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.     

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.     

Association Between Metformin Therapy and Mortality After Breast Cancer: A population-based study

OBJECTIVE

Metformin has been associated with a reduction in breast cancer risk and may improve survival after cancer through direct and indirect tumor-suppressing mechanisms. The purpose of this study was to evaluate the effect of metformin therapy on survival in women with breast cancer using methods that accounted for the duration of treatment with glucose-lowering therapies.

RESEARCH DESIGN AND METHODS

This population-based study, using Ontario health care databases, recruited women aged 66 years or older diagnosed with diabetes and breast cancer between 1 April 1997 and 31 March 2008. Using Cox regression analyses, we explored the association between cumulative duration of past metformin use and all-cause and breast cancer–specific mortality. We modeled cumulative duration of past metformin use as a time-varying exposure.

RESULTS

Of 2,361 breast cancer patients identified, mean (± SD) age at cancer diagnosis was 77.4 ± 6.3 years, and mean follow-up was 4.5 ± 3.0 years. There were 1,101 deaths(46.6%), among which 386 (16.3%) were breast cancer–specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92–1.02]) or breast cancer–specific mortality (0.91 [0.81–1.03]) per additional year of cumulative use.

CONCLUSIONS

Our findings failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes. Further research is needed to clarify this association, accounting for effects of cancer stage and BMI in younger populations or those with differing stages of diabetes as well as in nondiabetic populations.Pre-existing diabetes may increase the risk of death by as much as 40% in cancer patients (1). Up to 16% of patients with breast cancer have pre-existing diabetes and are thus at risk for worse outcomes (2,3). Metformin, an insulin sensitizer, is the most commonly prescribed diabetes treatment and is currently recommended as first-line therapy for patients with type 2 diabetes (4,5). If glycemic targets are not met with metformin alone, other glucose-lowering medications are added to or substituted for metformin. Recent evidence suggests that metformin may have antitumor effects (6). Several studies have evaluated the effect of metformin on cancer incidence, and meta-analyses suggest that metformin is associated with a 20–30% reduction in new cancers (6–8). However, of greater interest is the potential therapeutic role of metformin in patients with pre-existing cancer.There is mounting evidence that metformin may affect the prognosis of breast cancer. Metformin use has been associated with higher rates of pathologic complete response after chemotherapy in breast cancer patients with diabetes (9), and clinical trials have shown a reduction in tumor proliferation markers in nondiabetic breast cancer patients treated with metformin (10–12). However, observational studies evaluating the effect of metformin on survival after breast cancer have been inconsistent. One study of women with HER2+ breast cancer found metformin exposure was associated with a 48% reduction in overall mortality compared with other glucose-lowering medications (13). However, another study of women with triple-negative receptor breast cancer did not show a significant association between metformin and cancer mortality (hazard ratio [HR] 1.63 [95% CI 0.87–3.06]) (13,14). Interpretation of these previous studies is hampered by small sample sizes, heterogeneity of disease subtypes, inclusion of diabetic populations with varying disease severity and duration, and inconsistent definitions of metformin exposure. The objective of this study was to evaluate the relationship between cumulative metformin use and mortality in patients with breast cancer and recently diagnosed diabetes.     

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.     

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.     

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.     

Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients

OBJECTIVE

Metformin and statins have shown promise for cancer prevention. This study assessed whether the effect of metformin on prostate cancer (PCa) incidence varied by statin use among type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

The study cohort consisted of 5,042 type 2 diabetic male patients seen in the Veteran Administration Health Care System who were without prior cancer and were prescribed with metformin or sulfonylurea as the exclusive hypoglycemic medication between fiscal years 1999 and 2005. Cox proportional hazards analyses were conducted to assess the differential hazard ratio (HR) of PCa due to metformin by statin use versus sulfonylurea use, where propensity scores of metformin and statin use were adjusted to account for imbalances in baseline covariates across medication groups.

RESULTS

Mean follow-up was ∼5 years, and 7.5% had a PCa diagnosis. Statin use modified the effect of metformin on PCa incidence (P < 0.0001). Metformin was associated with a significantly reduced PCa incidence among patients on statins (HR 0.69 [95% CI 0.50–0.92]; 17 cases/533 metformin users vs. 135 cases/2,404 sulfonylureas users) and an increased PCa incidence among patients not on statins (HR 2.15 [1.83–2.52]; 22 cases/175 metformin users vs. 186 cases/1,930 sulfonylureas users). The HR of PCa incidence for those taking metformin and statins versus those taking neither medication was 0.32 (0.25–0.42).

CONCLUSIONS

Among men with type 2 diabetes, PCa incidence among metformin users varied by their statin use. The potential beneficial influence on PCa by combination use of metformin and statin may be due to synergistic effects.Prostate cancer (PCa) is the most common cancer detected in men in the U.S., accounting for ∼28% of the new cancer burden. Risk for PCa increases significantly with age, and the lifetime risk for a U.S. man is 1 in 6 (1). Although a large proportion of cases will not progress to a life-threatening state, a diagnosis of PCa can have significant daunting effects on the patient and his family, with concomitant lifestyle changes, particularly due to the high risk of voiding and sexual dysfunction resulting from currently available curative treatment options. Therefore, preventive strategies would have substantial benefit. Although risk for PCa has been shown to be lower for men with diabetes (2), preventing PCa is particularly important in men with type 2 diabetes because this population appears to be at higher risk for high-grade PCa compared with men without diabetes (3,4). Metformin and statins, two drug classes with sound safety profiles that are well tolerated, have shown promise for cancer prevention trials, although their efficacy in the prevention or treatment of PCa still remains to be seen (5–11).Metformin is a biguanide drug widely prescribed as a first-line oral antihyperglycemic agent for individuals with type 2 diabetes (12). Its glucose-lowering effects may require activation of AMP-activated protein kinase (AMPK) to inhibit hepatic gluconeogenesis (13), increase peripheral uptake of glucose, and delay gastrointestinal glucose absorption (14). In addition, preclinical and clinical data have suggested antineoplastic effects of metformin, and several potential mechanisms include a reduction of hyperinsulinemia, growth inhibition through activation of the AMPK pathway and downstream inhibition of the mammalian target of rapamycin (mTOR) pathway, blockade of cell cycle progression, and alteration of anti-inflammatory properties (5,15–17).Although the beneficial metabolic effects of metformin make it a good treatment candidate for preventing ensuing metabolic syndrome after androgen-deprivation therapy for PCa (18), there is currently mixed enthusiasm for use of metformin therapy in the prevention of PCa. Observational human studies have examined the effect of metformin on risk or recurrence of PCa. Studies conducted in the general population reported decreased risk for PCa among metformin users (19,20). Given that diabetes has been inversely correlated with PCa risk (2), these early reports may have been subject to this bias. In fact, two studies conducted exclusively among diabetic subjects did not observe a significant reduction in PCa risk by metformin use (21,22); rather, a possible dose-dependent increase in risk was reported (21).Because these results are unexpected and contrast not only with the preclinical data but also with clinical data for other cancers, such as breast cancer, it is important to examine this question in other cohorts using more rigorous approaches to adjust for heterogeneity and potential confounding. For example, because of the high prevalence of dyslipidemia among individuals with type 2 diabetes, a large number will also be treated with a lipid-lowering medication such as a statin drug (23). The combination treatment with metformin and statin has not been explored. Prior studies, such as in Azoulay et al. (21), have adjusted for statin use by including an indicator variable to capture any previous use or no use in their model because statin use has itself been associated with PCa risk. No study has formally examined the interactive and potentially synergistic effects of the combination treatment with both drugs.Supportive evidence for use of statins as a PCa prevention therapy is growing, and two clinical trials are currently being initiated in the U.S. to examine effects of statin use in PCa patients (24). As 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, statins may affect PCa tumorigenesis by blocking the mevalonate pathway and thus reducing cholesterol and/or through multiple pleiotropic effects, as reviewed in Papadopoulos et al. (25). Clinical data have shown cholesterol levels are strongly correlated with PCa risk, so reduction of cholesterol levels is likely a key factor in the anticancer effects of statins (26,27)We conducted a 7-year cohort study to compare the PCa incidence rate associated with metformin monotherapy versus sulfonylurea monotherapy among male patients with type 2 diabetes in the Veteran Health Administration Health Care System (VAHCS). Further, we assessed whether the metformin effect on the PCa incidence rate could be modified by statin use to better examine the heterogeneity of metformin effect.     

Efficacy of Primary Prevention Interventions When Fasting and Postglucose Dysglycemia Coexist: Analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2)

OBJECTIVE

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have different pathophysiological abnormalities, and their combination may influence the effectiveness of the primary prevention tools. The hypothesis was tested in this analysis, which was done in a pooled sample of two Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2).

RESEARCH DESIGN AND METHODS

Researchers analyzed and followed up on the details of 845 of the 869 IGT subjects in the two studies for 3 years. Incidence of diabetes and reversal to normoglycemia (normal glucose tolerance [NGT]) were assessed in group 1 with baseline isolated IGT (iIGT) (n = 667) and in group 2 with IGT + IFG (n = 178). The proportion developing diabetes in the groups were analyzed in the control arm with standard advice (IDPP-1) (n = 125), lifestyle modification (LSM) (297 from both), metformin (n = 125, IDPP-1), and LSM + metformin (n = 121, IDPP-1) and LSM + pioglitazone (n = 298, IDPP-2). Cox regression analysis was used to assess the influence of IGT + IFG versus iIGT on the effectiveness of the interventions.

RESULTS

Group 2 had a higher proportion developing diabetes in 3 years (56.2 vs. 33.6% in group 1, P = 0.000) and a lower rate of reversal to NGT (18 vs. 32.1%, P = 0.000). Cox regression analysis showed that effectiveness of intervention was not different in the presence of fasting and postglucose glycemia after adjusting for confounding variables.

CONCLUSIONS

The effectiveness of primary prevention strategies appears to be similar in subjects with iIGT or with combined IGT + IFG. However, the possibility remains that a larger study might show that the effectiveness is lower in those with the combined abnormality.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have a high potential to convert to type 2 diabetes. While an elevated basal hepatic glucose output and impaired early phase insulin secretion are the major abnormalities in IFG, IGT is characterized by more severe muscle insulin resistance (IR) and defects in late insulin secretion (1). Among Asian Indians, higher degrees of IR and β-cell dysfunction are seen in IFG than in IGT (2).Analysis of six prospective studies among subjects with IGT showed that the incidence of diabetes varied widely from 23 to 62% within two to twenty-seven years of follow-up (3). The incidence was higher among populations with high prevalence of diabetes than in white populations. Incidence rates of diabetes in subjects with IFG or IGT or with a combined abnormality were varied in different populations (4–8).Primary prevention studies have been done among subjects with IGT in different ethnic populations (9–14). Among these, only the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial (12) recruited subjects with either isolated IFG (iIFG) or isolated IGT (iIGT) or both. Rosiglitazone was found to be a potent agent in preventing diabetes in this trial (12). The Diabetes Prevention Programme (DPP) (9) recruited subjects with a fasting glucose in the range of 5.3–6.9 mmol/l (95–125 mg/dl) and 2-h postglucose of 7.8–11 mmol/l (140–199 mg/dl) and nearly one-third of the participants had IFG by the present criteria (15).Results of the Indian Diabetes Prevention Programme-1 (IDPP-1) showed that a moderate lifestyle modification (LSM) or a small dose of metformin (500 mg/day) reduced the risk of diabetes in a relatively nonobese but insulin resistant Asian Indian population (13). In the IDPP-2 study, we noted that pioglitazone did not improve the efficacy of LSM in Asian Indians (14). In both studies, subjects with persistent IGT and fasting glucose levels below 6.9 mmol/l were recruited. Therefore, some participants also had IFG. In view of the higher degree of biochemical abnormalities occurring when fasting and postprandial dysglycemia coexisted, it was considered important to study whether the combined abnormalities influenced the cumulative incidence of diabetes in comparison with subjects with iIGT. To increase the sample size, data from both IDPP studies were pooled. The participants'' baseline characteristics were identical in the two studies.     

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.     

Diabetes and risk of prostate cancer: a study using the National Health Insurance

OBJECTIVE

The link between diabetes and prostate cancer is rarely studied in Asians.

RESEARCH DESIGN AND METHODS

The trend of age-standardized prostate cancer incidence in 1995–2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men ≥40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors.

RESULTS

The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40–64, 65–74, and ≥75 years was 5.83 (5.10–6.66), 2.09 (1.60–2.74), 1.35 (1.07–1.71), and 1.39 (1.12–1.71). In logistic regression for all ages or for age ≥40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not.

CONCLUSIONS

Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40–64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages.The association between diabetes and prostate cancer has been inconsistently reported, even though two meta-analyses suggested that diabetic patients have a lower risk of prostate cancer of 9% (1) and 16% (2), respectively.While the two meta-analyses were examined, many studies were case-control and only three focused on the follow-up of cohorts of diabetic patients (3–5). Among the three cohorts, the cases of prostate cancer were 9 (3), 498 (4), and 2,455 (5), respectively; and only the last (5) showed a significant 9% risk reduction in diabetic patients. Except for the first study being conducted in residents with diabetes in Rochester, Minnesota (3), the diabetic patients in the other two were from hospitalized patients in Denmark (4) and Sweden (5), respectively. The meta-analyses have limitations including a mixture of case-control and cohort designs, a mixture of incident and dead cases, a small number of prostate cancer in most studies, and different sources of subjects with potential selection bias. Although the contamination of type 1 diabetes is possibly minimal because >90% of overall patients have type 2 diabetes, residual confounding could not be excluded if the two types of diabetes are not differentiated.Although some recent studies still suggested a lower risk of prostate cancer in diabetic patients including Caucasians (6,7), Iranians (8), Israelis (9), African Americans, Native Hawaiians, and Japanese Americans (6), the lower risk in African Americans and Native Hawaiians (6) was not significant. Two Japanese studies did not find any significant association (10,11). The Ohsaki Cohort Study suggested that diabetes was not predictive for total prostate cancer, but diabetic patients did show a higher risk of advanced cancer (11).Because diabetic patients are prone to develop cancer involving pancreas, liver, breast, colorectum, bladder, and endometrium (12–15) and the protective effect of diabetes on prostate cancer requires confirmation, this study evaluated the possible link between diabetes and prostate cancer, and the potential risk factors, by using the reimbursement database of the National Health Insurance (NHI) in Taiwan.     

New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes

OBJECTIVE

The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994–2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression.

RESULTS

Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40–0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53–0.75).

CONCLUSIONS

These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.Recent research suggests that the antidiabetic drug metformin, which exerts its effects by activating the AMP-activated protein kinase (AMPK), may have potential for the treatment of cancer in humans (1). The hypothesis that metformin may have anticancer effects is supported by laboratory studies showing that metformin is associated with reduced incidence of pancreatic cancer in hamsters (2) and delays onset of mammary (3) and other tumors (4) in tumor-prone mice. Metformin also inhibits growth of human breast cancer cells (5). Although the potential for prevention of cancer in humans using metformin has not been explored, we previously reported the results of a pilot case-control study that identified a reduced risk of cancer among patients with type 2 diabetes who had used metformin (6). However, the outcome was limited to hospital admissions for cancer, and the date of diagnosis was assumed to be date of first hospital admission.Other diabetic drugs may also have cancer-related effects. An independent epidemiological study found that users of sulfonylureas were at higher risk of cancer-related mortality than metformin users (7). Sulfonylureas (and insulin) increase circulating insulin levels, and hyperinsulinemia may promote carcinogenesis (8). Treatments such as metformin and glitazones reduce insulin resistance, with insulin resistance possibly associated with increased risk of cancer (9). The objective of this study was to test the hypothesis that metformin use is associated with a reduced risk of cancer in people with type 2 diabetes using a national cancer registry to ensure valid diagnoses of cancer with precise dates of diagnosis. We also adjusted results for the effects of exposure to other diabetic drugs.     

Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

OBJECTIVETo investigate the associations of metformin, serum vitamin B₁₂, calcium supplements, and cognitive impairment in patients with diabetes.RESULTSParticipants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B₁₂, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).CONCLUSIONSMetformin use was associated with impaired cognitive performance. Vitamin B₁₂ and calcium supplements may alleviate metformin-induced vitamin B₁₂ deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B₁₂ and calcium use on cognition in older people with diabetes who are taking metformin.In 2010, more than 346 million people had diabetes worldwide. Recent studies from the U.K. (1) and Italy (2) reported that the adult prevalence of diabetes was approximately 4.2%. In the U.S., the prevalence of diabetes in the adult population may be as high as 14% when undiagnosed cases are included (3). The prevalence of diabetes may be higher in some developing nations: in the developing region of southern China it was reported to be 21.7% in 2010 (4). The prevalence of diabetes is more than 20% in some Pacific Island nations, reaching 47% in 22- to 64-year-old American Samoans (5).In diabetes, hyperglycemia activates the cellular signaling protein kinase C, which induces production of the vasoconstrictor protein endothelin-1. Excess intracellular glucose is converted to sorbitol by the enzyme aldose reductase. When intracellular levels of glucose are high, this process exhausts the energy substrate NADPH, resulting in oxidative stress. High intracellular sorbitol levels cause osmotic stress and cell death. These biochemical changes in hyperglycemia are a proposed mechanism for macrovascular and microvascular complications and neuropathy (6–8). Diabetes is associated with a faster rate of cognitive decline in those with mild cognitive impairment (MCI) (9) and an increased risk for developing Alzheimer disease (AD) (10).Approximately 90% of patients with diabetes have type 2 diabetes (1). The biguanide metformin is a first-line treatment for type 2 diabetes, increasing glucose uptake in muscle while reducing liver gluconeogenesis (the synthesis of glucose from amino acids). These effects are mediated by activation of the cellular signaling protein AMP–activated protein kinase (11).Metformin first became available in the U.K. in 1958 and entered the Canadian market in 1971, but it has been available in the U.S. only since 1995. In a survey of 65,000 U.S. war veterans (12), metformin use among those with diabetes increased from 29% in 2000 to 63% in 2005. Among 242 Australian veterans who had diabetes, metformin was used by 75% in 2005 but decreased to 57% in 2009 (13).The rate of vitamin B₁₂ deficiency among patients who are taking metformin is reported to approach 30% (14–16). A drug interaction between metformin and the cubilin receptor inhibits the uptake of vitamin B₁₂ from the distal ileum, lowering serum vitamin B₁₂ levels. In a long-term, randomized, placebo-controlled trial, metformin therapy in type 2 diabetes was associated with a 19% reduction in serum vitamin B₁₂ concentrations compared with placebo (17). In a case-control study, Wile and Toth (18) reported that metformin use was associated with reduced vitamin B₁₂ levels and more severe peripheral neuropathy in patients with diabetes.In a prospective trial, calcium supplements were reported to reverse the drug interaction that causes vitamin B₁₂ deficiency induced by metformin (19). The clinical significance of alleviating metformin-induced vitamin B₁₂ malabsorption by calcium supplementation has not been previously investigated. By correcting vitamin B₁₂ levels in patients with diabetes who use metformin, calcium supplements may help to preserve cognitive function. In addition, neuronal signaling in memory and learning involves a calcium-mediated process, so calcium supplementation may also have a direct effect on the brain. Calcium dysregulation is the subject of one proposed theory for age-related cognitive changes and AD (20). The risks and potential benefits of calcium supplementation on cognition and for alleviating vitamin B₁₂ malabsorption merit further investigation.The amyloid plaques seen in the brains of patients with AD are formed by aggregation of Aβ peptides. In cell cultures, Chen and colleagues (21) reported that activation of AMP–activated protein kinase by metformin increased the expression of β-secretase, an enzyme that increases the formation of Aβ peptides. One recent case-control study that included 14,172 participants 65 years of age or older reported that taking metformin over the long term increased the risk of AD (odds ratio [OR] 1.71 [95% CI 1.12–2.60]) (22).Recent studies of murine models of diabetes indicate that metformin may attenuate irregularities in phosphorylation of tau proteins (23) or may facilitate neuroneogenesis (24) and so may be of benefit to those with AD. In 25,393 patients older than 50 years with type 2 diabetes, metformin was reported to reduce the risk of dementia by 24% (hazard ratio 0.76 [95% CI 0.58–0.98]) (25). The purpose of our study was to investigate the associations of metformin, serum vitamin B₁₂ levels, and cognition in a sample of patients with diabetes.     

Changes in Insulin Secretion and Insulin Sensitivity in Relation to the Glycemic Outcomes in Subjects With Impaired Glucose Tolerance in the Indian Diabetes Prevention Programme-1 (IDPP-1)

OBJECTIVE

The Indian Diabetes Prevention Programme-1 (IDPP-1) showed that lifestyle modification (LSM) and metformin were effective for primary prevention of diabetes in subjects with impaired glucose tolerance (IGT). Among subjects followed up for 3 years (n = 502), risk reductions versus those for the control group were 28.5, 26.4, and 28.2% in LSM, metformin (MET), and LSM plus MET groups, respectively. In this analysis, the roles of changes in secretion and action of insulin in improving the outcome were studied.

RESEARCH DESIGN AND METHODS

For this analysis, 437 subjects (93 subjects with normoglycemia [NGT], 150 subjects with IGT, and 194 subjects with diabetes) were included. Measurements of anthropometry, plasma glucose, and plasma insulin at baseline and at follow-up were available for all of them. Indexes of insulin resistance (homeostasis model assessment of insulin resistance) and β-cell function (insulinogenic index [ΔI/G]: 30-min fasting insulin divided by 30-min glucose) were also analyzed in relation to the outcome.

RESULTS

Subjects with IGT showed a deterioration in β-cell function with time. Individuals with higher insulin resistance and/or low β-cell function at baseline had poor outcome on follow-up. In relation to no abnormalities, the highest incidence of diabetes occurred when both abnormalities coexisted (54.9 vs. 33.7%, χ² = 7.53, P = 0.006). Individuals having abnormal insulin resistance (41.1%) or abnormal ΔI/G (51.2%, χ² = 4.87, P = 0.027 vs. no abnormalities) had lower incidence. Normal β-cell function with improved insulin sensitivity facilitated reversal to NGT, whereas deterioration in both resulted in diabetes. The beneficial changes were better with intervention than in the control group. Intervention groups had higher rates of NGT and lower rates of diabetes.

CONCLUSIONS

In the IDPP-1 subjects, beneficial outcomes occurred because of improved insulin action and sensitivity caused by the intervention strategies.Primary prevention studies in diabetes have been done in subjects with a high risk for diabetes, such as those with impaired glucose tolerance (IGT) (1–6) or with a history of gestational diabetes mellitus (7). Lifestyle modification (LSM) (1–5) and/or pharmacological agents such as metformin (MET) (1,5) and glitazones (6) have been shown to be effective in reducing the rate of conversion of IGT to diabetes in different ethnic groups. The benefits are seen in association with weight reduction in the obese population (1,2) or without significant weight changes in relatively nonobese population (3,5). The mechanisms that result in the beneficial changes are associated with two important pathophysiological components, namely impaired secretion and impaired action of insulin.The Indian Diabetes Prevention Programme-1 (IDPP-1) had shown that moderate, but consistent, LSM or use of MET reduced the risk of deterioration of IGT to diabetes by 28% in relation to that in a control group who had no intervention in a 3-year follow-up period (5). Combining LSM with MET showed no added benefit.IGT, an intermediate state in the natural history of type 2 diabetes, is characterized by a worsening in insulin resistance and insulin secretion (8). Asian Indians have higher rates of insulin resistance than Europeans and other white populations despite being relatively nonobese (9,10).The chief pathophysiological components of type 2 diabetes, namely impaired secretion and action of insulin are detectable many years before the diagnosis of clinical diabetes (11). A combined occurrence of both defects due to gradual deterioration, eventually results in diabetes. This analysis was done to identify the changes in insulin secretion and insulin action that produced the improved outcome with the primary prevention strategies in the IDPP-1 cohort.     

Physical Activity, Adiposity, and Diabetes Risk in Middle-Aged and Older Chinese Population: The Guangzhou Biobank Cohort Study

OBJECTIVE

Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population.

RESEARCH DESIGN AND METHODS

Middle-aged and older Chinese (n = 28,946, ≥50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003–2008. Multivariable regression was used in a cross-sectional analysis.

RESULTS

BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60–4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17–1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P = 0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22–4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41–3.59).

CONCLUSIONS

In this population, WHR was a better measure of adiposity-related diabetes risk than BMI or waist circumference. Higher moderate-to-vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals.Type 2 diabetes is a worldwide cause of morbidity and mortality. Adiposity, especially abdominal adiposity, seems to be at the core of development of hyperglycemia and type 2 diabetes (1). Increased physical activity may mitigate some of the diabetogenic impact of adiposity (2–4). Individuals who are obese but fit could even have a lower risk of mortality than those who are normal weight but unfit (5,6). However, being physically active does not completely abolish the obesity-related risk for cardiovascular disease and associated mortality (7). Adiposity is still the main risk factor for the development of type 2 diabetes (2–4,8). Although increased physical activity has been shown to be associated with reduced type 2 diabetes risk independent of adiposity, the protective effects may differ by the level of adiposity. However, the group that could benefit most from physical activity for the prevention of diabetes is still unclear (2–4,8–10).Understanding the relationship between adiposity and physical activity is important to stratify risk groups for the development of effective diabetes prevention strategies from public health and clinical perspectives. Most of the studies relate to Caucasians (2–4,8–10), whereas Asians, including Chinese and Indians, are possibly more vulnerable to insulin resistance (11). The number of Chinese adults with type 2 diabetes was estimated to be ∼28.1 million in 2000 and may double by 2030, with China being second only to India (12). The purpose of this study was to investigate the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose (IFG), and type 2 diabetes in 28,946 middle-aged and older Chinese participants in the Guangzhou Biobank Cohort Study.     

Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study

OBJECTIVE

Diabetes is associated with many forms of cancer. Recent evidence has suggested that some treatments for diabetes are associated with an increased cancer risk. Less is known about the association between endogenous insulin in the prediabetes state and cancer risk.

RESEARCH DESIGN AND METHODS

We investigated cumulative cancer incidence and cancer incidence density over 29 years, according to basal insulin, in a cohort of 1,695 nondiabetic men and women of four ethnic origins, aged 51.8 ± 8.0 years at baseline. Total mortality among the 317 subjects (18.7%) who developed cancer at least 2 years after baseline was assessed.

RESULTS

In a Cox proportional hazards model, the all-site hazard ratio of cancer incidence comparing the highest insulin quartile with the other three quartiles was 1.09 (95% CI 0.85–1.40), adjusted for age, sex, and ethnicity. BMI, smoking, and fasting blood glucose were not statistically significant in this model. Basal insulin level was not significantly associated with cancer of specific sites (breast, prostate, colon/rectum, or bladder). Fasting insulin in the upper quartile conferred a 37% increased risk for total mortality among cancer patients, adjusting for age, sex, and ethnic origin (95% CI 0.94–2.00, P = 0.097) compared with that of the lower quartiles. Male sex, older age, and North African origins were associated with a greater risk of mortality during follow-up time.

CONCLUSIONS

This long-term cohort study may suggest a role for basal elevated insulin levels, mainly as a negative predictor in cancer prognosis.The American Diabetes Association and the American Cancer Society recently issued a consensus report showing cancer incidence to be associated with diabetes (1). Type 2 diabetes has been associated with increased incidence, in the range of 1.2–2.5 of cancers of the pancreas (2), breast (3), colon (4), and bladder (5). In addition, a recent meta-analysis of 23 studies found diabetes to be associated with an increased mortality hazard ratio (HR) of 1.41 (95% CI 1.28–1.55) among individuals with cancer (6). Furthermore, some treatments for diabetes have been implicated in increasing the risk of malignancy (7). The development of some types of insulin has been discontinued secondary to increased mitogenic side effects (8). The affinity of binding to the IGF-1 receptor (IGF-1R) has been implicated.We and others have shown basal hyperinsulinemia to predict type 2 diabetes (9,10). Further, elevated levels of circulating insulin and C-peptide have been associated with an increased risk of colorectal and pancreatic cancers (11). Though the risk of breast cancer was less certain in the latter study, two recent analyses of the Women''s Health Initiative found a positive association between insulin levels and breast cancer (12,13).Studies in animals (14–17) and in vitro (18,19) suggest a role for insulin in tumor progression. Glucose tolerance status from 2-h glucose tolerance tests has been shown to associate with the risk of cancer mortality (4). However, the effect of elevated basal insulin on cancer prognosis has not been investigated in vivo.The current study examined the effect, up to 29 years later (mean follow-up time 21.7 ± 6.5 years), of elevated levels of basal insulin on the cumulative incidence of cancer and on cancer survival in a cohort of the Jewish population, representing the four main ethnic origins of immigration to Israel.     

Visceral Fat Area and Markers of Insulin Resistance in Relation to Colorectal Neoplasia

OBJECTIVE

Although abdominal obesity and related metabolic abnormalities are hypothesized to promote colorectal carcinogenesis, direct confirmation of this effect is required. Here, we examined the relation of early-stage colorectal neoplasia to visceral fat area and markers of insulin resistance.

RESEARCH DESIGN AND METHODS

Subjects were participants in a comprehensive health screening conducted at the Hitachi Health Care Center, Ibaraki, Japan. During a 3-year period (2004–2007), a total of 108 patients with early-stage colorectal neoplasia, including 22 with early cancer, were identified among individuals who received both colorectal cancer screening and abdominal computed tomography scanning. Three control subjects matched to each case subject were randomly selected from those whose screening results were negative. Conditional logistic regression analysis was used to examine the association of measures of obesity and markers of insulin resistance with colorectal neoplasia, with adjustment for smoking and alcohol drinking.

RESULTS

Visceral fat area, but not subcutaneous fat area, was significantly positively associated with colorectal cancer, with odds ratios (95% CI) for the lowest to highest tertile of visceral fat area of 1 (reference), 2.17 (0.45–10.46), and 5.92 (1.22–28.65), respectively (P^trend = 0.02). Markers of insulin resistance, particularly fasting glucose, were also positively associated with colorectal cancer risk. In contrast, no associations were observed for colorectal adenomas.

CONCLUSIONS

These results suggest that visceral adipose tissue accumulation and insulin resistance may promote the development of early-stage cancer but not adenoma in the colorectum.Although the role of obesity as a strong predictor of various chronic diseases, including type 2 diabetes and cardiovascular disease, has been established, accumulating evidence also indicates the importance of obesity and its related metabolic disorders in the development of cancer (1). In Japan, the incidence of colorectal cancer has sharply increased over the last several decades and is now among the highest in the world (2). This time trend, as well as findings from migrant studies (3), suggests the involvement of environmental factors in colorectal carcinogenesis. Epidemiological studies (4,5) have shown that colorectal cancer risk is more strongly associated with waist circumference than with BMI, indicating the etiological importance of abdominal or visceral fat disposition, rather than overall adiposity. However, given that waist circumference is only a surrogate of visceral fat mass, more direct evidence is required before the link between visceral adiposity and cancer risk can be considered conclusive.Several studies have assessed the association between visceral fat area, as measured using computed tomography (CT) scanning, and colorectal neoplasia (6–10), but results have been mixed. For example, a Japanese study (7) demonstrated an increased prevalence of colorectal adenomas among individuals with higher visceral fat area, whereas a larger, more recent study (8) did not. Given that adenomatous polyps are common but only a minority progress to cancer (11), the association with cancer should also be explored, but evidence to date is sparse. In a Turkish study (10), patients with colorectal cancer tended to have a smaller rather than larger visceral fat area than that in control subjects. This unexpected finding may have been due to weight loss in the course of cancer development, however, a possibility that highlights the importance of assessing visceral fat before the diagnosis of cancer or development of symptoms.An insulin hypothesis has been proposed to explain the observed association between obesity or abdominal obesity and colorectal neoplasia (12,13). Accumulation of visceral fat is a strong determinant of insulin resistance and hyperinsulinemia (14) and, as experimental data show (15), insulin promotes colorectal carcinogenesis. Compatible with the insulin hypothesis, epidemiological data appear consistent in showing a positive association between colorectal neoplasia and markers of hyperinsulinemia or insulin resistance (rev. in 16). These findings notwithstanding, however, a role for insulin resistance in promoting the development of adenoma, cancer, or both in the colorectum has yet to be confirmed. To further explore these issues, we examined the relation of visceral fat mass assessed by CT and measures of insulin resistance to adenoma and cancer in the colorectum among asymptomatic individuals who underwent screening.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.