Options for the intensification of insulin therapy when basal insulin is not enough in type 2 diabetes mellitus

In the early treatment of type 2 diabetes mellitus (T2DM), the addition of a basal insulin, such as insulin glargine, to existing oral therapy can help patients attain recommended glycaemic control targets, including haemoglobin A_1c (HbA_1c) <7% and fasting blood glucose <5.5 mmol/l (<100 mg/dl). For patients close to but not at target, the management of postprandial glucose excursions with a rapid-acting insulin, such as insulin glulisine, can provide further improvements in glycaemic control. In this review, the options for intensifying insulin therapy with the addition of one or more daily doses of prandial insulin are discussed. In addition, the advantages/disadvantages of choosing a basal–bolus vs. a premixed insulin strategy are discussed. A conceptually simple approach for the treatment of T2DM is for optimization of the basal insulin dose (added to oral antidiabetic drugs) to target fasting glycaemia followed by the addition of a single prandial dose of rapid-acting insulin to target the largest glucose excursion. A second and third dose of prandial insulin can then be added if HbA_1c remains above target and to manage postprandial glucose excursions at other meals. Prospective studies are underway to further examine this concept and determine the benefit of this approach not only on overall glycaemic control but also on cardiovascular risk.     

Insulin management in overweight or obese type 2 diabetes patients: the role of insulin glargine

Type 2 diabetes mellitus (T2DM) and obesity commonly co-exist. Improved clinical management of T2DM and improved glycaemic control with traditional therapies including insulin usually result in some weight gain – a frequently perceived barrier to the introduction of insulin by both patient and healthcare professionals. Weight gain of 2.5 kg per 1% change in haemoglobin A_1c (HbA_1c) is common in many studies. Strategies to minimize weight gain, particularly in obese patients, are essential to help patients better manage their diabetes and improve quality of life. Insulin analogues with lower risk of hypoglycaemia and better within-patient variability compared with human insulin may help facilitate reaching treatment goals. Moreover, weight gain can be minimized by earlier insulinization and the use of basal insulin, such as insulin glargine, instead of premixed insulin. Data specific to the obese patient with T2DM are presented; they are currently limited but do indicate that insulin glargine therapy is associated with improved glycaemic control as well as less weight gain than other insulins, such as premixed insulin and prandial insulin regimens. Retrospective subanalyses of earlier trials and ongoing studies would shed further light on the impact of insulin therapy in obese people with T2DM in addition to determination of optimal therapeutic strategies.     

Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial

Aims:  Insulin analogues are widely used but few data exist comparing different analogue regimens. We compared two such regimens in type 2 diabetes mellitus (T2DM) uncontrolled by oral antidiabetic agents (OADs) with or without basal insulin.
Methods:  In a 26-week multinational, multicentre, randomized treat-to-target trial, OADs were discontinued and subjects randomized to analogue basal–bolus therapy (insulin detemir once daily and insulin aspart mealtimes) or biphasic insulin aspart 30 (30% rapid-acting insulin aspart), twice daily. Insulin was titrated to targets for fasting, predinner and postprandial plasma glucose (PG), as appropriate.
Results:  Of 719 subjects, 92% completed the study; 58% achieved haemoglobin fraction A_1c (HbA_1c) ≤7.0%, with reductions of 1.56% (to 6.96%) with basal–bolus therapy and 1.23% (to 7.17%) with biphasic insulin aspart. Reduction with basal–bolus therapy was superior in the overall population by 0.23% (p = 0.0052), with no difference between regimens in insulin-naive patients. Major hypoglycaemia occurred in five basal–bolus patients (0.9%) and in no patients with biphasic insulin aspart. Incidence of minor hypoglycaemia was similar in both groups. All insulin doses increased during titration, with increase in lunchtime insulin aspart dose and equal distribution of breakfast and dinner biphasic insulin aspart doses. Insulin detemir remained once daily in 87% of patients.
Conclusions:  Modern insulin analogue regimens, adjusted to PG targets, enable a majority of people with T2DM to reach HbA_1c≤7.0% after failure of OADs and OAD-basal insulin therapy. Insulin-treated patients may benefit more from transfer to analogue basal–bolus therapy, while insulin-naive individuals benefit equally well from the more convenient biphasic analogue regimen.     

Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE

Aim:  The aim of this study was to evaluate the safety and efficacy of insulin detemir in type 2 diabetes patients previously receiving NPH insulin (NPH group, n = 175) or insulin glargine (glargine group, n = 118) in combination with oral antidiabetic drugs (OADs).
Methods:  Patients were transferred to insulin detemir, while the OAD regimen and number of injections remained the same. The incidence of serious adverse drug reactions, including major hypoglycaemia, and haemoglobin A_1c (HbA_1c), fasting glucose, within-patient fasting glucose variability and body weight change were measured at 14 weeks.
Results:  Glycaemic control improved in both NPH (HbA_1c = −0.2%, p < 0.05; fasting glucose −1.0 mmol/l, p < 0.0001) and glargine (HbA_1c = −0.6%, p < 0.0001; fasting glucose −1.4 mmol/l, p < 0.0001) groups, including a reduction in fasting glucose variability (p < 0.01 for both). The incidence of total and nocturnal hypoglycaemia was reduced in both NPH and glargine groups. The incidence of major hypoglycaemia was low and did not change significantly during the follow-up period. Mean body weight was significantly reduced in the NPH (−0.7 kg, p < 0.01) and glargine (−0.5 kg, p < 0.05) groups.
Conclusions:  These results indicate that in type 2 diabetes, transferring from other basal insulins to insulin detemir in combination with OADs was associated with improvements in glycaemic control, which were accompanied by a reduced risk of hypoglycaemia and a reduction in body weight.     

Lower risk of hypoglycemia with insulin detemir than with neutral protamine hagedorn insulin in older persons with type 2 diabetes: a pooled analysis of phase III trials

OBJECTIVES: To compare the safety and efficacy of insulin detemir with that of neutral protamine Hagedorn (NPH) insulin in older (aged ≥65) and younger (aged 18–64) persons with type 2 diabetes mellitus (DM).
DESIGN: Pooled, post hoc analysis of data from three open-label, randomized studies.
SETTING: Three multinational Phase III trials.
PARTICIPANTS: Four hundred sixteen older and 880 younger persons with DM, treated for 22 to 26 weeks with basal insulin plus mealtime insulin or oral agents.
MEASUREMENTS: Hemoglobin A_1c (HbA_1c), fasting plasma glucose, glucose variability, hypoglycemic episodes.
RESULTS: Mean treatment difference for HbA_1c (insulin detemir–NPH insulin) indicated that insulin detemir was not inferior to NPH insulin for both age groups (0.035%, 95% confidence interval (CI)=−0.114–0.183 and 0.100%, 95% CI=−0.017–0.217, for older and younger persons, respectively). Relative risk of all hypoglycemic episodes (insulin detemir/NPH insulin) was 0.59 (95% CI-0.42–0.83) for older persons and 0.75 (95% CI-0.59–0.96) for younger persons. Adverse events were similar between treatments. Fasting plasma glucose was similar between treatments (mean treatment difference 0.97 mg/dL, 95% CI=−8.01–9.95, and 4.69 mg/dL, 95% CI=−2.30–11.67, for older and younger persons, respectively). Mean treatment difference for weight was −1.02 kg (95% CI −1.61 to −0.42) and −1.13 (95% CI −1.58 to −0.69) for older and younger persons, respectively.
CONCLUSION: Previously reported benefits of insulin detemir, particularly less hypoglycemia and less weight gain, compared with NPH insulin, were the same for older and younger persons with DM at similar levels of HbA_1c.     

Three different premixed combinations of biphasic insulin aspart – comparison of the efficacy and safety in a randomized controlled clinical trial in subjects with type 2 diabetes

Aim:  To evaluate clinical efficacy and safety of biphasic insulin aspart (BIAsp) 30 twice daily (b.i.d.) vs. BIAsp 50 or BIAsp 70 (high-mix regimens) thrice daily (t.i.d.) all in combination with metformin in a 36-week clinical trial in subjects with type 2 diabetes.
Methods:  Efficacy measurements included haemoglobin A_1c (HbA_1c) and eight-point plasma glucose (PG); safety included adverse events (AEs) and hypoglycaemic episodes. The three treatment groups (approximately 200 subjects in each group) were well matched regarding sex ratio, ethnicity, age and body mass index.
Results:  After 12 weeks, 43% and 54% in the BIAsp 50 and 70 groups, respectively, switched their dinner insulin to BIAsp 30. Both high-mix regimens were non-inferior to BIAsp 30 b.i.d., as measured by change in HbA_1c, and the BIAsp %50 regimen was superior. The odds for meeting the American Diabetes Association and The American Association of Clinícal Endocrinologist HbA_1c targets of <7% and ≤6.5%, respectively, were significantly higher with the BIAsp 50 regimen than with BIAsp 30. A significantly lower PG level was achieved from lunch until 02:00 hours with both high-mix regimens compared with BIAsp 30 b.i.d. AEs were mild or moderate with all three regimens. Frequency of hypoglycaemic episodes was comparable for the BIAsp 50 and the BIAsp 30 b.i.d. regimens but was significantly higher with BIAsp 70 t.i.d.
Conclusions:  Glycaemic control improved with BIAsp 50 t.i.d. without higher incidence of hypoglycaemia compared with BIAsp 30 b.i.d.; with BIAsp 70 t.i.d. lower PG levels from lunch to 02.00 hours, but more hypoglycaemic episodes were obtained compared with BIAsp 30 b.i.d. (Clinical Trials.gov ID no: NCT00184574).     

Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes

Background: In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control.
Methods: One hundred T1DM patients with haemoglobinA_1c (HbA_1c) ≥8.5% during the year before enrolment entered a 1-month run-in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year.
Results: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non-HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA_1c (previously reported) was not significant different between treatments.
Conclusion: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.     

Continuous subcutaneous insulin infusion leads to immediate, stable and long-term changes in metabolic control

Background:  Evaluations of continuous subcutaneous insulin infusion (CSII) usually focus on one pre- and one post-CSII measurement to assess metabolic therapy outcome.
Aim:  Extending this research, the aim of the present study was to provide a more fine-grained analysis of achieved glycaemic control.
Methods:  In 52 patients with type 1 diabetes (mean age of 37.85 years at CSII begin; s.d. ± 12.41), haemoglobin A_1c (HbA_1c) levels were assessed every 3 months over a period of 5 years (1 year before and 4 years after the introduction of CSII). Mixed models were utilized to describe changes in glycaemic control.
Results:  The pre–post course showed that already in the first quarter, a statistically significant lower HbA_1c level was obtained [7.30%, in contrast to 8.21% at the last quarter with intensified conventional therapy (ICT)]. In the following 15 quarters, the mean HbA_1c levels remained constantly lower than that with ICT. Overall, the aggregated mean HbA_1c level of patients with CSII therapy was 7.19%, in contrast to 8.08% with ICT; thus, an overall decrease by 11% was achieved. In addition, individual differences in blood glucose level and age of diabetes onset as a predictor for therapy success were analysed.
Conclusions:  The data show an immediate, stable and long-term effect of CSII on HbA_1c. In addition, a significant relationship between metabolic control and age of diabetes onset was found, as well as a reduction of variance in HbA_1c levels between subjects after change to CSII.     

The influence of the Pro12Ala mutation of the PPAR-gamma receptor gene on metabolic and clinical characteristics in treatment-naïve patients with type 2 diabetes

Peroxisome proliferator activated receptor-gamma is an important factor in adipocyte differentiation and energy metabolism and is thus a candidate gene for obesity, insulin resistance and dyslipidaemia. We therefore assessed the associations between the most common variant of the PPAR-γ, the Pro12Ala (P12A) substitution in the PPAR-γ₂ gene, with BMI, blood pressure, fasting plasma glucose, HbA_1c, total cholesterol, LDL and HDL cholesterol and plasma triglyceride in 183 treatment-naïve patients with type 2 diabetes (T2D). The P12A allele associated with lower fasting plasma glucose but had no influence on HbA_1c or BMI. In obese patients (BMI > 29 kg/m²), the P12A substitution associated with elevated total and non-HDL cholesterol levels.     

Patterns of glycaemic control in Australian primary care (NEFRON 8)

Background: Intensive glycaemic control delays the onset and progression of diabetes-related complications, especially microvascular complications. However, only limited information is available regarding glucose-lowering treatment practices in Australian primary care. The aim of the study was to describe patterns of glycaemic control in subjects participating in the National Evaluation of the Frequency of Renal Impairment co-existing with Non-Insulin Dependent Diabetes Mellitus study.
Methods: Expressions of interest were invited from all registered general practitioners in Australia, from which 500 investigators were randomly selected and asked to provide data on 10–15 consecutive adults with type 2 diabetes presenting to their practice.
Results: Just less than half of the 3893 enrolled patients had a haemoglobin (Hb)A_1c <7.0% (47.7%, 95% confidence interval (CI) 46.1–49.3%) and quarter had an HbA_1c≥8.0% (24.3%, 95%CI 22.9–25.9%. For patients using lifestyle alone, one or two oral glucose-lowering agents or insulin there was a progressive decline in the proportion achieving an HbA_1c <7.0%, that is, 81, 55, 31 and 24%, respectively. There was a very good concordance between general practitioners' perception of optimal control (HbA_1c <7.0%) and the actual glycaemic levels achieved in this study.
Conclusion: Current targets for glycaemic control in type 2 diabetes have generally been followed in Australian general practice, but there is still a significant gap in the achievement of recommended glycaemic goals. A quarter of the patients clearly have poor glycaemic control. The immediate steps that can be taken to improve glycaemic control include the early use of combination oral glucose-lowering therapies and the increased use of insulin.     

Is There Any Relationship between Metabolic Parameters and Left Ventricular Functions in Type 2 Diabetic Patients without Evident Heart Disease?

Background: The aim of the present study was to evaluate left ventricle (LV) systolic and diastolic function, using tissue Doppler echocardiography (TDE) and color M-mode flow propagation velocity, in relation to blood glucose status in normotensive patients with type 2 diabetes mellitus (T2DM) who had no clinical evidence of heart disease. Methods: Seventy-two patients with T2DM (mean age 49.1 ± 9.8 years) without symptoms, signs or history of heart disease and hypertension, and 50 ages matched healthy controls (mean age 46.1 ± 9.8 years) had echocardiography. Systolic and diastolic LV functions were detected by using conventional echocardiography, TDE and mitral color M-mode flow propagation velocity (V_E). Fasting blood glucose level (FBG) after 8 hours since eating a meal, postprandial blood glucose level (PPG), and HbA_1C level were determined. The association of FBG, PPG and HbA_1C with the echocardiographic parameters was investigated. Results: It was detected that although systolic functions of two groups were similar, diastolic functions were significantly impaired in diabetics. No relation of FBG and PPG with systolic and diastolic functions was determined. However, HbA_1C was found to be related to diastolic parameters such as E/A, Em/Am, V_E and E/V_E (β=−0.314, P = < 0.05; β=–0.230, P < 0.05; β=–0.602, P < 0.001, β= 0.387, P < 0.005, respectively). In addition to HbA_1C, LV, diastolic functions were also correlated with age and diabetes duration. Conclusion: Diastolic LV dysfunction may develop even in absence of ischemia, hypertension, and LVH in T2DM. FBG and PPG have no effect on LV functions, but HbA_1C levels may affect diastolic parameters.     

Weight changes in type 2 diabetes and the impact of gender

Aims:  Many studies suggest that weight gain occurs during treatment of type 2 diabetes, irrespective of the treatment type. The aim of this study was to address the questions (i) whether weight gain is inevitable in patients treated for type 2 diabetes, and (ii) whether treatment escalation is prompted by a rise in glycaemic control [haemoglobin A_1c (HbA_1c)] or weight gain.
Methods:  A diabetes database was used to identify all patients with type 2 diabetes attending our clinic between 1 January 1990 and 31 December 2000. To facilitate further analysis, independent anonymized database resources were established. Data collected included height, weight, gender, HbA_1c, age and diabetes treatment at each visit.
Results:  One thousand and eighty-four patients were included; after 6 months of treatment, patients' average weight had reduced by 1.0 kg (s.d. 4.6) (p < 0.001). Sixty per cent of the patients had either a decrease or no change in weight, while 40% demonstrated a weight gain. Women demonstrated more weight loss than men. After a mean follow-up of 50 months (s.d. 25.7), 439 patients (40%) who received treatment with diet alone, diet followed by metformin or metformin alone demonstrated a maintained weight reduction in addition to improved glycaemic control. A rise in HbA_1c rather than weight gain prompted treatment change.
Conclusions:  This study provides evidence that weight gain is not a necessary consequence of the treatment of type 2 diabetes. Women were more successful than men in losing weight, and diet, with or without the addition of metformin, was the treatment type most usually associated with weight loss.     

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.     

Haemoglobin A1 in Diabetes Mellitus

Summary: Haemoglobin A₁ in diabetes mellitus. P. C. Bartley and T. E. Hambling
HbA₁ was measured by a rapid method in a routine hospital laboratory. The normal range of 5·0–8·5% compares favourably with other studies. Patients with uncontrolled diabetes had levels of HbA₁ of up to 20·5% while well controlled patients had levels of HbA₁ in the normal range. The level of HbA₁ is relatively stable in normal subjects and does not correlate with age, sex or weight. There was a correlation (p < 0·001) with a 1–2 hour postprandial, post-insulin blood sugar in insulin dependent diabetics. There was a relationship between type of therapy and HbA₁ level at presentation. From the study of two ketoacidotic patients, it is apparent that the level of HbA₁ decreases about six weeks after the decrease in blood sugar. It is concluded that the measurement of HbA₁ is a useful adjunct in the assessment of diabetic control.     

Reaching glycaemic targets while minimizing hypoglycaemia in insulin-treated type 2 diabetes patients

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by both insulin resistance and β-cell failure, resulting in a decline in insulin secretion and increased blood glucose levels. By the time T2DM is clinically diagnosed, only 50% of normal β-cell function remains, leading to altered control of fasting and/or postprandial glucose. The aim of this review is to summarize the options for introduction of basal insulin, in particular insulin glargine, and the advantages and disadvantages of using insulin glargine vs. alternative insulins or vs. oral agents. Overall, the studies included in this review show that insulin glargine is associated with a lower risk of hypoglycaemia vs. both neutral protamine Hagedorn insulin and premixed insulin formulations, alongside clinically important improvements in glycaemic control. Furthermore, insulin glargine is associated with greater improvements in glycaemic control vs. intensification of oral therapy. Thus, insulin glargine should be a preferred option when starting insulin therapy for people with T2DM.     

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.     

Synergistic effect of the human GLP-1 analogue liraglutide and a dual PPARα/γ agonist on glycaemic control in Zucker diabetic fatty rats

Aim/Hypothesis:  Combination therapies are increasingly common in the clinical management of type 2 diabetes. We investigated to what extent combined treatment with the human glucagon-like peptide-1 (GLP-1) analogue liraglutide and the dual PPARα/γ agonist ragaglitazar would improve glycaemic control in overtly diabetic Zucker diabetic fatty (ZDF) rats.
Methods:  Ninety overtly diabetic male ZDF rats were stratified into groups with matched haemoglobin A1c (HbA_1c) (9.0 ± 0.1%). Liraglutide (15 and 50 μg/kg subcutaneously twice daily), ragaglitazar (1 and 3 mg/kg perorally once daily) and their vehicles were studied as monotherapy and in combination in a 3 × 3 factorial design.
Results:  After 4-week treatment, synergistic effects on HbA_1c, non-fasting morning blood glucose (BG) and/or 24-h BG profiles were observed with three of the four combinations. The relationship between plasma insulin and BG in combination-treated animals approached that of historical lean ZDF rats representing normal glucose homeostasis, suggesting that insulin secretion and insulin sensitivity were markedly improved. Increased insulin immunostaining in islets further supports the improved beta-cell function and/or insulin sensitivity in combination-treated animals. The synergistic effect on glycaemic control was found without a similar synergistic increase in beta-cell mass in the combination groups.
Conclusions/Interpretation:  Our data demonstrate that combination treatment with a human GLP-1 analogue and a dual PPARα/γ agonist through distinct mechanism of actions synergistically improves glycaemic control in the ZDF rat.     

Optimum management of type 2 diabetes – timely introduction, optimization and intensification of basal insulin

The natural progression of type 2 diabetes mellitus (T2DM) requires continuing medical care, early insulin intensification and patient self-management education to reduce the risk of long-term complications, including microvascular and macrovascular complications. However, too few people are on insulin, and all too commonly have poor glycaemic control. This paradigm significantly increases the risk for long-term complications. It is becoming increasingly apparent that the early introduction of basal insulin, such as insulin glargine, is essential to provide clinically important improvements in glycaemic control. In this review, we discuss the rationale for the earlier insulinization in T2DM in order to reach and maintain treatment targets and to provide further support for the recent American Diabetes Association and European Association for the Study of Diabetes consensus statement.     

Refining basal insulin therapy: what have we learned in the age of analogues?

BACKGROUND: The basal insulin analogues glargine and detemir have been subject to a series of trials comparing their clinical profiles to the conventional preparation, neutral protamine Hagedorn (NPH). Careful review of these trials provides opportunities to learn clinically useful lessons about these insulins. METHODS: MedLine-indexed trials comparing glargine or detemir to NPH were scrutinized for control, tolerability and dose data. Separate considerations were made for types 1 and 2 diabetes, and for basal-bolus and basal plus oral glucose-lowering drugs (OGLD) therapy. Attention was paid to dosing schedules and 24-h glycaemic profiles. RESULTS: Collectively, the trials demonstrated an improved balance between glycaemic control and tolerability for both analogues compared to NPH, regardless of regimen and diabetes type. Neither once-daily glargine nor detemir reliably provides 24-h basal insulin replacement in all patients with type 1 diabetes; a waning of effect frequently obliges twice-daily administration. When added to OGLDs in type 2 diabetes, goal-titrated once-daily basal insulin generally lowered HbA(1c) by approximately 1.5%, whereas twice-daily administration tended to increase insulin dose disproportionately to improvement in control. Hence, adding bolus insulin may be a preferable intensification method to dividing the basal dose. Varying injection time or dividing the basal insulin dose predictably affects the pattern of hypoglycaemia and bolus dose requirements. Morning administration tends to require higher dosing than evening administration. CONCLUSIONS: Scrutiny of trials involving glargine and detemir has increased our understanding of how best to dose basal insulins. An individualized approach is still necessary however, and several questions remain that require further research.     

Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia

Aims: To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin.
Methods: In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A_1C (HbA_1C) at week 26.
Results: At week 26, mean HbA_1C changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg (–0.63 ± 0.08%) and alogliptin 25 mg (−0.71 ± 0.08%) than placebo (−0.13 ± 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA_1C decreases of ≥0.5, ≥1.0 and ≥1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 ± 0.2 kg), alogliptin 12.5 mg (0.7 ± 0.2 kg) and alogliptin 25 mg (0.6 ± 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups.
Conclusions: Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens.