) that included 4,597 subjects and a Dutch study (2) that included 4,747 participants found no association between type 2 diabetes and depressive symptoms. In a general-practice setting study that included 2,849 male and 3,160 female subjects, depression was not more prevalent in people with screen-detected diabetes or impaired glucose regulation (IGR) than in people with normal glucose regulation (NGR) (5). Contrary to these studies, within the Hertfordshire Cohort Study (6) there was a relationship between depression scores and diagnosed and previously undiagnosed diabetes. A U.S. study (8) including 4,293 U.S. veterans indicated that men with undiagnosed type 2 diabetes had nearly double the odds of major depression compared with those with normal fasting glucose.In 1992, it was stated about the relationship between depression and diabetes that “the etiology is unknown but is probably complex; and biological, genetic, and psychological factors remain as potential contributors. Several neuroendocrine and neurotransmitter abnormalities common to both depression and diabetes have been identified, adding to etiological speculations” (11). It has been suggested that stress-induced activation of the hypothalamic-pituitary-adrenal axis may result in the development of metabolic abnormalities and depression (12). In addition, possible neuroendocrine abnormalities associated with both diabetes and depressive symptoms may include abnormalities in vitamin B₁₂ and sex hormone–binding globulin (SHBG) levels. Low vitamin B₁₂ levels have been found to relate to type 2 diabetes (13) and depressive symptoms (14–16). Low levels of SHBG may predict diabetes (17). SHBG binds circulating sex hormones, which have been suggested to be associated with depressive symptoms (18). In addition to these biological factors, the observed association between diabetes and depressive symptoms could be a reflection of the burden of diabetes and comorbidities.In the present study, our aim was to analyze the prevalence of depressive symptoms in people with NGR, IGR (including impaired fasting glycemia and impaired glucose tolerance), screen-detected (previously unknown) diabetes, and previously known type 2 diabetes. Furthermore, our aim was to study the association between glucose tolerance and depressive symptoms, taking into account potential confounding demographic and biological factors as well as comorbidity.     

Cost-Effectiveness of Bariatric Surgery for Severely Obese Adults With Diabetes

OBJECTIVE

To analyze the cost-effectiveness of bariatric surgery in severely obese (BMI ≥35 kg/m²) adults who have diabetes, using a validated diabetes cost-effectiveness model.

RESEARCH DESIGN AND METHODS

We expanded the Centers for Disease Control and Prevention–RTI Diabetes Cost-Effectiveness Model to incorporate bariatric surgery. In this simulation model, bariatric surgery may lead to diabetes remission and reductions in other risk factors, which then lead to fewer diabetes complications and increased quality of life (QoL). Surgery is also associated with perioperative mortality and subsequent complications, and patients in remission may relapse to diabetes. We separately estimate the costs, quality-adjusted life-years (QALYs), and cost-effectiveness of gastric bypass surgery relative to usual diabetes care and of gastric banding surgery relative to usual diabetes care. We examine the cost-effectiveness of each type of surgery for severely obese individuals who are newly diagnosed with diabetes and for severely obese individuals with established diabetes.

RESULTS

In all analyses, bariatric surgery increased QALYs and increased costs. Bypass surgery had cost-effectiveness ratios of $7,000/QALY and $12,000/QALY for severely obese patients with newly diagnosed and established diabetes, respectively. Banding surgery had cost-effectiveness ratios of $11,000/QALY and $13,000/QALY for the respective groups. In sensitivity analyses, the cost-effectiveness ratios were most affected by assumptions about the direct gain in QoL from BMI loss following surgery.

CONCLUSIONS

Our analysis indicates that gastric bypass and gastric banding are cost-effective methods of reducing mortality and diabetes complications in severely obese adults with diabetes.In recent years, bariatric surgery has emerged as a popular treatment to reduce body weight and improve obesity-related complications, particularly in the diabetic population. Several studies have shown that surgery can lead to significant weight loss, with excess body weight reduced by >50% (1,2). Although weight loss declines over time, the Swedish Obese Subjects (SOS) Study found significant weight loss even 10 years after surgery (3,4). In addition to sustained weight loss, bariatric surgery may provide additional benefits to people with diabetes. Among severely obese patients with diabetes, bariatric surgery often leads to diabetes remission, with remission rates that are as high as 80% in the short run (1) and that remain significant in the long run (3,4).Although the evidence suggests that bariatric surgery is a successful long-term treatment of obesity for people with diabetes, it is an expensive procedure. The average cost of surgery exceeds $13,000 (5), with additional costs possible in the months following surgery (6). This raises the question of whether bariatric surgery is cost-effective for severely obese people with diabetes.Several studies have estimated the cost-effectiveness of bariatric surgery and found that surgery is either cost-effective (7–10) or that it leads to cost savings over time (6,11–13). The existing studies tend to be relatively simple, and only two (10,13) focus on people with diabetes. The studies generally do not model the microvascular complications associated with diabetes, the effect of surgery on blood pressure and cholesterol levels, or the resulting outcomes.This study used the Centers for Disease Control and Prevention (CDC)-RTI Diabetes Cost-Effectiveness Model to analyze the cost-effectiveness of bariatric surgery in severely obese adults with diabetes. We separately estimated the cost-effectiveness of gastric bypass surgery relative to usual diabetes care and the cost-effectiveness of gastric banding surgery relative to usual diabetes care. Gastric bypass and gastric banding are the two forms of bariatric surgery most commonly studied (1). We examined the cost-effectiveness of each type of surgery for severely obese people who are newly diagnosed with diabetes (no more than 5 years after diagnosis) and for people with established diabetes (at least 10 years after diagnosis).     

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.