Glycaemic control and adverse events in patients with type 2 diabetes treated with metformin + sulphonylurea: a meta-analysis

Aim:  The aim of this study was to quantify the effect of a sulphonylurea on glycaemic control and the risk adverse events when incorporated into the treatment regimen of patients with type 2 diabetes inadequately controlled on metformin.
Methods:  A systematic review was carried out to identify randomized controlled trials of sulphonylurea therapy in patients with type 2 diabetes whose glycaemic control was inadequate after maximal treatment with metformin. Data on reductions in haemoglobin A_1C (HbA_1C), fasting plasma glucose (FPG) and risk of hypoglycaemic events were extracted from each study and pooled in meta-analyses. Data on weight change were also extracted and tabulated.
Results:  Six studies including 1364 patients were identified. Based on random effects meta-analysis, the pooled estimate of change in HbA_1C from baseline was 0.9% (95% CI 0.7–1.1, p = 0.00011 vs. baseline) and for change in FPG from baseline was 1.8 mmol/l (95% CI 1.1–2.5, p = 0.0026 vs. baseline). The odds of experiencing a hypoglycaemic event was significantly higher in sulphonylurea-treated patients than in those on comparator treatments (OR = 5.3, 95% CI 1.7–16.3, p = 0.03). Mean weight change ranged from +2.5 to −0.1 kg, depending on the comparator treatment.
Conclusions:  This analysis has demonstrated that, in patients with type 2 diabetes whose control is inadequate on metformin monotherapy, the magnitude of incremental HbA_1C reduction achieved by the addition of a sulphonylurea is unlikely to exceed 1%, even after titration to maximum tolerated doses. Additionally, clinically relevant side-effects such as symptomatic hypoglycaemia and weight gain may be experienced.     

Treatment choice and effectiveness of adding sulphonylurea or glitazones to metformin for the treatment of type 2 diabetes mellitus

Aim: This study investigates the treatment choice between, and the effectiveness of, adding sulphonylurea or glitazone to ongoing metformin therapy for patients with type 2 diabetes mellitus in the clinical practice setting. Methods: A multicentre observational study using data from clinical records was conducted in Finland, France, Germany, Norway, Poland, Spain and the UK. Data were collected for patients who added sulphonylurea or glitazone to metformin. Effectiveness was defined as a change in haemoglobin A1c (HbA_1c) from baseline to approximately 1 year after the initiation of additional therapy. To allow for comparisons between the two medication regimens, propensity score matching was employed. Treatment choice was analysed using a probit regression model. We hypothesized that treatment choice was associated with factors reflecting patient’s characteristics, patient’s experience with diabetes, patient‘s health or to physician’s characteristics at baseline. Results: Compared with baseline, adding sulphonylurea to metformin reduced HbA_1c by 0.8% (p < 0.0001), while adding glitazone to metformin reduced HbA_1c by 0.9% (p < 0.0001). Percentage at HbA_1c goal (6.5%) increased from 6.9 to 23.8% for the sulphonylurea group and 8.3 to 33.3% for the glitazone group. Both groups had similar changes in high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol and triglycerides. In the probit regression model, age, HbA_1c, weight, treatment for weight reduction, history of macrovascular complications and type of physician were significant factors associated with treatment choice. Conclusions: This study is consistent with the results of long‐term randomized clinical trials in a clinical practice setting. Both regimens were able to reduce HbA_1c by about 1%.     

Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study

Aims/hypothesis. This study analysed cause-specific mortality in Type II (non-insulin-dependent) diabetic patients using either sulphonylurea alone or in combination with metformin. Methods. Patients were followed from the first day they were taking either the combination or sulphonylurea alone. Odds ratios by Cox regression analyses were adjusted for age, sex, duration of diabetes, study area, year of inclusion and fasting blood glucose at inclusion. Results. We included 169 patients taking sulphonylurea and metformin in combination and 741 patients taking only sulphonylurea. Mean (range) follow-up time was 6.1 (0.1–13.0) years. The adjusted odds ratio for overall mortality was 1.63 (95 % confidence interval 1.27–2.09) in patients taking sulphonylurea and metformin combination vs those using sulphonylurea alone. For mortality from ischaemic heart disease and stroke the adjusted odds ratios were 1.73 (95 % confidence interval 1.17–2.55) and 2.33 (95 % confidence interval 1.17–4.63), respectively. Conclusion/interpretation. There was a higher cardiovascular mortality in Type II diabetic patients taking sulphonylurea and metformin in combination than in those taking only sulphonylurea. Hence, it cannot be excluded that this kind of combination therapy possibly increases cardiovascular mortality. It is feasible that the increased mortality was secondary to a more aggressive type of diabetes in the patients using sulphonylurea and metformin in combination. Combination therapy is known to promote additional blood glucose reduction but there is as yet no evidence that a sulphonylurea and metformin combination is more beneficial on micro- or macrovascular disease than sulphonylurea or metformin alone. [Diabetologia (2000) 43: 558–560] Received: 6 December 1999 and in revised form: 7 February 2000     

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

Aims: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed‐dose combination of sitagliptin and metformin versus metformin monotherapy in drug‐naive patients with type 2 diabetes. Methods: This double‐blind study (18‐week Phase A and 26‐week Phase B) randomized 1250 drug‐naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. Results: At week 18, mean change from baseline HbA1c was ?2.4% for sitagliptin/metformin FDC and ?1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (?3.8 mmol/l) versus metformin monotherapy (?3.0 mmol/l; p < 0.001). Homeostasis model assessment of β‐cell function (HOMA‐β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Conclusion: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.     

Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus

OBJECTIVES: To study effects of insulin-induced hypoglycaemia on the cardiac repolarization, using QT interval measurements, in patients with type 2 diabetes. DESIGN: Hypoglycaemia was induced by an i.v. insulin-infusion and blood glucose was clamped at 2.7 mmol L-1 for 60 min (T = 90-150 min) in two experiments, with (+GLIB) and without (-GLIB) glibenclamide. In a third experiment, with similar hyperinsulinaemia, glucose was clamped at a euglycaemic level (;5 mmol L-1). ECG was continuously recorded for arrhythmia-monitoring, and 12-lead ECGs were recorded at T = 0 and 150 min. QT intervals were measured, and we determined QT dispersion (difference between the maximum and the minimum QT interval) reflecting interlead variability of repolarization. SUBJECTS: Thirteen patients with type 2 diabetes, on combined insulin and glibenclamide treatment, were studied during hypoglycaemia, and eight of them participated in the euglycaemic experiment. RESULTS: No significant arrhythmias were seen during hypoglycaemia but the mean QT intervals and QT dispersion increased significantly (P < 0.001), with no differences between -GLIB and +GLIB. During the euglycaemic clamp all QT measurements remained unchanged. Serum potassium decreased significantly (P < 0.001) during all three clamps, but the decrease was more pronounced during hypoglycaemia. The change in potassium was not correlated to the degree of QT prolongation or QT dispersion. CONCLUSIONS: Significant changes in the repolarization of the heart can be seen during hypoglycaemia in patients with type 2 diabetes, indicating an increased risk of arrhythmia at low blood glucose levels.     

Earlier triple therapy with pioglitazone in patients with type 2 diabetes

Aims: This study assessed the efficacy of add‐on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. Methods: This multicentre, double‐blind, parallel‐group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA_1c) ≤6.5%] or titrated up to 45 mg (if HbA_1c >6.5%), or placebo for a further 4 months. The primary efficacy end‐point was improvement in HbA_1c (per cent change). Secondary end‐points included changes in fasting plasma glucose (FPG), insulin, C‐peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐B) were calculated. Results: Pioglitazone add‐on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between‐group difference after 7 months of triple therapy was 1.18% in HbA_1c and ?2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA_1c level of <8.5% achieved the HbA_1c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA_1c level was ≥ 8.5%, 13% achieved the HbA_1c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA‐IR, insulin, proinsulin and C‐peptide decreased and HOMA‐B increased in the pioglitazone group relative to the placebo group. Conclusions: In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA_1c, FPG and surrogate measures of β‐cell function. Patients were more likely to reach target HbA_1c levels (< 7.0%) with pioglitazone treatment if their baseline HbA_1c levels were < 8.5%, highlighting the importance of early triple therapy.     

Lipoprotein risk factors for cardiovascular disease in patients with type 2 diabetes mellitus treated with oral antihyperglycaemic agents

Aims:  To compare lipoprotein risk factors for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM) treated with a sulphonylurea (SU) compound only, metformin (MET) only, or combined SU + MET.
Methods:  The study population consisted of 62 patients with type 2 DM, whose antihyperglycaemic treatment program had been stable for at least 3 months, divided into three groups: 26 patients in the SU group, 17 patients in the MET group and 19 patients in the SU + MET group. None of the patients were taking lipid-lowering drugs. Fasting venous blood samples were taken to measure concentrations of glucose, total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and remnant lipoprotein-cholesterol (RLP-C) as well as for determination of LDL particle diameter.
Results:  The three groups were similar in terms of age, gender, body mass index and fasting plasma glucose concentrations. Total cholesterol concentrations were significantly lower (p < 0.05 for trend) in those treated with SU + MET as compared with the other two groups. However, there were no significant differences between the three groups in their plasma concentrations of TG, LDL-C, HDL-C or RLP-C; furthermore, the proportion of individuals within each treatment group with small LDL particle diameter was also not different.
Conclusions:  The lipoprotein profile of patients with type 2 DM, matched for level of fasting hyperglycaemia, was similar irrespective of treatment with SU alone, MET alone or SU + MET. Thus, we could not identify any changes in lipoprotein metabolism that could account for differences in risk of CVD as a function of treatment.     

Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.