Enrolment criteria for diabetes cardiovascular outcome trials do not inform on generalizability to clinical practice: The case of glucagon-like peptide-1 receptor agonists.

AIM: To evaluate the generalizability of cardiovascular outcome trials (CVOTs) on glucagon-like peptide-1 receptor agonists (GLP-1RAs), we assessed what proportion of real-world patients with type 2 diabetes (T2D) constitute true CVOT-like populations. MATERIALS AND METHODS: We applied inclusion/exclusion (I/E) criteria of each GLP-1RA CVOT to a cross-sectional database of 281 380 T2D patients from Italian diabetes outpatient clinics. We calculated the proportion of patients eligible for each CVOT and compared their clinical characteristics with those of trial patients. In addition, we used a Bayesian network-based method to sample the greatest subsets of real-world patients yielding true CVOT-like populations. RESULTS: Between 98 725 and 124 164 T2D patients could be evaluated for CVOT eligibility. After excluding patients who were already on GLP-1RAs and applying I/E criteria, 35.8% of patients would be eligible for REWIND, 34.1% for PIONEER-6, 13.4% for EXSCEL, 10.1% for SUSTAIN-6, 9.5% for HARMONY and 9.4% for LEADER. Overall, 45.4% of patients could be eligible for at least one of the CVOTs. These patients, however, were extremely different to trial patients in most of the clinical characteristics, including demographics, concomitant medications and complications. The greatest CVOT-like subsets of real-world patients were 0.5% for SUSTAIN-6, 1.0% for EXSCEL, 1.2% for LEADER, 1.8% for PIONEER-6 and 7.9% for REWIND. CONCLUSIONS: A very small proportion of real-world patients constitute true CVOT-like populations. These findings question whether any meaningful information can be drawn from applying trial enrolment criteria to real-world T2D patients.

Effects of exenatide and metformin in combination on some adipocytokine levels: a comparison with metformin monotherapy.

The aim of this study was to evaluate the effects of exenatide on levels of serum adipocytokines and on ß-cell function. The study was conducted between 2008 and 2012. After a run-in period with metformin, 174 patients with type-2 diabetes were randomly distributed to either a group receiving exenatide at 10 µg twice daily, or a group receiving the placebo, for 12 months. We evaluated body mass index (BMI), blood pressure, glycemic control, lipid profile, fasting plasma insulin (FPI), HOMA-IR, HOMA-ß, fasting plasma proinsulin (FPPr), proinsulin : fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, omentin-1, and microalbuminuria. We used ELISA methods to assess the various parameters. Patients also underwent a combined euglycemic-hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. After 12 months, a combination of exenatide and metformin produced a better decrease in body mass, BMI, glycemic control, FPI, FPPr, FPPr/FPI ratio, HOMA-IR, and glucagon level. Treatment with exenatide + metformin was superior to the placebo + metformin in increasing HOMA-ß, C-peptide, and ß-cell function. Significant negative correlations were found between M value, an index of insulin sensitivity, and measured adipocytokines. In conclusion, the combination of exenatide + metformin plays a role in improving some adipocytokine levels, and is better than metformin alone. The significant negative correlation between M value and measured adipocytokines is another confirmation of the positive effects linked to the improvement in insulin sensitivity.

Olmesartan/amlodipine combination versus olmesartan or amlodipine monotherapies on blood pressure and insulin resistance in a sample of hypertensive patients.

Despite the wide range of antihypertensive medications, about 45.5% of treated patients fail to achieve the desired blood pressure (BP) target. This study evaluated the effects of an olmesartan/amlodipine single pill combination compared to olmesartan or amlodipine monotherapies on BP, lipid profile, insulin resistance, and insulin sensitivity parameters. Two hundred and seventy-six patients were randomly assigned to olmesartan (20 mg), amlodipine (10 mg), or a single pill containing olmesartan/amlodipine (5/20 mg) for 12 months. We evaluated the following parameters at the baseline, and after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), and lipid profile. At the baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess M value. Olmesartan/amlodipine gave a greater decrease in SBP and DPB compared to amlodipine and olmesartan at 6 (P < .05) and 12 months (P < .01). There was a decrease in FPG with olmesartan/amlodipine after 12 months compared to amlodipine (P < .05). Olmesartan/amlodipine decreased FPI and homeostasis model assessment index compared to both baseline (P < .05) and olmesartan and amlodipine (P < .05). Olmesartan/amlodipine gave an increase in M value, compared to baseline (P < .01) and to olmesartan monotherapy (P < .05) and amlodipine monotherapy (P < .01). In this randomized, double-blind clinical trial, olmesartan/amlodipine combination resulted more effective than olmesartan and amlodipine monotherapies in reducing BP, in improving insulin resistance, and insulin sensitivity parameters in patients with stage I essential hypertension. The combination also resulted in less peripheral edema.

Effect of Acarbose on Glycemic Variability in Patients with Poorly Controlled Type 2 Diabetes Mellitus Receiving Stable Background Therapy: A Placebo-Controlled Trial.

STUDY OBJECTIVE: To evaluate the effect of acarbose on glycemic control and glycemic variability, using a continuous glucose-monitoring system, in patients with type 2 diabetes mellitus who were not well controlled on metformin and vildagliptin therapy. DESIGN: Multicenter, randomized, double-blind, placebo-controlled study. SETTING: Clinical research units at three hospitals in Italy. PATIENTS: Fifty-three patients with type 2 diabetes who were taking stable dosages of metformin 850 mg 3 times/day and vildagliptin 50 mg twice/day for at least 3 months and who were not adequately controlled with these therapies. INTERVENTION: Patients were randomized to either placebo or acarbose 100 mg 3 times/day to be added to their metformin-vildagliptin regimen. MEASUREMENTS AND MAIN RESULTS: Glycemic excursions were assessed by using a continuous glucose-monitoring system for 1 week. Glycemic control was estimated as the mean blood glucose (MBG) level, the area under the glucose concentration-time curve for a glucose level above 70 mg/dl (AUC above 70) or 180 mg/dl (AUC above 180), and the percentage of time that the glucose level was above 70 mg/dl (T above 70) or 180 mg/dl (T above 180). Intraday glycemic variability was assessed by the standard deviation of the blood glucose level, the mean amplitude of glycemic excursions (MAGE), the M value, and continuous overlapping net glycemic action. Day-to-day glycemic variability was assessed as the mean of daily difference (MODD). The MBG level was ~20 mg/dl lower in the acarbose group than in the placebo group (p<0.05), particularly during the postprandial period. The AUC above 70 did not significantly differ between the two groups, whereas the AUC above 180 was ~40% lower in the acarbose group than in the placebo group during the daytime (p<0.01). The T above 180 was significantly higher in the placebo group than in the acarbose group (31% vs 8%, p<0.01. Moreover, the standard deviation and MAGE values were significantly lower in the acarbose group. The MODD value was not significantly changed in either group, and no significant differences were recorded between groups. All adverse events were mild in both groups, with only a significantly greater frequency of flatulence noted in the acarbose group (5% with acarbose vs 0.5% with placebo, p<0.05). CONCLUSION: The addition of acarbose to metformin and vildagliptin background therapy in patients with inadequately controlled type 2 diabetes decreased intraday glycemic variability, especially postprandial variability, but it was not associated with a significant change in interday glycemic variability.

Barnidipine or Lercanidipine on Echocardiographic Parameters in Hypertensive, Type 2 Diabetics with Left Ventricular Hypertrophy: A Randomized Clinical Trial.

The aim of this study was to evaluate the effects of lercanidipine or barnidipine on echocardiographic parameters, in hypertensive, type 2 diabetics with left ventricular hypertrophy. One hundred and forty-four patients were randomized to lercanidipine, 20 mg/day, or barnidipine, 20 mg/day, in addition to losartan, 100 mg/day, for 6 months. We evaluated: blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA(1c)), lipid profile, creatinine, estimated glomerular filtration rate (eGFR), sodium, potassium, and acid uric. Echocardiography was performed at baseline and after 6 months. Both lercanidipine and barnidipine decreased blood pressure. Left ventricular mass index was reduced to a greater extent with barnidipine + losartan. Interventricular septal thickness in diastole was reduced by barnidipine + losartan. Posterior wall thickness in diastole was decreased by both treatments, even if barnidipine + losartan were more effective. Ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction was increased by barnidipine + losartan, but not by lercanidipine + losartan. Finally, isovolumetric relaxation and time and left atrial volume index were reduced by barnidipine + losartan, while lercanidipine + losartan did not affect them. In conclusion, barnidipine + losartan provided a greater improvement of echocardiographic parameters compared to lercanidipine + losartan.

Comparison of the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus.

The aim of this study was to evaluate the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. We enrolled 148 normocholesterolemic patients with mild-to-moderate hypertension and type 2 diabetes mellitus. Patients were treated with barnidipine, 20 mg day(-1), in combination with losartan, 100 mg day(-1), or with telmisartan+hydrochlorothiazide, 80/12.5 mg day(-1), for 6 months. We assessed blood pressure (BP) on a monthly basis; additionally, blood samples were collected to assess, at baseline and after 6 months, the following parameters: fasting plasma glucose; glycated hemoglobin; fasting plasma insulin; HOMA index; and some adipocytokines, such as adiponectin (ADN), resistin, leptin, visfatin and vaspin. Patients were also subjected to an euglycemic hyperinsulinemic clamp to assess the M value and glucose infusion rate to ascertain their insulin sensitivity. One hundred and forty-one patients completed the study. The BP was reduced in both groups, although the reduction was greater with barnidipine+losartan (P<0.001 vs. baseline and P<0.01 vs. telmisartan+hydrochlorothiazide). Barnidipine+losartan increased the M value and glucose infusion rate during the euglycemic hyperinsulinemic clamp (P<0.05 vs. baseline and vs. telmisartan+hydrochlorothiazide). With respect to the levels of adipocytokines, ADN was increased (P<0.05), and resistin and leptin were reduced from baseline with barnidipine+losartan (P<0.05 vs. baseline), but they were not reduced with telmisartan+hydrochlorothiazide. Visfatin and vaspin were reduced by barnidipine+losartan compared with baseline (P<0.05). The adipocytokine levels obtained with barnidipine+losartan were significantly better than those obtained with telmisartan+hydrochlorothiazide (P<0.05 for all parameters). In addition to providing a greater BP reduction, barnidipine+losartan improved the insulin sensitivity, as assessed by an euglycemic hyperinsulinemic clamp, and improved some of the adipocytokines related to insulin resistance.

Different aspects of sartan + calcium antagonist association compared to the single therapy on inflammation and metabolic parameters in hypertensive patients.

This study aims to evaluate the effects of an angiotensin receptor blocker (ARB)/calcium channel blocker combination on blood pressure control, lipid profile, insulin sensitivity, and inflammation markers. We randomized 276 hypertensive patients to olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20/5 mg for 12 months. We evaluated the following: body weight, systolic and diastolic blood pressure, fasting plasma glucose, fasting plasma insulin (FPI), M value, lipid profile, adiponectin (ADN), high sensitivity C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor-1ß (MIP-1ß). Olmesartan/amlodipine combination better reduced blood pressure, FPI, homeostasis model assessment index, and increased M value and ADN compared to olmesartan and amlodipine monotherapies. Olmesartan/amlodipine significantly decreased Hs-CRP, MCP-1, and MIP-1ß. In this multicenter, randomized, double-blind, clinical study, ARB/calcium antagonist combination resulted to be more effective than single monotherapies in reducing blood pressure, in improving insulin sensitivity, and in reducing inflammation parameters in patients with stage I essential hypertension.

Results from a 12 months, randomized, clinical trial comparing an olmesartan/amlodipine single pill combination to olmesartan and amlodipine monotherapies on blood pressure and inflammation.

AIM: Hypertension affects nearly 1 in 3 adults in the United States, and it is an important modifiable risk factor for coronary artery disease, heart failure, renal failure, and stroke. The aim of this study was to evaluate the effects of a fixed-dose olmesartan/amlodipine combination on blood pressure control, lipid profile, insulin sensitivity, and inflammation compared to singles monotherapies. METHODS: We randomized 276 hypertensive patients to olmesartan 20 mg, amlodipine 10mg or a single pill containing a fixed-dose olmesartan/amlodipine combination 20/5mg for 12 months. We evaluated: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, omentin, chemerin, high sensitivity C-reactive protein (Hs-CRP). At baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess insulin sensitivity (M value). RESULTS: Olmesartan/amlodipine combination was more effective than amlodipine or olmesartan in reducing blood pressure. Olmesartan/amlodipine combination, but not amlodipine, decreased FPG after 12 months. Olmesartan/amlodipine combination better decreased FPI and HOMA index and increased M value compared to olmesartan and amlodipine monotherapies. Olmesartan/amlodipine significantly decreased chemerin and omentin compared to olmesartan and amlodipine. CONCLUSION: Other than to be more effective in reducing blood pressure, olmesartan/amlodipine single pill combination gave also a major increase of insulin sensitivity and a decrease of inflammatory markers compared to single monotherapies.

Variation of some inflammatory markers in hypertensive patients after 1 year of olmesartan/amlodipine single-pill combination compared with olmesartan or amlodipine monotherapies.

The purpose of this study was to evaluate a fixed olmesartan/amlodipine combination on blood pressure control, lipid profile, insulin sensitivity, and some inflammatory markers compared with single-drug monotherapy. A total of 276 hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg, or a single pill containing olmesartan/amlodipine combination 20/5 mg for 12 months. We evaluated the following at baseline and after 6 and 12 months: body weight, body mass index, systolic (SBP) and diastolic blood pressures (DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, tumor necrosis factor-α (TNF-α), retinol binding protein-4 (RBP-4), and interleukins 6 and 7 (IL-6 and IL-7). At baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp. The olmesartan/amlodipine combination provided a greater decrease of SBP and DPB compared with amlodipine and olmesartan monotherapies. The olmesartan/amlodipine combination decreased FPG after 12 months compared with amlodipine monotherapy. The combination decreased FPI and homeostasis model assessment index and increased M value both compared with baseline and with olmesartan and amlodipine monotherapies. Olmesartan/amlodipine decreased IL-7, but not IL-6, compared with single drug components. The olmesartan/amlodipine combination is effective and safe in reducing blood pressure and has some additive effects not shown by single drugs, such as an improvement of IL-7.

A randomized, double-blind, comparative therapy evaluating sitagliptin versus glibenclamide in type 2 diabetes patients already treated with pioglitazone and metformin: a 3-year study.

OBJECTIVES: This study evaluated if triple oral therapy can be useful in improving glycemic control compared with metformin monotherapy and with a metformin and pioglitazone combination. Furthermore, we also compared a triple metformin+pioglitazone+glibenclamide combination with a metformin+pioglitazone+sitagliptin one. SUBJECTS AND METHODS: After a 2-year run-in therapy-augmenting phase with metformin and pioglitazone, 453 overweight, type 2 diabetes patients were randomized to 1 year of sitagliptin versus 1 year of glibenclamide to evaluate, as the primary outcome, the variation of ß-cell function both in a fasting state and after an euglycemic hyperinsulinemic and hyperglycemic clamp. As secondary outcomes we evaluated glycemic control and insulin resistance. RESULTS: Both the triple therapy combinations were more effective in reducing glycated hemoglobin compared with metformin monotherapy and with dual therapy metformin+pioglitazone. Fasting plasma insulin level and the homeostasis model assessment insulin resistance index were significantly increased by triple therapy with glibenclamide and decreased by the one with sitagliptin. Although sitagliptin did not change the homeostasis model assessment ß-function index, this value was significantly increased by glibenclamide. The fasting plasma proinsulin level was decreased by sitagliptin. Triple therapy with sitagliptin greatly improved ß-cell function measures compared with the glibenclamide one and also compared with metformin monotherapy and with the metformin+pioglitazone combination. CONCLUSIONS: Dual combination therapy is more effective than monotherapy in improving glycemic control. When double therapy is not enough to reach an adequate glycemic control, sitagliptin should be preferred to glibenclamide as the third agent because of its positive effect on ß-cells.

Variations in inflammatory biomarkers following the addition of sitagliptin in patients with type 2 diabetes not controlled with metformin.

OBJECTIVE: The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation remain obscure. The aim of this study was to evaluate the effects of the addition of sitagliptin on the ß-cell function and various inflammatory biomarkers in type 2 diabetic patients. METHODS: After a run-in period of taking metformin, 178 diabetic patients with poor glycemic control were randomized to take sitagliptin at a dose of 100 mg once a day or a placebo in addition to metformin for 12 months. We evaluated the following parameters at three, six, nine and twelve months: body mass index (BMI), glycemic control, the homeostasis model assessment insulin resistance index (HOMA-IR), the homeostasis model assessment ß-cell function index (HOMA-ß), the proinsulin/fasting plasma insulin ratio (Pr/FPI ratio) and the levels of fasting plasma insulin (FPI), fasting plasma proinsulin (FPPr), C-peptide, glucagon, resistin, vaspin, omentin-1 and tumor necrosis factor-α (TNF-α). Before and twelve months after the addition of sitagliptin, the patients underwent combined euglycemic hyperinsulinemic and hyperglycemic clamping with subsequent arginine stimulation to assess insulin sensitivity and secretion. RESULTS: Treatment with sitagliptin + metformin was more effective than placebo + metformin in improving glycemic control, the HOMA-IR and the glucagon level and increasing the HOMA-ß and all ß-cell measurements after combined euglycemic hyperinsulinemic and hyperglycemic clamping with subsequent arginine stimulation. Regarding inflammatory biomarkers, sitagliptin + metformin more effectively reduced the levels of resistin, vaspin and omentin-1 than placebo + metformin. CONCLUSION: When treatment with metformin alone is not adequate for obtaining glycemic control, the addition of sitagliptin can be considered due to its actions in preserving the ß-cell function and reducing the levels of biomarkers of inflammation.

Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies.

BACKGROUND: Hypertension is known to be one of the main risk factors for cardiovascular disease. OBJECTIVES: To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL-8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp. RESULTS: Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy. CONCLUSIONS: Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers.

Variation in inflammatory markers and glycemic parameters after 12 months of exenatide plus metformin treatment compared with metformin alone: a randomized placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the effects of exenatide on some inflammatory markers and to quantify the effect of exenatide on ß-cell function. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Seven hospitals in Italy. PATIENTS: A total of 174 white treatment-naive adults with type 2 diabetes and a glycated hemoglobin (HbA(1c)) level higher than 7.5%. INTERVENTION: After an open-label run-in period of 8 ± 2 months with metformin, patients were randomized to take exenatide (5 µg twice/day for the first 4 weeks, 10 µg twice/day thereafter) or a placebo volume equivalent for 12 months. MEASUREMENTS AND MAIN RESULTS: Body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index, homeostasis model assessment ß-cell function index (HOMA-ß), fasting plasma proinsulin (FPPr), proinsulin-to-fasting plasma insulin ratio (Pr:FPI ratio), C-peptide, glucagon, vaspin, chemerin, and resistin were evaluated at baseline, at randomization, and at 3, 6, 9, and 12 months. Patients also underwent a combined euglycemic, hyperinsulinemic, and hyperglycemic clamp with subsequent arginine stimulation to assess insulin sensitivity and insulin secretion. HbA(1c) was significantly improved with exenatide plus metformin compared with placebo plus metformin. Exenatide plus metformin was also significantly more effective than placebo plus metformin in increasing HOMA-ß C-peptide, and all measures of ß-cell function after the euglycemic hyperinsulinemic and hyperglycemic clamp. We observed that exenatide plus metformin also reduced resistin compared with placebo plus metformin. No variations in vaspin and chemerin were noted in group-to-group comparisons. We observed a significant correlation between M value increase, an index of insulin sensitivity, and a decrease in inflammatory parameters in the exenatide plus metformin group. CONCLUSIONS: The combination of exenatide plus metformin was more effective than metformin alone in improving glycemic control, ß-cell function, and inflammatory parameters.

Effects of a combination of sitagliptin plus metformin vs metformin monotherapy on glycemic control, ß-cell function and insulin resistance in type 2 diabetic patients.

AIMS: To evaluate the impact on glycemic control, insulin resistance, and insulin secretion of sitagliptin+metformin compared to metformin in type 2 diabetic patients. METHODS: Patients were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to sitaglipin 100 mg or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-ß, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, adiponectin (ADN), and high sensitivity-C reactive protein (Hs-CRP). Before, and after 12 months since the addition of sitagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. RESULTS: Both treatments similarly decreased body weight, and BMI; on the other hand, they both improved glycemic control, glucagon and HOMA-IR, but sitagliptin+metformin were more effective in reducing these parameters. Sitagliptin+metformin, but not placebo+metformin, decreased FPPr, FPPR/FPI ratio, and increased C-peptide values, even if no differences between the groups were recorded. Sitaglitin+metformin gave also a greater increase of HOMA-ß, M value, C-peptide response to arginine and disposition index compared to placebo+metformin group. CONCLUSIONS: Other than improving glycemic control, sitagliptin+metformin also improved ß-cell function better than metformin alone.

A randomized, double-blind, placebo-controlled trial evaluating sitagliptin action on insulin resistance parameters and ß-cell function.

AIM: To evaluate the impact on glycemic control, insulin secretion and on insulin resistance of a sitagliptin + metformin combination compared to metformin monotherapy in type 2 diabetic, naïve to treatment, patients. MATERIALS AND METHODS: A total of 178 Caucasian type 2 diabetic patients were randomized to take sitagliptin 100 mg once a day or placebo in addition to previously taken metformin, for 12 months. The authors evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-ß, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, and chemerin. Before and 12 months after the addition of sitagliptin, patients underwent tests to assess insulin sensitivity and insulin secretion. RESULTS: Sitagliptin + metformin gave a better decrease of glycemic control, HOMA-IR and glucagon levels compared to placebo + metformin; sitagliptin + metformin also better increased HOMA-ß and all ß-cell measurements recorded after the clamp. Regarding adipocytokines, sitagliptin + metformin better reduced RBP-4, visfatin and chemerin levels, compared to placebo + metformin. CONCLUSION: When metformin alone is not enough to reach an adequate glycemic control, sitagliptin can be a valid option, because of its effects in reducing insulin resistance and in preserving ß-cell function.

Exenatide or glimepiride added to metformin on metabolic control and on insulin resistance in type 2 diabetic patients.

The aim of this study was to evaluate the effect of exenatide compared to glimepiride on body weight, glycemic control and insulin resistance in type 2 diabetic patients taking metformin. One hundred and eleven patients with uncontrolled type 2 diabetes mellitus and intolerant to metformin at the highest dosages (2500-3000 mg/day) were enrolled in this study. Patients were randomized to receive exenatide 5 µg twice a day or glimepiride 1mg three times a day and titrated after 1 month to exenatide 10 µg twice a day or glimepiride 2mg three times a day for 12 months in a randomized, single-blind, controlled study. We evaluated at the baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c), glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR) index, adiponectin, tumor necrosis factor-α, and high sensitivity-C reactive protein. Both treatments gave a similar improvement of glycemic control, without any differences between the two groups. Only exenatide gave a decrease of BMI, insulin resistance parameters such as fasting plasma insulin, HOMA-IR, and adiponectin and a decrease of inflammatory parameters such as tumor necrosis factor-α, and high sensitivity-C reactive protein. Furthermore, the values obtained with exenatide were significantly better than the values recorded with glimepiride. We can conclude that exenatide was better than glimepiride in improving insulin resistance and inflammatory state. Furthermore, adiponectin increase, and tumor necrosis factor-α reduction seem to be related to weight loss obtained with exenatide.

Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients.

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA(1c), FPG, and PPG and a significant increase of homeostasis model assessment beta-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-alpha with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-alpha values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-alpha decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA(1c), FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if sitagliptin produced a better protection of beta-cell function.