Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries.

AIMS: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). METHODS: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management. RESULTS: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62 ± 12 years; body mass index (BMI) 29.3 ± 5.4 kg/m(2); diabetes duration 10 ± 7 years; haemoglobin A1c (HbA1c) 8.9 ± 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 ± 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 ± 6 U (0.16 ± 0.09 U/kg) to 22 ± 16 U (0.27 ± 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c. CONCLUSIONS: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs.

Factors associated with injection omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy study.

AIM: To examine factors associated with insulin injection omission/non-adherence on a global basis. METHODS: Telephone survey of 1530 insulin-treated adults with self-reported diabetes (110 type 1 and 1420 type 2) in China, France, Japan, Germany, Spain, Turkey, UK or USA. Participants had a mean age of ∼60 years, ∼15 years duration of diabetes and ∼9 years duration of insulin treatment. Regression analysis assessed the independent associations (p < 0.05) of country, participant characteristics and treatment-related beliefs/perceptions with number of days in the past month that an insulin injection was missed or not taken as prescribed. RESULTS: One third (35%) of respondents reported one or more days (mean: ∼3 days) of insulin omission/non-adherence. Insulin omission/non-adherence differed widely across countries (range = 20-44%); differences in days of insulin omission/non-adherence were maintained after adjustment for other risk factors. Most risk factors had similar relationships with insulin omission/non-adherence across countries (few interactions with country). Insulin omission/non-adherence was more frequent among respondents who were male, younger, had type 2 diabetes or more frequent hypoglycaemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/logistical barriers and difficulties with insulin adherence, were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing. CONCLUSIONS: The results of this large-scale study suggest that insulin omission/non-adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non-adherence and lead to improved clinical outcomes.

Impact of statins on the coagulation status of type 2 diabetes patients evaluated by a novel thrombin-generation assay.

PURPOSE: Dyslipidemia is common in type 2 diabetes (T2D) and contributes to cardiovascular disease (CVD) by exacerbating atherosclerosis and hypercoagulability. Statins can stabilize atherosclerotic plaque and reduce prothrombotic status. In the present study we aimed to evaluate the coagulation activity and the effect of statins on procoagulant state of T2D patients using a novel activated protein C (APC)-dependent thrombin-generation assay. METHODS: Procoagulant status (by HemosIL ThromboPath (ThP) assay) and in vivo platelet activation (by plasma soluble (s)CD40L levels) were analyzed in a retrospective, cross-sectional study of 198 patients with long-standing T2D and 198 controls. RESULTS: Procoagulant status of T2D patients was enhanced when compared to control subjects (p < 0.0001). Similarly, sCD40L levels were increased in T2D (p < 0.0001). When testing ThP as the dependent variable in a multivariate regression model, sCD40L (p < 0.0001) and statin treatment (p = 0.019) were independent predictors of the procoagulant state of T2D patients. Subgroup analysis showed a significant improvement of coagulability in T2D patients on statins (p = 0.012). CONCLUSIONS: The use of a standardized, easy-to-run, and commercially available APC-dependent thrombin-generation assay detected the presence of a procoagulant status in a large series of patients with long-standing T2D and demonstrated a significant impact of statins in the coagulation status of patients with T2D.

Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study.

AIMS: To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. METHODS: Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. RESULTS: One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. CONCLUSIONS: Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia.

Weight beneficial treatments for type 2 diabetes.

CONTEXT: The close link between type 2 diabetes and excess body weight highlights the need to consider the weight effects of different treatment regimens. We examine the impact of "weight-friendly" type 2 diabetes pharmacotherapies and suggest treatment strategies that mitigate weight gain. EVIDENCE ACQUISITION: Evidence was identified via PubMed search by class and agent and in bibliographies of review articles, with final articles for inclusion selected by author consensus. EVIDENCE SYNTHESIS: Substantial evidence confirms the weight benefits of metformin and shows that, of the newer available agents, glucagon-like peptide-1 (GLP-1) agonists and amylin analogs promote weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors and bile acid sequestrants are weight-neutral. Liraglutide and exenatide appear to have similar effects on weight; however, recent research suggests a potentially greater effect of liraglutide on glycemic control compared to exenatide, when used as a second-line therapy. Mounting evidence suggests that insulin detemir may provide the most favorable weight benefits of available insulins. CONCLUSIONS: Weight-beneficial agents should be considered in patients, particularly obese patients, who fail to reach glycemic targets on metformin therapy. We propose the following treatment choices based on potential weight benefit and blood glucose increment: long-acting GLP-1 agonists (liraglutide), DPP-4 inhibitors, bile acid sequestrants, amylin analogs, and basal insulin for patients with elevated fasting plasma glucose; and short-acting (exenatide) or long-acting GLP-1 agonists, amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants for patients with elevated postprandial glucose. The weight-sparing effects of insulin detemir, notably in patients with high body mass index, should also be considered when initiating insulin therapy.

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study.

OBJECTIVE: PREDICTIVE is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks. RESEARCH DESIGN AND METHODS: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8 +/- 10.9 years, BMI 29.8 +/- 4.8 kg/m(2), and HbA(1C) 8.82 +/- 1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies. MAIN OUTCOME MEASURES: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change. RESULTS: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p = 0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA(1C) decreased by a mean 1.25% (SD +/- 1.25%; p < 0.0001), with 30% of patients (n = 383) achieving HbA(1C) <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were -3.62 mmol/L (SD +/- 2.93; p < 0.0001) and -0.48 mmol/L (SD +/- 1.03; p < 0.0001), respectively. Body weight decreased by a mean 0.5 kg (SD +/- 3.3; p < 0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25-30, 30-35, and >35 kg/m(2)). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (-1.20 kg) reported in those with BMI >35 kg/m(2). CONCLUSIONS: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.

Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study.

AIM: The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE) Study is a large, multi-centre, observational study assessing the safety and efficacy of insulin detemir in everyday clinical practice. METHODS: This subgroup analysis of the German cohort of PREDICTIVE evaluates over 3 months, patients with type 2 diabetes who were transferred to insulin detemir +/- oral antidiabetic drugs (OADs) from an OAD-only regimen (n = 1321), NPH insulin +/- OADs (n = 251) or insulin glargine +/- OADs (n = 260). RESULTS: Among all groups, 3 months after starting treatment with insulin detemir, total, daytime and nocturnal hypoglycaemic events/patient were reduced by 84, 80 and 90%, respectively, from baseline. No major hypoglycaemic events were reported during treatment with insulin detemir. HbAlc was significantly reduced from baseline in each of the subgroups (-1.29,-0.60 and-0.59% for patients previously taking OADs only, NPH insulin +/- OADs and insulin glargine +/- OADs respectively; p < 0.0001), as was fasting blood glucose (FBG) (-58.1,-29.1 and-24.6 mg/dl; p < 0.0001) and FBG variability-8.2 mg/dl,-5.7 mg/dl; p < 0.0001 and -5.1 mg/dl; p = 0.0008). All subgroups combined lost an average of 0.9 kg of body weight (p < 0.0001) during the study. Total daily basal insulin dose increased slightly from baseline for those patients on a prior insulin regimen, and in this study 79% of patients used insulin detemir once daily. CONCLUSIONS: These data confirm the short-term safety and efficacy of insulin detemir +/- OADs in a real-world scenario and support the findings of randomized controlled clinical trials with insulin detemir, including its limited effects on body weight.

An electronic case manager for diabetes control.

OBJECTIVE: To evaluate the usage and safety of an electronic case manager (ECM) system designed to facilitate the task of glycemic control. Sustained improvement in blood glucose control is the proven treatment outcome that will reduce or eliminate the long-term complications of diabetes. RESEARCH DESIGN AND METHODS: A customized microcomputer system served as the ECM. Located at the clinic, this voice-interactive system required the remote patient to need only a touch-tone telephone. Patients accessed the system to report daily self-measured glucose levels or hypoglycemic symptoms together with associated lifestyle events. System beta-testing was in an open-case series (n = 184) in an academic diabetes center with the goal of evaluating the ECM in terms of utilization, frequency of crises, and fiscal matters. RESULTS: Of the patients, 58% (n = 107) actively used the ECM for their daily diabetes care, accumulating 788 patient-months of follow-up. Over 45,000 telephone calls were received by the ECM during the start-up year. Each call was processed instantly and automatically. Patients benefited from having 24-h access to the ECM. Prevalence of diabetes-related crises (hyperglycemia > 400 mg/dl [22 mmol/l] or hypoglycemia < 50 mg/dl [2.8 mmol/l]) decreased approximately threefold (P < 0.05), with a concomitant statistically significant decrease in HbA1c of 0.8% at 6 months (n = 45, P = 0.024) and 0.9% at 12 months (n = 30, P = 0.044). The ECM provided 24-h on-line assistance in adjusting daily insulin and/or tablet therapy, automatic generation of standardized medical reports, electronic medical-legal documentation, as well as a marked reduction in the time spent on the phone with patients. Clinic visits in managing complex diabetes were reduced approximately twofold (P < 0.0001), and the effort spent by case managers was estimated. CONCLUSIONS: Patients with diabetes who accessed the ECM system received timely, cost-effective, and reliable medical intervention. This reduced the incidence of diabetic crises and the need for frequent clinic visits. The ECM empowers case managers to provide safer and superior diabetes care.

Hypercalcemia in association with acute renal failure and rhabdomyolysis. Case report and literature review.

The syndrome of hypercalcemia during the course of acute renal failure (usually associated with rhabdomyolysis) occurs most commonly in young men with very severe renal failure. Although fewer than 90 such patients have been reported, the prevalence of hypercalcemia in patients with rhabdomyolysis-associated renal failure averages 30%. Hypercalcemia occurs most commonly in the diuretic phase and resolves spontaneously. The mean duration of hypercalcemia is 14 days. The pathogenesis of this syndrome has not been clearly defined. In the rare instances where it has been measured, intact PTH is suppressed. In contrast, both elevated and suppressed values of plasma 1,25-dihydroxyvitamin D have been reported. The release of calcium from ectopic calcification in damaged muscle tissue provides a potential explanation for this syndrome. Therapy for the hypercalcemia should generally be conservative given its self-limited nature.