Aim:The study aim was to evaluate the efficacy and safety of initial combination therapy with saxagliptin þ metformin vs. saxagliptin or metformin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multicentre, randomized, double-blind, active-controlled phase 3 trial, 1306 treatment-naïve patients with T2D !18 to 77 years, glycosylated haemoglobin (HbA1c) !8 to 12%, fasting C-peptide concentration !1.0 ng/ml, body mass index 40 kg/m 2 were randomized to receive saxagliptin 5 mg þ metformin 500 mg, saxagliptin 10 mg þ metformin 500 mg, saxagliptin 10 mg þ placebo or metformin 500 mg þ placebo for 24 weeks. From weeks 1-5, metformin was uptitrated in 500-mg/day increments to 2000 mg/day maximum in the saxagliptin 5 mg þ metformin, saxagliptin 10 mg þ metformin and metformin þ placebo treatment groups. The main outcome measure was HbA1c change from baseline to week 24. Selected secondary outcomes included change from baseline to week 24 in fasting plasma glucose (FPG), proportion of patients achieving HbA1c <7% and postprandial glucose area under the curve (PPG-AUC).Results: At 24 weeks, saxagliptin 5 mg þ metformin and saxagliptin 10 mg þ metformin demonstrated statistically significant adjusted mean decreases vs. saxagliptin 10 mg and metformin monotherapies in HbA1c (À2.5 and À2.5% vs. À1.7 and À2.0%, all p < 0.0001 vs. monotherapy) and FPG (À60 and À62 mg/dl vs. À31 and À47 mg/dl, both p < 0.0001 vs. saxagliptin 10 mg; p ¼ 0.0002 saxagliptin 5 mg þ metformin vs. metformin; p < 0.0001 saxagliptin 10 mg þ metformin vs. metformin). Proportion of patients achieving an HbA1c <7% was 60.3 and 59.7%, respectively, for saxagliptin 5 mg þ metformin and saxagliptin 10 mg þ metformin (all p < 0.0001 vs. monotherapy). PPG-AUC was significantly reduced [À21 080 mgÁmin/dl (saxagliptin 5 mg þ metformin) and À21 336 mgÁmin/dl (saxagliptin 10 mg þ metformin) vs. À16 054 mgÁmin/dl (saxagliptin 10 mg) and À15 005 mgÁmin/dl (metformin), all p < 0.0001 vs. monotherapy]. Adverse event occurrence was similar across all groups. Hypoglycaemic events were infrequent. Conclusion: Saxagliptin þ metformin as initial therapy led to statistically significant improvements compared with either treatment alone across key glycaemic parameters with a tolerability profile similar to the monotherapy components.

This prospective study gives evidence of an anti-inflammatory and antiatherogenic effect of pioglitazone versus glimepiride. This effect is independent from blood glucose control and may be attributed to peroxisome proliferator-activated receptor gamma activation.

C-reactive protein (CRP) is a liver-derived pattern recognition molecule that is increased in inflammatory states. It rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. Since cardiovascular disease is at least in part an inflammatory process, CRP has been investigated in the context of arteriosclerosis and subsequent vascular disorders. Based on multiple epidemiological and intervention studies, minor CRP elevation [high-sensitivity CRP (hsCRP)] has been shown to be associated with future major cardiovascular risk (hsCRP:<1 mg/L=low risk; 1-3 mg/L=intermediate risk; 3-10 mg/L=high risk; >10 mg/L=unspecific elevation). It is recommended by the American Heart Association that patients at intermediate or high risk of coronary heart disease may benefit from measurement of hsCRP with regard to their individual risk prediction. Elevation of hsCRP is associated with increased risk of type 2 diabetes development in patients with all levels of metabolic syndrome. In type 1 and type 2 diabetes mellitus, hemoglobin A1c significantly correlates with hsCRP levels and future cardiovascular risk. Also, hsCRP levels increase with the stage of beta-cell dysfunction and insulin resistance. Non-diabetes drugs that have been shown to reduce hsCRP concentrations include aspirin, statins, cyclooxygenase-2 inhibitors, and fibrates. Recent intervention studies have also demonstrated the distinct efficacy of different anti-diabetes treatments on a variety of cardiovascular risk markers. Intensive insulin therapy may reduce inflammation, but this effect may be influenced by the degree of weight gain. Treatment with peroxisome proliferator-activated receptor gamma has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparator studies. Since this effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a classspecific effect. Whether these findings translate into a reduction of overall cardiovascular mortality will soon be shown by the currently running thiazolidinedione outcome studies. Positive results in these trials will further strengthen the value and acceptance of hsCRP, which is recommended as a predictive laboratory marker for cardiovascular disease risk also in patients with diabetes mellitus.

OBJECTIVE -In later stages of type 2 diabetes, proinsulin and proinsulin-like molecules are secreted in increasing amounts with insulin. A recently introduced chemiluminescence assay is able to detect the uncleaved "intact" proinsulin and differentiate it from proinsulin-like molecules. This investigation explored the predictive value of intact proinsulin as an insulin resistance marker.RESEARCH DESIGN AND METHODS -In total, 48 patients with type 2 diabetes (20 women and 28 men, aged 60 Ϯ 9 years [means Ϯ SD], diabetes duration 5.1 Ϯ 3.8 years, BMI 31.2 Ϯ 4.8 kg/m 2 , and HbA 1c 6.9 Ϯ 1.2%) were studied by means of an intravenous glucose tolerance test and determination of fasting values of intact proinsulin, insulin, resistin, adiponectin, and glucose. Insulin resistance was determined by means of minimal model analysis (MMA) (as the gold standard) and homeostatis model assessment (HOMA).RESULTS -There was a significant correlation between intact proinsulin values and insulin resistance (MMA P Ͻ 0.05 and HOMA P Ͻ 0.01). Elevation of intact proinsulin values above the reference range (Ͼ10 pmmol/l) showed a very high specificity (MMA 100% and HOMA 92.9%) and a moderate sensitivity (MMA 48.6% and HOMA 47.1%) as marker for insulin resistance. Adiponectin values were slightly lower in the insulin resistant group, but no correlation to insulin resistance could be detected for resisitin in the cross-sectional design.CONCLUSIONS -Elevated intact proinsulin seems to indicate an advanced stage of ␤-cell exhaustion and is a highly specific marker for insulin resistance. It might be used as arbitrary marker for the therapeutic decision between secretagogue, sensitizer, or insulin therapy in type 2 diabetes. Diabetes Care 27:682-687, 2004I n the past decades, insulin resistance and cardiovascular disease in type 2 diabetic patients have been linked to hyperinsulinemia as an independent risk factor (1-3). However, many studies were not able to confirm the negative impact of insulin on cardiovascular risk (4 -6). One explanation for this overall confusing data may be found in the cross-reactivity between insulin and its precursor molecule, proinsulin, which was present in many assays for insulin measurement. Relatively few and contradicting data are available on the relation of proinsulin to insulin resistance, cardiovascular disease, and atherosclerosis (6 -8). Prospective studies have demonstrated that the determination of the proinsulin-to-insulin ratio may be used to predict deterioration in glucose tolerance (9,10). Des31,32 proinsulin is a commonly secreted by-product of ␤-cell secretion in later stages of type 2 diabetes and is involved in the development of macrovascular disease, whereas des64,65 is usually not present in the circulation (11,12).Assays that try to differentiate between intact proinsulin and the specific and unspecific proinsulin derivatives were used in cross-sectional and prospective follow-up studies to investigate the real relation of immunoreactive insulin with coronary risk and to explore and con...

Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

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Abstract19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg