Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes

Chronic inflammation contributes to insulin resistance and type 2 diabetes mellitus (T2DM). We investigated whether treatment with salsalate, an anti-inflammatory medication, improves glycemia in a group of newly diagnosed drug-naïve patients with T2DM. The study was a randomized, double-blind, placebo-controlled trial. Diagnosis of T2DM was made within 2 months of enrollment, and participants had not received any anti-glycemic agent. Sixty adults were randomized to receive salsalate (3 g/day) or placebo for 12 weeks. Fasting plasma glucose and insulin, glucose 2 h after 75 g oral glucose, HbA1C, lipid profile, HOMA-IR, and HOMA-B were determined before and after treatment. Salsalate reduced fasting glucose from 6.3 ± 0.2 mmol/l to 5.4 ± 0.2 mmol/l (P < 0.01) and TG from 1.9 ± 0.2 mmol/l to 1.5 ± 0.2 mmol/l (P < 0.03). Fasting insulin levels were increased in the salsalate group from 18.8 ± 1.6 to 21.6 ± 3.9, while they decreased in the placebo group. HbA1c rose in the placebo group from 6.2% ± 0.2 to 7.9% ± 1.1 mmol/mol, but decreased in the intervention group from 6.1% ± 0.5 to 5.6% ± 0.2 mmol/mol (P < 0.04 for between-group comparison). HOMA-IR did not change but HOMA-B increased ~1.7-fold (P = 0.06) in the salsalate group. The results show that salsalate is effective in improving glycemic control in newly diagnosed naïve patients with T2DM. The optimal duration of treatment with salsalate and sustainability of its effect requires further study (IRCT138709011465N1).     

Predictors of glycemic control after decline of insulin therapy by patients with type 2 diabetes

AimDecline of insulin therapy by patients is common but poorly investigated. We conducted this study to determine patient and treatment characteristics predictive of glycemic control after declining clinician recommendation to initiate insulin therapy.MethodsWe retrospectively studied adults with type 2 diabetes mellitus treated at two academic medical centers between 1993 and 2014 who declined their healthcare provider recommendation to initiate insulin.ResultsIn a multivariable analysis of 300 study patients adjusted for demographics, comorbidities and clustering within providers, higher baseline HbA1c (OR 1.85; 95% CI 1.40 to 2.39; p < 0.001) and lifestyle changes (OR 8.39; 95% CI 3.26 to 21.55; p < 0.001) were associated with greater, while non-adherence to diabetes medications (OR 0.014; 95% CI 0.0025 to 0.085; p < 0.001) and discontinuation of a non-insulin diabetes medication (OR 0.30; 95% CI 0.11 to 0.80; p = 0.016) were associated with lower probability of HbA1c decrease after declining insulin therapy.ConclusionWe identified patient characteristics and treatment strategies associated with success and failure of glycemic control after insulin therapy decline by the patient. This information can assist in selection of optimal therapeutic approaches for these individuals.     

Sitagliptin added to voglibose monotherapy improves glycemic control in patients with type 2 diabetes

Aims/Introduction

Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized study assessed the efficacy and safety of the addition of sitagliptin to ongoing voglibose monotherapy (0.2–0.3 mg three times daily) in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control (glycated hemoglobin ≥6.9% and <10.5%).

Materials and Methods

The present study had an initial 12‐week, double‐blind treatment period in which patients were randomized (1:1) to sitagliptin 50 mg/day (n = 70) or placebo (n = 63), followed by a 40‐week, open‐label treatment period during which all patients received sitagliptin 50 mg/day, that could have been increased to 100 mg/day for patients meeting predefined glycemic criteria.

Results

After 12 weeks, treatment with sitagliptin resulted in placebo‐subtracted mean changes from baseline in glycated hemoglobin (the primary end‐point), fasting plasma glucose and 2‐h postmeal glucose of –0.9%, –22.5 mg/dL and –51.3 mg/dL, respectively (all, P < 0.001). During the double‐blind period, adverse experiences were reported with similar frequency in both treatment groups, and the occurrences of hypoglycemia and gastrointestinal adverse experiences were low. In the open‐label period, sustained improvements in glycemic parameters were observed with sitagliptin treatment, and sitagliptin was generally well tolerated.

Conclusions

Sitagliptin added on to ongoing voglibose monotherapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control. This trial was registered with ClinicalTrails.gov (no. NCT00837577).     

Combination therapy with insulin and oral agents: optimizing glycemic control in patients with type 2 diabetes mellitus

The United Kingdom Prospective Diabetes Study (UKPDS) showed that tight glycemic control with any of several therapeutic regimens has the potential to significantly reduce the risk for long-term microvascular complications of type 2 diabetes. An important question that remains to be answered is what is the best approach to optimizing glycemic control in patients with this disease. This article reviews results of studies in which insulin was used alone or in combination with oral antidiabetic agents for treatment of patients with type 2 diabetes. Analysis of comparative studies (13 in insulin-naive and 26 in previously insulin-treated patients) showed that combination therapy involving one to two insulin injections per day plus oral therapy is usually more effective than insulin monotherapy for achieving and maintaining glycemic control. Combination treatment for type 2 diabetes can be significantly improved by newly developed preparations that lack the major limitations of older products. Once-daily administration of isophane insulin (NPH insulin) is limited by a 15-18-h duration of action and a peak effect that occurs about 6 h after injection. Insulin glargine, a new insulin analogue developed using recombinant DNA technology, has a flat pharmacodynamic profile and a 24-h duration of action. Results from a recent comparative study indicate that insulin glargine plus oral therapy may provide better post-dinner glucose control as well as less symptomatic and nocturnal hypoglycemia than oral therapy combined with NPH insulin. The studies reviewed in the present article support the conclusion that combination therapy with insulin glargine combined with one or more oral antidiabetic agents may be the treatment of choice for achieving glycemic control in patients with type 2 diabetes.     

Insulin therapy improves endothelial function in type 2 diabetes

A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent [acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58+/-2 years, body mass index 28.5+/-0.6 kg/m(2), and fasting plasma glucose 229+/-11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 microg/min) were significantly blunted in type 2 diabetic patients (7.5+/-0.7 mL x dL(-1) x min(-1)) compared with normal subjects (11.6+/-0.9 mL x dL(-1) x min(-1), P<0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8+/-1.6 mL x dL(-1) x min(-1) (P<0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.     

Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: An observational study in clinical practice

This open-label, prospective study evaluated the effectiveness and safety of empagliflozin as add-on therapy in inadequately controlled type 2 diabetes (T2D) patients (glycated haemoglobin [HbA1c], 7.5-12%) who were already using three other types of orally active antidiabetic agents. A total of 268 T2D patients were enrolled and divided into two groups, empagliflozin (EMPA 25 mg/d, n = 142) or insulin glargine (INS, n = 126), respectively. After the treatment period of 24 weeks, HbA1c and fasting plasma glucose (FPG) were significantly reduced (HbA1c, P = 0.004; FPG, P = 0.008, respectively) in the EMPA group compared to the INS group. Also, EMPA treatment evoked a significant reduction in body weight (P < 0.001) and systolic blood pressure (P = 0.017) compared to the INS group. Hypoglycaemic adverse events were significantly higher in the INS group compared to the EMPA group (P = 0.001). In conclusion, this study demonstrated that a regimen comprising four different orally active antidiabetic agents, including EMPA, was effective and safe as a therapeutic strategy for treating T2D patients for glycaemic control and improvement of other cardiovascular and metabolic indices.     

Insulin glargine improves glycemic control and health-related quality of life in type 1 diabetes

Background and aimsGlargine improves glucose control and reduces the risk of nocturnal hypoglycemia compared with neutral protamine Hagedorn (NPH) insulin. To date, only one study has measured the effects of glargine on health-related quality of life (HRQL); the aim of this study was therefore to confirm the beneficial effects of glargine on disease-specific HRQL in type 1 diabetes.Methods and resultsForty-seven patients (mean age, 46 range, 25–74; males, 54%) with diabetes of at least 1-year duration, and with suboptimal glucose control under intensive insulin treatment (IIT), were switched from NPH to glargine. Forty patients maintained on IIT were used as controls. Diabetes-related HRQL was assessed using the Well-being Enquiry for Diabetics (WED), before and after a 6- to 8-month switch to glargine. An 11-item questionnaire based upon diabetes-specific issues was used to assess treatment satisfaction and perceived changes after switching.On glargine, the mean glycosylated hemoglobin decreased by 0.7% (treatment vs. baseline, P < 0.0001) and several WED scores improved (discomfort, P = 0.020; impact, P = 0.0002; total score, P = 0.0005). WED changes were associated with a lower perceived risk of hypoglycemia and less problems in daily life on glargine.ConclusionsThe results of this study show that the beneficial effect of glargine is not limited to better metabolic control; the burden of type 1 diabetes mellitus on everyday life is also reduced.     

Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial

BACKGROUND: The long-term benefits of good glycemic control are well established. The aim of this proof-of-concept study was to determine whether glycemic control can be improved in patients with type 2 diabetes mellitus with suboptimal glycemic control, despite therapeutic dosages of oral antihyperglycemic agents (OHAs), by the addition of preprandial inhaled insulin (INH). METHODS: Sixty-eight patients with inadequately controlled type 2 diabetes mellitus (glycosylated hemoglobin, 8.1%-11.9%), despite therapy with a sulfonylurea and/or metformin, were randomized to receive INH in addition to their prestudy OHA therapy (INH + OHA group, n = 32) or to continue taking their prestudy OHA alone for 12 weeks (OHA group, n = 36). Premeal INH doses were delivered in 1 to 2 inhalations of 1-mg or 3-mg doses (equivalent to 3 IU and 9 IU, respectively, of subcutaneously injected regular insulin). RESULTS: At week 12, there was a significantly greater reduction in glycosylated hemoglobin for the INH + OHA cohort (mean reduction, -2.3%) compared with the OHA-only cohort (mean reduction, -0.1%, P<.001). Eleven patients (34%) receiving INH + OHA achieved glycosylated hemoglobin values of less than 7%, compared with none taking OHAs only. Fasting plasma glucose improved significantly more in the INH + OHA group compared with the OHA-only group (-60.69 mg/dL (-3.37 mmol/L] greater reduction, P<.001), and the postprandial increase in glucose was significantly lower in those patients receiving INH + OHA (P =.02). There was 1 report of severe hypoglycemia in the INH + OHA group (home blood glucose, 54 mg/dL [3.0 mmol/L]) and a greater increase in body weight. Pulmonary function was unchanged in both groups. CONCLUSION: The addition of preprandial INH to existing OHAs improves glycemic control without the need for injections in patients with type 2 diabetes mellitus failing to achieve satisfactory control with OHAs alone.     

Postprandial glycemic control with biphasic insulin aspart in patients with type 1 diabetes

We sought to investigate the ability of biphasic insulin aspart 30 (BIAsp 30) to control postprandial hyperglycemia and hyperlipidemia in a meal-test comparison with biphasic human insulin 30 (BHI 30). In this randomised crossover trial, 50 patients with type 1 diabetes (mean age, 35.7 +/- 9.4 years; body mass index [BMI], 24.0 +/- 2.6 kg/m(2); HbA(1c), 8.6% +/- 1.1%) were studied on 3 separate days, where the following treatments were given in random order: BIAsp 30 injected immediately before a standard breakfast, BHI 30 injected 30 minutes before breakfast (BHI 30(t=-30)), and BHI 30 injected immediately before breakfast (BHI 30(t=0)). The dose was 0.40 U/kg for all 3 treatments. BIAsp 30 reduced the area under the baseline adjusted 4-hour postprandial serum glucose curve (AUC(0-4h)) by 23% compared with BHI 30(t=0) (P <.0001) and by 9% compared with BHI 30(t=-30) (P =.013). Maximum serum glucose concentration (C(max)) was lower for BIAsp 30 compared with BHI 30(t=0) (14.0 +/- 2.4 v 16.5 +/- 2.8 mmol/L, P <.0001), and time to maximal serum glucose concentration (t(max)) was approximately 20 minutes shorter for BIAsp 30, irrespective of timing of BHI 30 injection (P <.0001). There were no significant differences among the 3 treatments with respect to postprandial levels of free fatty acids or triglycerides. The pharmacokinetic results were consistent with the above observations, ie, significantly larger insulin AUC(0-4h), higher C(max) and shorter t(max) were observed for BIAsp 30 compared with BHI 30, irrespective of timing of BHI 30 injection. We conclude that postprandial glycemic control was more effective with BIAsp 30 than with BHI 30, irrespective of timing of BHI 30 injection.     

Rosiglitazone reduces liver fat and insulin requirements and improves hepatic insulin sensitivity and glycemic control in patients with type 2 diabetes requiring high insulin doses

BACKGROUND: Liver fat is an important determinant of insulin requirements during insulin therapy. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists reduce liver fat. We therefore hypothesized that type 2 diabetic patients using exceptionally high doses of insulin might respond well to addition of a PPARgamma agonist. METHODS: We determined the effect of the PPARgamma agonist rosiglitazone on liver fat and directly measured hepatic insulin sensitivity in 14 patients with type 2 diabetes (aged 51 +/- 3 yr, body mass index 36.7 +/- 1.1 kg/m2), who were poorly controlled (glycosylated hemoglobin A 1c (HbA 1c) 8.9 +/- 0.4%) despite using high doses of insulin (218 +/- 22 IU/d) in combination with metformin. Liver fat content (1H-magnetic resonance spectroscopy), hepatic insulin sensitivity [6 h hyperinsulinemic euglycemic clamp (insulin 0.3 mU/kg.min) combined with [3-3H]glucose], body composition (magnetic resonance imaging), substrate oxidation rates (indirect calorimetry), clinical parameters, and liver enzymes were measured before and after rosiglitazone treatment (8 mg/d) for 8 months. RESULTS: During rosiglitazone, HbA(1c) decreased from 8.9 +/- 0.4% to 7.8 +/- 0.3% (P = 0.007) and insulin requirements from 218 +/- 22 to 129 +/- 20 IU/d (P = 0.002). Liver fat content decreased by 46 +/- 9% from 20 +/- 3% to 11 +/- 3% (P = 0.0002). Hepatic insulin sensitivity, measured from the percent suppression of endogenous glucose production by insulin, increased from -40 +/- 7% to -89 +/- 12% (P = 0.001). The percent change in liver fat correlated with the percent decrease in HbA 1c (r = 0.53, P = 0.06), insulin dose (r = 0.66, P = 0.014), and suppression of endogenous glucose production (r = 0.76, P = 0.003). CONCLUSIONS: Our results suggest that rosiglitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses. The mechanism is likely to involve reduced liver fat and enhanced hepatic insulin sensitivity.     

Short-term intensive glycemic control improves vibratory sensation in type 2 diabetes

Strict long-term glycemic control has been reported to prevent or improve diabetic peripheral neuropathy, but the effects of short-term glycemic control have not been clarified in patients with type 2 diabetes. To investigate reversibility of impaired vibratory sensation by short-term glycemic control, we used the TM31 liminometer and C64 tuning fork methods to measure peripheral neuropathy. Thirty-one type 2 diabetes patients with poor glycemic control (HbA1c: 10.8+/-0.4%, mean+/-S.E.M., range from 7.9% to 16.2%) were administered strict glycemic control. Vibratory sensation before and after short-term glycemic control was evaluated, and the metabolic profile including plasma glucose, HbA1c, total cholesterol, HDL cholesterol, triglyceride, and free fatty acid (FFA) was measured. After 20.0+/-2.1 days of strict glycemic control, vibratory sensation improved significantly in both upper and lower extremities, assessed by TM31 liminometer and C64 tuning fork. Along with the improved glycemic control, lipid metabolism (total cholesterol, triglyceride and FFA) was significantly improved. Thus, short-term intensive glycemic control can improve vibratory sensation, metabolic changes in glucose and lipid metabolism being the factors responsible for improved of peripheral nerve function.     

Comorbidity and glycemic control in patients with type 2 diabetes

BACKGROUND: It is commonly believed that good glycemic control is hard to achieve in patients with diabetes mellitus and concurrent chronic illnesses. OBJECTIVE: To determine the impact of comorbidity on glycemic control at presentation and subsequent follow-up in patients with type 2 diabetes. METHODS: We studied 654 consecutive patients who presented to a diabetes clinic in 1997. Comorbidity was rated using the Chronic Disease Score (CDS) index, which is a validated, weighted score that takes into account the patient's age, sex, and classes of medications. Univariate and multivariate linear regressions were used to determine the contribution of age, body mass index (calculated as weight in kilograms divided by the square of height in meters), diabetes duration, type of therapy, and CDS to initial hemoglobin A(1c) (HbA(1c)) level. A similar analysis was performed for the 169 patients with follow-up HbA(1c) levels 6 months after presentation. RESULTS: Patients were 90% African American, and 66% female, with average age of 53 years. Average diabetes duration was 5 years; body mass index, 33; HbA(1c) level, 8.8%; and CDS, 1121 (range, 232-7953). At presentation, patients with higher CDSs tended to be older and to have a lower HbA(1c) level, but multivariate linear regression showed that receiving pharmacological therapy, younger age, and having a lower C-peptide level were the only significant contributors to HbA(1c) level. In the 169 follow-up patients, presenting characteristics were not significantly different from those of the full cohort: average initial HbA(1c) level was 8.8%; CDS, 1073. Their HbA(1c) level at 6 months averaged 7.5% and the CDS had no significant impact on their follow-up HbA(1c) level. CONCLUSION: Comorbidity does not appear to limit achievement of good glycemic control in patients with type 2 diabetes.     

Effects of basal and premixed insulin on glycemic control in type 2 diabetes patients based on multicenter prospective real‐world data

BackgroundTo investigate the different efficacies of glycemic control between basal and premixed insulin in participants with type 2 diabetes (T2DM) when non‐insulin medications fail to reach treatment targets.MethodsThis was a prospective, large‐scale, real‐world study at 10 diabetes centers in China. Between June 2017 and June 2021, we enrolled 1104 T2DM participants initiated with either once‐daily basal insulin or twice‐daily premixed insulin when the glycosylated hemoglobin (HbA1c) control target was not met after at least two non‐insulin agents were administered. A Cox proportional hazards regression model adjusting for multiple influencing factors was performed to compare the different effects of basal and premixed insulin on reaching the HbA1c control target.ResultsAt baseline, basal insulin (57.3%) was prescribed more frequently than premixed insulin (42.7%). Patients with a higher body mass index (BMI) or higher HbA1c levels were more likely to receive premixed insulin than basal insulin (both p < 0.001). After a median follow‐up of 12.0 months, compared to those with premixed insulin, the hazard ratio for reaching the HbA1c target to those with basal insulin was 1.10 (95% CI, 0.92‐1.31; p = 0.29) after adjustment, and less weight gain was observed in those with basal insulin than with premixed insulin (percentage change of BMI from baseline −0.37[5.50]% vs 3.40[6.73]%, p < 0.0001).ConclusionsIn this real‐world study, once‐daily basal insulin was more frequently prescribed and had similar glycemic control effects but less weight gain compared with twice‐daily premixed insulin when used as initiation therapy for those in whom glycemic control with non‐insulin medications failed.     

Differences in inpatient glycemic control and response to subcutaneous insulin therapy between medicine and surgery patients with type 2 diabetes

ObjectiveTo determine differences in inpatient glycemic control and response to two different glargine-based insulin regimens in general medicine and surgery patients with type 2 diabetes (T2D).MethodsThis is a post-hoc analysis of a prospective, multicenter, randomized trial of 298 non-ICU medicine and surgery patients with T2D treated with Basal Bolus regimen with glargine once daily and glulisine before meals and with Basal Plus regimen with glargine once daily and supplemental doses of glulisine before meals for blood glucose (BG) > 140 mg/dl. Major study outcomes included differences in mean daily BG, frequency of treatment failures (defined as > 2 consecutive BG > 240 mg/dl or a mean daily BG > 240 mg/dl), and hypoglycemia between the medicine and surgery cohorts.ResultsPatients treated with Basal Bolus or with Basal Plus experienced similar improvement in mean daily BG after 1st day of therapy (p = 0.16), number of treatment failures (p = 0.11) and hypoglycemic events (p = 0.50). Compared to surgery patients (n = 130), medicine patients (n = 168) had higher admission BG (p = 0.01) and HbA1c levels (p < 0.01); however, they had similar response to either treatment regimen without differences in mean daily BG after 1st day of therapy (p = 0.18), number of treatment failures (p = 0.58), daily insulin requirements (p = 0.36), or in the frequency of hypoglycemia (p = 0.79).ConclusionThe Basal Plus regimen with glargine once daily and correction doses with glulisine before meals resulted in similar glycemic control to basal bolus regimen. We observed no differences in response to either basal insulin regimen between medicine and surgery patients with type 2 diabetes.     

Long-term benefits of insulin therapy and glycemic control in overweight and obese adults with type 2 diabetes

ProblemObesity and type 2 diabetes have reached epidemic proportions in the United States. Obese patients are at especially high risk for the development of metabolic syndrome, a clustering of metabolic abnormalities associated with insulin resistance that usually precede the development of cardiovascular disease. Overweight or obesity, along with insulin resistance, is frequently present in people with type 2 diabetes.MethodsA literature search of the PubMed and MEDLINE databases, using the terms diabetes, obesity, metabolic syndrome, glycemic control, antidiabetic therapy, and insulin, was performed. Articles published between 1985 and 2006 that examined diabetes management in the obese population were selected and reviewed.ResultsThere is new evidence suggesting that tight glycemic control and earlier initiation of insulin therapy can improve outcomes in obese patients with type 2 diabetes, thereby reducing the risk for the development of both macrovascular and microvascular complications of the disease. Insulin also appears to exhibit anti-inflammatory effects, which may provide additional protection against the development of atherosclerosis. Despite the benefits of insulin therapy, many patients and physicians remain reluctant to start insulin due to concerns about weight gain.ConclusionNewer insulin formulations can effectively improve glycemic control without significant effects on patient weight and, therefore, may be particularly useful in patients who are overweight or obese. Implementation of comprehensive treatment regimens that emphasize dietary modification, physical activity, and exercise, and aggressive use of pharmacological agents to achieve tight glycemic control through physiological regimens offer the most promise for reducing long-term complications in obese patients with type 2 diabetes.     

Insulin therapy in elderly patients with type 2 diabetes: the role of insulin glargine

Within the USA, between 1980 and 2005, the prevalence of diagnosed diabetes has increased in all age groups, with the age group 65–74 years having the highest prevalence. The treatment of type 2 diabetes mellitus (T2DM) in elderly people is made more difficult than in their younger counterparts, primarily owing to the impact of co-morbidities, complications and hypoglycaemia as well as technical difficulties with insulin injections. Accordingly, the treatment approach for elderly patients with T2DM may need to be modified to accommodate co-morbidities and illnesses associated with ageing. Risks associated with insulin therapy, particularly hypoglycaemia, have traditionally limited the use of insulin in this patient population. Insulin glargine is associated with a low risk of hypoglycaemia compared with neutral protamine Hagedorn insulin, for example, and could thus provide a treatment of choice for healthcare providers when considering the increasing prevalence of diabetes in the elderly population. A regimen based on insulin glargine plus oral agents provides clinicians with a tool to help meet therapeutic targets in this population without increasing risk of hypoglycaemia.