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.     

Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial

OBJECTIVE

To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea.

RESEARCH DESIGN AND METHODS

In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports.

RESULTS

At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (−1.03% [−11.3 mmol/mol] and −0.66% [−7.2 mmol/mol], respectively; least squares mean difference between groups, −0.37% [95% CI, −0.50 to −0.25] or −4.0 mmol/mol [−5.5 to −2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis–related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups.

CONCLUSIONS

Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.Patients with type 2 diabetes often require combinations of antihyperglycemic agents (AHAs) to maintain glycemic control because of the progressive nature of the disease (1,2). Metformin is the recommended first-line pharmacologic therapy for type 2 diabetes (1,2). For patients who do not achieve or sustain sufficient glycemic control with metformin, a second AHA is often added (2). With further decline in glycemic control (3,4), the addition of a third oral agent is increasingly common. Currently available classes of AHAs, such as dipeptidyl peptidase-4 inhibitors, peroxisome proliferator–activated receptor (PPAR)γ agonists, and sulfonylureas, have distinct risk/benefit profiles (2,5). A recent position statement by the American Diabetes Association and the European Association for the Study of Diabetes recommends individualization of treatment for patients and suggests the use of pharmacologic agents with complementary mechanisms of action in triple therapy combinations if A1C targets are not attained with dual combination therapy (2).Canagliflozin is an inhibitor of the sodium glucose cotransporter 2 (SGLT2) in development for the treatment of patients with type 2 diabetes (6–10). SGLT2 is responsible for the majority of glucose reabsorption in the kidney (11). Almost all glucose is reabsorbed from the tubules until renal tubular resorptive capacity is exceeded and urinary glucose excretion (UGE) ensues; the glucose concentration at which this occurs is referred to as the renal threshold for glucose. Canagliflozin lowers the renal threshold for glucose, markedly increasing UGE and thereby reducing blood glucose concentrations in patients with hyperglycemia. The increase in UGE results in a mild osmotic diuresis and also provides a net caloric loss (with most patients with type 2 diabetes losing an average of 80–120 g/day) (12). This mechanism of action, distinct from the mechanisms of glucose-lowering of current AHA classes and independent of insulin, should provide additive glycemic control across stages of type 2 diabetes and range of classes, including add-on to the combination of metformin and a sulfonylurea agent. This 52-week Canagliflozin Treatment and Trial Analysis–dipeptidyl peptidase-4 inhibitor (CANTATA-D2; second comparator trial) study evaluated the efficacy and safety of canagliflozin 300 mg compared with sitagliptin 100 mg as add-on therapy in subjects with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea agent.     

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.     

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVE

To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes.

RESEARCH DESIGN AND METHODS

This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m².

RESULTS

Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient.

CONCLUSIONS

Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.Type 2 diabetes is characterized by insulin resistance and progressive β-cell failure. Treatment often must be intensified over time, usually by a combination of agents that address both insulin resistance and β-cell dysfunction (1,2). However, several available therapies increase the risk for hypoglycemia and weight gain, which may reduce patient adherence and lead to poor glycemic control (3).Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppression of glucagon secretion in a glucose-dependent manner, delays gastric emptying, and decreases appetite (4). GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (4). Liraglutide is a human GLP-1 analog with 97% homology to native GLP-1 (5). Liraglutide has a half-life in humans of 13 h compared with 1–2 min for native GLP-1, making liraglutide suitable as a once-daily treatment for patients with type 2 diabetes (6).In previously published phase 3 trials (the Liraglutide Effect and Action in Diabetes [LEAD] Program), treatment with liraglutide produced substantial and clinically significant reductions in A1C and fasting and postprandial glucose (PPG) levels, with a low risk of hypoglycemia, and moderate weight loss (7–10). Liraglutide treatment alone or in combination with oral antidiabetes drugs (OADs) demonstrated significantly larger A1C reductions compared with glimepiride (monotherapy) (7), rosiglitazone (in combination with a sulfonylurea) (8), and insulin glargine (in combination with metformin and sulfonylurea) (10). When initiated as monotherapy in a subgroup of previously treatment-naïve patients with type 2 diabetes, a mean A1C reduction of 1.6% was observed, with mean A1C values sustained below 7.0% over 52 weeks (7). In combination with metformin, liraglutide reduced body weight by 2–3 kg, with the majority of the weight loss being fat (11). In addition, a decrease in systolic blood pressure (SBP) has been previously demonstrated (7–10). No major hypoglycemic events occurred during the randomized treatment period when liraglutide was used as monotherapy or with metformin (7,9). The current study investigated liraglutide treatment in combination with metformin and a thiazolidinedione (TZD) (rosiglitazone) as part of the LEAD program. These three glucose-lowering agents are of particular interest, as they have complementary modes of action and are not generally associated with increased risk of hypoglycemia.     

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.     

Pleiotropic Action of Short-Term Metformin and Fenofibrate Treatment, Combined With Lifestyle Intervention, in Type 2 Diabetic Patients With Mixed Dyslipidemia

OBJECTIVE

To compare the effect of short-term metformin and fenofibrate treatment, administered alone or in sequence, on glucose and lipid metabolism, cardiovascular risk factors, and monocyte cytokine release in type 2 diabetic patients with mixed dyslipidemia.

RESEARCH DESIGN AND METHODS

We studied 128 type 2 diabetic patients with mixed dyslipidemia complying throughout the study with lifestyle intervention who were randomized twice, initially to either metformin or placebo, and then to micronized fenofibrate or placebo.

RESULTS

Fenofibrate alleviated diabetic dyslipidemia–induced changes in plasma high-sensitivity C-reactive protein, fibrinogen, and plasminogen activator inhibitor (PAI)-1 and in monocyte cytokine release, whereas metformin or lifestyle intervention improved mainly glucose and lipid metabolism. The strongest pleiotropic effect was observed when fenofibrate was added to metformin.

CONCLUSIONS

Fenofibrate, particularly administered together with metformin, is superior to metformin and lifestyle intervention in exhibiting beneficial effects on systemic inflammation, hemostasis, and monocyte secretory function in type 2 diabetic patients with mixed dyslipidemia.Peroxisome proliferator–activated receptor (PPAR)-α activators (fibrates) administered to patients with dyslipidemia (1–4) or early glucose metabolism abnormalities (5) produce many non–lipid-related effects, including anti-inflammatory, antioxidant, and antithrombotic actions and improvement in endothelial function. Apart from normalizing glucose metabolism, metformin, the only oral antidiabetic medication shown to decrease cardiovascular events independent of glycemic control (6), improved dyslipidemia, hemostasis, and systemic inflammation (7). To the best of our knowledge, no previous clinical study has ever compared clinical benefits of metformin and fibrates when it comes to their pleiotropic effects and assessed whether metformin-fibrate combination is superior to treatment with only one of these drugs.     

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

OBJECTIVE

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

RESEARCH DESIGN AND METHODS

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

RESULTS

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

CONCLUSIONS

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

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel insulin-independent treatment

OBJECTIVE

To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

RESULTS

At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

CONCLUSIONS

In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.Treatment of hyperglycemia in patients with type 2 diabetes remains a challenge, particularly in those who require insulin as the disease progresses (1,2). Various combinations of insulin with oral antidiabetic agents (OADs) have been investigated (2–8). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as a result of weight gain and worsening insulin resistance as well as progressive failure of insulin secretion.Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin (2). Weight gain with insulin therapy, used alone or with OADs (7–9), is in part a consequence of reducing glucosuria (10,11). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain, whereas metformin causes weight loss and dipeptidyl peptidase-4 inhibitors are weight neutral. Overall, there is a need for novel agents that can be safely administered to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.A novel approach to treating hyperglycemia targets receptors for renal glucose reabsorption (12). Agents that selectively block sodium-glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, inhibit glucose reabsorption and induce its elimination through urinary excretion (13). Preclinical models have shown that SGLT2 inhibition lowers blood glucose independently of insulin (14–17). Dapagliflozin, a highly selective inhibitor of SGLT2, has demonstrated efficacy, alone or in combination with metformin, in reducing hyperglycemia in patients with type 2 diabetes (18,19) but has not been tested in patients requiring insulin. This study was designed to determine whether dapagliflozin is effective in lowering blood glucose in patients with type 2 diabetes who have not responded adequately to insulin combined with oral therapies that act through insulin-dependent mechanisms.     

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.     

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.     

Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.

RESEARCH DESIGN AND METHODS

In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m², A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.

RESULTS

Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.

CONCLUSIONS

Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.Early intervention to improve glycemic control reduces microvascular complications in type 2 diabetes (1–4) and may provide long-term macrovascular benefits (5). Despite numerous available therapies, over half of patients with type 2 diabetes are unable to achieve the American Diabetes Association (ADA) target A1C level (<7%) (6–8). Moreover, weight gain and treatment-induced hypoglycemic episodes (9,10) are major barriers to achieving glycemic control (10).Antidiabetic therapies based on glucagon-like peptide-1 (GLP-1) retain the ability of native GLP-1 to stimulate glucose-dependent insulin secretion and suppress inappropriately elevated glucagon secretion (11,12). Native GLP-1 also slows gastric emptying and reduces food intake, which leads to modest weight loss (11). However, native GLP-1 is rapidly inactivated (half-life 1–2 min) by dipeptidyl peptidase-4 (DPP-4), limiting its therapeutic potential (13). Exenatide (half-life 2.4 h) improves glycemic control in combination with metformin, a sulfonylurea, or a thiazolidinedione (14–18). Despite modest weight loss and improved glycemic control, gastrointestinal (GI) intolerability and twice-daily administration may lead to discontinuation (19).Albiglutide (formerly known as albugon) is a GLP-1 receptor agonist developed through the fusion of two repeats of human GLP-1 (7–36) molecules to recombinant human albumin (20). The GLP-1 dimer was used to avoid potential reductions of the interaction of the GLP-1 moiety of the monomer with its receptor in the presence of albumin. A single amino acid substitution (ala8→gly) renders the molecule resistant to DPP-4. The structure of albiglutide provides an extended half-life (∼5 days), which may allow weekly or less frequent dosing. Furthermore, albiglutide is relatively impermeant to the central nervous system (21), which may have implications for GI tolerability. In nonclinical studies, albiglutide stimulated cAMP production through the GLP-1 receptor and induced insulin secretion from INS-1 cells in vitro and in animal models (21–22). It also delayed gastric emptying and reduced food intake in rodents (21–23).This study was designed to explore a wide range of doses (4–100 mg) and schedules (weekly to monthly) to assess glycemic control and adverse event profiles for albiglutide. Exenatide was included as an open-label reference to provide clinical perspective for a GLP-1 receptor agonist.     

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.     

Many Americans Have Pre-Diabetes and Should Be Considered for Metformin Therapy

OBJECTIVE

To determine the proportion of the American population who would merit metformin treatment, according to recent American Diabetes Association (ADA) consensus panel recommendations to prevent or delay the development of diabetes.

RESEARCH DESIGN AND METHODS

Risk factors were evaluated in 1,581 Screening for Impaired Glucose Tolerance (SIGT), 2,014 Third National Health and Nutrition Examination Survey (NHANES III), and 1,111 National Health and Nutrition Examination Survey 2005–2006 (NHANES 2005–2006) subjects, who were non-Hispanic white and black, without known diabetes. Criteria for consideration of metformin included the presence of both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), with ≥1 additional diabetes risk factor: age <60 years, BMI ≥35 kg/m², family history of diabetes, elevated triglycerides, reduced HDL cholesterol, hypertension, or A1C >6.0%.

RESULTS

Isolated IFG, isolated IGT, and IFG and IGT were found in 18.0, 7.2, and 8.2% of SIGT; 22.3, 6.4, and 9.4% of NHANES III; and 21.8, 5.0, and 9.0% of NHANES 2005–2006 subjects, respectively. In SIGT, NHANES III, and NHANES 2005–2006, criteria for metformin consideration were met in 99, 96, and 96% of those with IFG and IGT; 31, 29, and 28% of all those with IFG; and 53, 57, and 62% of all those with IGT (8.1, 9.1, and 8.7% of all subjects), respectively.

CONCLUSIONS

More than 96% of individuals with both IFG and IGT are likely to meet ADA consensus criteria for consideration of metformin. Because >28% of all those with IFG met the criteria, providers should perform oral glucose tolerance tests to find concomitant IGT in all patients with IFG. To the extent that our findings are representative of the U.S. population, ∼1 in 12 adults has a combination of pre-diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention.Diabetes is a public health epidemic (1) associated with high morbidity, mortality (1), and cost (2). Currently, an estimated 38 million Americans have the disease, nearly 40% of which is undiagnosed, and another 87 million have pre-diabetes: impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (3). Diabetes develops insidiously over several years, during which time glucose metabolism progresses slowly from normal to pre-diabetes and then more rapidly to diabetes. Based on observational and prospective studies, ∼25–40% of individuals with pre-diabetes go on to develop diabetes over 3–8 years (4–6), and there is evidence of complications in 50% of patients at the time of diagnosis of diabetes (7).Because progression from pre-diabetes can be prevented or delayed by lifestyle change and/or medication (4–6), the American Diabetes Association (ADA) has issued a consensus statement recommending early identification and preventive treatment in high-risk individuals (8). The panel statement recommends that individuals with both IFG and IGT and one additional risk factor (age <60 years, BMI ≥35 kg/m², family history of diabetes in first-degree relative, elevated triglycerides, reduced HDL cholesterol, or A1C >6.0%) should be considered for treatment with metformin, in addition to lifestyle modification, which includes weight loss and physical activity.To determine what proportion of the American population presenting with either IFG or IGT would merit consideration for metformin treatment in accordance with the recent ADA recommendations, we evaluated healthy volunteers without known diabetes who were screened for diabetes/pre-diabetes by the 75-g oral glucose tolerance test (OGTT).     

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.     

Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes

OBJECTIVE

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 μg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) ≥70–<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C ≤7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.

RESULTS

More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean ± SEM values for FPG and A1C at 24 weeks (122 ± 7 vs. 123 ± 5 mg/dl and 7.2 ± 0.2 vs. 7.0 ± 0.1%, respectively) and similar least squares mean reductions from baseline to end point (−31 ± 6 vs. −34 ± 6 mg/dl and −1.1 ± 0.2 vs. −1.3 ± 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 ± 0.7 vs. +0.0 ± 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.

CONCLUSIONS

In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.Adding basal insulin therapy to oral agents improves glycemic control for many patients with type 2 diabetes, but up to 50% of patients continue to have A1C values >7% (1,2,3,4,5). Persistent after-meal hyperglycemia is generally observed in such patients (6). The usual next step in treatment is addition of mealtime insulin injections, but this approach increases risks of weight gain and hypoglycemia (4,6).Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by β-cells, and, in individuals with abnormal β-cell function, glucose- and mixed meal–stimulated secretion of both hormones is delayed and reduced (7,8,9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11).Pramlintide, an injectable synthetic analog of amylin, slows gastric emptying, attenuates postprandial glucagon secretion, enhances satiety, and reduces food intake (12,13,14). Pramlintide is approved as adjunctive treatment for patients with diabetes who use mealtime insulin with or without oral antihyperglycemic drugs (OADs) and have not achieved desired glucose control. Recently, a 16-week, double-blind, placebo-controlled study of patients with type 2 diabetes showed that pramlintide reduces A1C and weight without increasing insulin-induced hypoglycemia when added to basal insulin ± OADs without mealtime insulin (15).Pramlintide may offer an additional therapeutic option for mealtime use by patients with type 2 diabetes already using basal insulin. Rapid-acting insulin analogs (RAIAs) and pramlintide have different mechanisms of action and different patterns of desired and unwanted effects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight gain and hypoglycemia (6), whereas pramlintide is associated with weight loss and nausea (15,16). This study was designed to compare the efficacy and side effects of pramlintide versus RAIAs when added to basal insulin to intensify treatment of type 2 diabetes.     

Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

OBJECTIVE

Interleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses.

RESEARCH DESIGN AND METHODS

Among 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m² and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat.

RESULTS

Thirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study.

CONCLUSIONS

IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.Type 2 diabetes is caused by inability of the functional β-cell mass to compensate for increased insulin needs due to insulin resistance (1). During the course of the disease, β-cell function progressively declines irrespective of treatment with glucose-lowering drugs (2–4). β-Cell mass is reduced through apoptosis (5) and type 2 diabetes is associated with a low-grade systemic inflammation (6), but the mechanisms underlying β-cell failure and destruction in type 2 diabetes remain elusive.In vitro, long-term exposure to high glucose and the peptide hormone leptin secreted by adipose tissue induce β-cell apoptosis and production of the proinflammatory cytokine interleukin (IL)-1 in β-cells and pancreatic islets, respectively (7,8). IL-1 inhibits the function and induces apoptosis of β-cells (9) and has been implicated as a mediator of the β-cell destruction leading to type 1 diabetes (10). Exogenous addition of interleukin-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1 signaling, protects the β-cells from the deleterious effects of high glucose and leptin exposure (7,8).Both β-cell expression and serum levels of IL-1Ra are reduced in patients with type 2 diabetes (8,11). This inadequate IL-1 antagonism seems to be a genetic trait because genetic polymorphisms in the gene encoding IL-1Ra are associated with altered serum levels of IL-1Ra (12–15).We showed previously that 13 weeks of IL-1Ra treatment improved β-cell function and reduced A1C and markers of systemic inflammation in patients with type 2 diabetes (16). The aim of this 39-week follow-up study was to investigate the durability of these effects.     

Effects of Metformin With or Without Supplementation With Folate on Homocysteine Levels and Vascular Endothelium of Women With Polycystic Ovary Syndrome

OBJECTIVE

To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium.

RESEARCH DESIGN AND METHODS

A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 μg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated.

RESULTS

After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects.

CONCLUSIONS

Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism, ovarian dysfunction, and polycystic ovarian morphology. Young patients with PCOS but no additional risk factors for cardiovascular disease have a significant impairment of endothelial structure and function (1). In particular, when compared with control subjects matched for age and BMI, patients with PCOS had abnormal brachial artery diameter at baseline (BAD-B) and after reactive hyperemia (BAD-RH) and showed abnormal flow-mediated dilation (FMD) and an increased intima-media thickness (IMT) in their common carotid arteries (1). In addition, plasma concentrations of endothelin-1 (ET-1), a biochemical marker of endothelial function, were altered significantly (1).A subsequent clinical study showed that a 6-month course of biguanidine metformin improved these parameters of endothelial structure and function significantly, which suggested that metformin has a beneficial effect in reducing the long-term risk of cardiovascular disease in patients with PCOS (2).Moreover, in patients with type 2 diabetes, metformin has been demonstrated to increase serum levels of homocysteine (Hcy) (3–5). Increased concentrations of Hcy are a well-known risk factor for coronary heart disease and stroke (6). The acute effect of metformin on insulin sensitivity could either increase serum Hcy levels directly or induce malabsorption of vitamin B12 indirectly (7). Other unknown adjunctive mechanisms cannot be excluded.Based on these considerations, the aim of the present study was to evaluate whether the administration of metformin exerts any effect on serum Hcy levels in patients with PCOS and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium.     

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.