Is statin-induced diabetes clinically relevant? A comprehensive review of the literature.

In those predisposed to the development of diabetes (the insulin resistant, obese and older patients) statins may increase the risk of developing diabetes. Despite the fact that the conversion to diabetes is generated from post hoc analyses, it seems to be a class effect with a dose-response relationship. However, statins have not been clearly shown to increase diabetic microvascular complications (retinopathy, nephropathy and neuropathy). Thus, the clinical significance of increased glucose levels in patients treated on statins is uncertain. While the exact mechanism for how statins increase the risk of diabetes is unknown, a possible explanation is through a reduction in adiponectin levels. Despite the fact that higher statin doses are more likely to lead to new-onset diabetes, for every case of diabetes caused, there are approximately three cardiovascular events reduced with high dose versus moderate dose statin therapy. Overall, the small risk of developing type 2 diabetes with statin therapy is far outweighed by the potential of statins to decrease cardiac events.

Combine and conquer: advantages and disadvantages of fixed-dose combination therapy.

The majority of patients with type 2 diabetes mellitus (T2DM) do not achieve the glycaemic goals recommended by leading diabetes organizations using monotherapy alone, and often require multiple antihyperglycaemic agents to achieve glycaemic control. Fixed-dose combination (FDC) therapies offer a means to simplify complex treatment regimens, and have several advantages that help patients reach their glycaemic goals. In this review, four key benefits are identified and discussed in support of FDCs for treatment of patients with T2DM: (i) Greater efficacy compared with higher dose monotherapy, (ii) Reduced risk of adverse reactions relative to higher dose monotherapy, (iii) Lower overall costs and (iv) Improved medication concordance. Given these advantages, the place of fixed combination therapy in the course of treatment is discussed. Establishing a therapeutic strategy that incorporates fixed combination therapy (including combinations with insulin) will simplify the treatment of diabetes, ideally resulting in improved medication concordance, clinical outcomes and quality of life for patients with T2DM.

Beware the low urine pH--the major cause of the increased prevalence of nephrolithiasis in the patient with type 2 diabetes.

There is an increased prevalence of nephrolithiasis and an increase in the incidence of renal colic in patients with diabetes, obesity, hypertension and insulin resistance because of an increased frequency of uric acid crystallization. Uric acid crystallization occurs in the milieu of an acid urine and is not due to hyperuricosuria as with insulin resistance, urinary uric acid levels are generally decreased because of increased renal tubular reabsorption. However, in the presence of insulin resistance, there is decreased renal tubular generation of ammonia and increased sodium absorption leading to acidification of the urine and uric acid crystallization. The presence of a low urine pH should alert the clinician to the increased risk of nephrolithiasis particularly in the obese, diabetic or hypertensive patient. Prevention of nephrolithiasis can be achieved in susceptible individuals either by alkalizing the urine and/or by further decreasing the uric acid content of the urine with a xanthine oxidase inhibitor such as allopurinol.

Why does quick-release bromocriptine decrease cardiac events?

A placebo-controlled prospective safety study of quick-release bromocriptine in patients with type 2 diabetes has shown a 40% reduction in cardiovascular events. Possible explanations for this decrease are that through re-establishing diurnal variation a decrease in insulin resistance and its associated risk factors occurs. In addition, a decrease in the activity of the sympathetic nervous and renin-angiotensin systems and re-establishment of diurnal variations in the pituitary-adrenal axis may play a role. However, the most probable explanation is that because of the lowering of insulin resistance there are decreases in hepatic glucose production and an increased uptake of glucose leading to decreased levels of postprandial glucose, free fatty acids and triglycerides, which cause decreases in inflammation, oxidative stress and accumulation of atheroma.

Triple oral fixed-dose diabetes polypill versus insulin plus metformin efficacy demonstration study in the treatment of advanced type 2 diabetes (TrIED study-II).

AIM: To compare the efficacy of a fixed-dose triple oral diabetes polypill containing 1 or 2 mg glimepiride, 500 mg sustained-release metformin, and 15 mg pioglitazone (GMP) administered once daily with human insulin 70/30 mix and 500 mg sustained-release metformin administered twice daily (IM) in insulin-naÏve subjects with type 2 diabetes mellitus inadequately controlled [haemoglobin A1c (HbA1c) over 8.0%] on a combination of glimepiride and metformin. METHODS: One hundred and one subjects were randomized to GMP or IM regimens for 12 weeks. The primary outcome was the change in HbA1c and secondary outcomes were changes in fasting plasma, and postprandial plasma glucoses and the number of patients achieving a drop in HbA1c of over 1%. Other secondary outcomes were changes in the lipid profile, C-peptide level, body weight as well as physician assessments of efficacy and patient assessment of tolerability. RESULTS: The primary outcome of a change in HbA1c showed a trend towards a lower HbA1c with GMP therapy (-1.33% vs. -0.83%; p = 0.059). The number of subjects achieving a decrease in HbA1c of greater than 1.0% was significantly greater in the GMP therapy (72.5% vs. 22%; p = 0.0001). Both regimens equally and significantly reduced fasting and postprandial glucose levels (p = 0.05). Weight gain was nonsignificantly greater with IM (2.69 vs. 0.92 kg; p = 0.223). Investigator assessment of efficacy was significantly better with GMP (p = 0.001) as was tolerability as assessed by patients (p = 0.0001). CONCLUSION: When compared with suboptimally titrated IM there was a trend towards a lower HbA1c with GMP and significantly more GMP subjects obtained an HbA1c under 7%. Global assessments by investigators and subjects showed both a greater efficacy and tolerability with GMP.

Therapies for diabetic dyslipidaemia.

Correction of diabetic dyslipidaemia in diabetic patients is the most important factor in reducing cardiac risk. Diabetic dyslipidaemia is characterized by elevated triglycerides, low total high-density lipoprotein (HDL) and small dense low-density lipoprotein (LDL) particles. The most important therapeutic goal in diabetic dyslipidaemia is correction of the non-HDL-cholesterol (HDL-C) level. Glycaemic control with particular attention to postprandial glucose control plays a role not only in improving dyslipidaemia but also in lowering cardiac events. Pioglitazone is particularly effective for improving the manifestations of diabetic dyslipidaemia, in addition to its favorable effects on systemic inflammation and hyperglycaemia. Use of statins in addition to lifestyle change is recommended in most if not all type 2 diabetic patients and the goal should be to lower the LDL to a level recommended for the patient with existing cardiovascular disease (CVD) (non-HDL-C level <100 mg/dl). In addition, therapies for normalization of HDL and triglyceride levels should be deployed. Most patients with type 2 diabetes (T2D) will require combining a lipid-lowering therapy with therapeutic lifestyle changes to achieve optimal lipid levels. Combinations usually include two or more of the following: a statin, nicotinic acid, omega-3 fats and bile acid sequestrants (BASs). Fibrates may also be of use in diabetic patients with persistently elevated triglycerides and depressed HDL-C levels, although their role in lowering adverse CV events is questionable.

Rediscovering bile acid sequestrants.

AIM: In the recently published The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) mega-trial, rosuvastatin significantly reduced cardiovascular events at the expense of a small but significant increase in the risk of developing type 2 diabetes. The increased risk of new-onset diabetes was in keeping with a recent meta-analysis which suggested that statins, with the possible exception of pravastatin, marginally increase the risk of developing type 2 diabetes. METHODS: Although the net effect of rosuvastatin was obviously very positive, we hypothesized that the addition of a bile aid sequestrant to a statin would not only further decrease lipid levels and potentially further decrease cardiovascular events but also protect against the development of diabetes. This is particularly relevant because the bile acid sequestrant, colesevelam, has recently been approved for therapy of diabetes. RESULTS: Colesevelam like other bile acid sequestrants lowers low-density lipoprotein levels by 16% and C-reactive protein by 22% beyond the reductions that occur with statin therapy alone. Bile acid sequestrants confer lipid-lowering, glucose-lowering, and anti-inflammatory benefits, and have been shown to reduce risk of cardiovascular events. CONCLUSIONS: Therefore, colesevelam should be the most effective and logical agent to add to a statin in the diabetic and insulin-resistant patient, because in addition to lowering cardiac risk it may prevent the development of diabetes, as well as improving glycaemic control in the established diabetic patient.

Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients.

CONTEXT: Vasoconstricting beta-blocker use is associated with a reduction in HDL cholesterol, higher triglyceride, total cholesterol and LDL cholesterol levels, whereas carvedilol, a vasodilating beta-blocker, has not been associated with these effects. OBJECTIVE: To compare in a randomized, double-blind study, the effects of the beta 1-blocker metoprolol tartrate with the combined alpha 1, beta-blocker carvedilol on serum lipid concentrations. METHODS: A prospective randomized, double-blind, parallel-group trial compared the effects of carvedilol and metoprolol on total cholesterol, triglycerides, calculated LDL, HDL and non-HDL cholesterol levels at baseline and after 5 months of therapy as a secondary objective in the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensive (GEMINI) study. In this study, 1235 participants with type 2 diabetes and hypertension who were receiving renin-angiotensin system blockers were randomized either to carvedilol, receiving 6.25-25 mg twice daily, or to metoprolol tartrate, receiving 50-200 mg twice daily. If needed, hydrochlorothiazide and a dihydropyridine calcium channel blocker were added to achieve blood pressure goals. RESULTS: In the metoprolol tartrate group, triglycerides and non-HDL cholesterol increased and both the LDL and the HDL cholesterol levels decreased. In the carvedilol group, total LDL and HDL cholesterol decreased, non-HDL cholesterol was unchanged and triglycerides increased. Comparing the carvedilol and metoprolol tartrate groups, there was no statistically significant difference in LDL and HDL cholesterol levels, but there was a significantly greater decreases with carvedilol in total cholesterol [-2.9%, 95% confidence interval (CI) -4.60 to -1.15, p < 0.001], triglycerides (-9.8%, 95% CI -13.7, -5.75%, p < 0.001) and non-HDL cholesterol (-4.03%, 95% CI -6.3 to -1.8, p < 0.0006). At the end of the study, significantly more participants in the metoprolol tartrate group had had initiation of statin therapy or the statin dose increased than those in the carvedilol group (11 vs. 32%, p = 0.04). CONCLUSIONS: In patients with type 2 diabetes currently receiving a renin-angiotensin blocker, compared with metoprolol tartrate, the addition of carvedilol for blood pressure control resulted in a significant decrease in triglyceride, total cholesterol and non-HDL cholesterol levels. The use of metoprolol resulted in a significantly greater rate of initiation of statin therapy or an increase in the dose of existing statin therapy when compared with carvedilol utilization.

Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

beta-blocker use and diabetes symptom score: results from the GEMINI study.

AIM: The Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two beta-blockers in people with type 2 diabetes and hypertension treated with renin-angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two beta-blockers on commonly reported symptoms. METHODS: The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. RESULTS: Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (-0.08; 95% CI -0.15, -0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (-0.12; 95% CI -0.23, -0.02; p = 0.02) and hyperglycaemia symptoms (-0.16; 95% CI -0.27, -0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. CONCLUSION: Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated beta-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes.

Long-term glycaemic efficacy and weight changes associated with thiazolidinediones when added at an advanced stage of type 2 diabetes.

OBJECTIVE: To describe the outcome of 35 patients with type 2 diabetes prospectively followed for 6 years after the addition of a thiazolidinedione (TZD) to a failing regimen of a sulphonylurea and metformin -- triple oral therapy. METHODS: Study patients were assessed for the need for the addition of insulin to their regimen, and follow-up clinical and laboratory findings were analysed. RESULTS: At a mean follow-up of 72 +/- 1.5 months (range 53-80), 18 (51%) of patients remained well controlled on triple oral therapy with a mean glycosylated haemoglobin (HbA1c) value of 6.9 +/- 0.2% (upper limit of normal 6.2%). In 17 other patients, triple oral therapy failed and the use of insulin was necessary after a mean duration of 38 (range 18-68) months. The mean HbA1c in these patients was 8.0 +/- 0.3%. The group that was maintained on triple oral therapy gained 15.2 +/- 1.9 lbs over the 6-year study which was significantly higher than the baseline weight. Alternatively, the group that failed and had insulin added to their therapy gained 20.2 +/- 4.5 lbs over the same period which was also significantly different from baseline but not from the triple oral therapy group. Although after 3 years a trend towards weight loss occurred in the triple oral therapy group, the insulin-added group continued to gain weight. Stimulated C-peptide levels increased significantly in the triple therapy group from 3.6 +/- 0.9 to 4.3 +/- 1.2 ng/ml and had not increased or decreased non-significantly from 3.7 +/- 0.8 to 3.2 +/- 0.6 ng/ml at the time of insulin initiation in the insulin-requiring group. CONCLUSION: When used late in the course of type 2 diabetes, TZDs result in improved and prolonged glycaemic control which persisted for a median time of 6 years. Weight gain with TZDs peaks and then plateaus (and even trends downwards) at 3 years, although the addition of insulin to a failing oral therapy regimen results in a further and continuing weight gain in spite of inferior glycaemic control. Continuing glycaemic control with triple oral therapy is dependent on preservation or augmentation of endogenous insulin production.

Outcomes of initiation of therapy with once-daily combination of a thiazolidinedione and a biguanide at an early stage of type 2 diabetes.

CONTEXT: Utilization of the biguanide metformin and a thiazolidinedione (TZD) with new onset diabetes has the benefit of lowering A1cs into the normal range without the problem of severe hypoglycaemia. OBJECTIVE: To assess the effectiveness of once-daily combined metformin and TZD therapy compared with other therapeutic regimens typically utilized at later stages of type 2 diabetes. METHODS: A random chart review of 300 type 2 diabetic patients and extraction of data for body mass index (BMI), duration of diabetes and C-peptide and A1c was performed. In the 210 type 2 diabetic subjects in whom this information was currently available, the data were analysed. RESULTS: Eighty-six patients on once-daily metformin and rosiglitazone had an average A1c of 6.2% (group A), and 58 subjects on triple therapy (metformin, rosiglitazone and glimepiride) (group B) had an average haemoglobin A1c (HbA1c) of 6.9%. The 22 subjects on one injection of insulin per day in addition to triple therapy (group C) had an average HbA1c of 7.6%, and the 44 subjects on more than one insulin injection per day plus metformin and/or rosiglitazone (group D) had an average HbA1c of 8.3%. HbA1cs below 7.0% were found in 91.9% of group A, 21.7% of group B, 36.4% of group C and 56.8% of group D. HbA1cs below 6.5% were found in 78.2% in group A, 15.5% in group B, 22.7% in group C and 31.8% in group D. HbA1cs below 6.0% were found in 41.9% in group A, 6.9% in group B, 9.1% in group C and 13.6% in group D. On univariate analyses, the HbA1c was positively associated with the duration of diabetes and the BMI and negatively associated with random C-peptide levels. Alternatively, on multiple regression analysis, there was no statistical correlation between the duration of diabetes or BMI with the HbA1c. However, there was a strong statistical correlation between the random C-peptide level and the HbA1c (p = 0.002). CONCLUSION: Early initiation of therapy for type 2 diabetes with a once-daily combination of metformin and rosiglitazone provides the greatest opportunity to achieve A1cs within the normal range. The level of achieved glycaemic control is not dependent on the number or potency of the therapies utilized but is dependent on the level of endogenous insulin production. The use of a TZD as part of initial therapy of type 2 diabetes with its documented ability to preserve or improve beta-cell function has the potential to achieve prolonged normoglycaemia in the type 2 diabetic patient.

Clinical evidence of thiazolidinedione-induced improvement of pancreatic beta-cell function in patients with type 2 diabetes mellitus.

BACKGROUND: There is growing evidence in animal and in vitro studies showing that thiazolidinediones (TZDs) improve pancreatic beta cell (beta-cell) function. The aim of this study was to evaluate the effect of thiazolidinediones on the beta-cell function of patients with Type 2 diabetes mellitus (T2DM) in clinical practice. PATIENTS AND METHODS: This is an observational, nested case-control study. We identified 28 patients (TZD group), with T2DM, who had had a meal-stimulated C-peptide level documented before the addition of troglitazone to a failing double-therapy regimen with metformin (MET) and sulphonylurea (SU). As a control group (CTRL), we identified 26 patients, with T2DM, who also had had a meal-stimulated C-peptide documented before adding MET to a failing SU monotherapy regimen. We then proceeded to prospectively remeasure their meal-stimulated C-peptide levels and compared the changes over time between the two groups. RESULTS: Both groups were well matched for age, body mass index (BMI), and HgbA1c before and after treatment. The C-peptide in the TZD group increased significantly during therapy (from 3.2 +/- 0.5 to 4.2 +/- 0.5, p = 0.01), whereas it remained unchanged in the CTRL group (from 4.8 +/- 0.6 to 5.0 +/- 0.5, p = 0.74). The C-peptide/glucose ratio also increased significantly in the TZD group (from 1.9 +/- 0.3 to 3.1 +/- 0.3, p = 0.0003) whereas it remained unchanged in the CTRL group (from 3.4 +/- 0.7 to 3.4 +/- 0.3, p = 0.97). Furthermore, the C-peptide/glucose ratio of the TZD group, which was significantly lower at baseline compared with the CTRL group (1.9 +/- 0.3 vs. 3.4 +/- 0.7, p = 0.04), caught up to its level during treatment (3.1 +/- 0.3 vs. 3.4 +/- 0.3, p = 0.48). CONCLUSION: Thiazolidinediones seem to induce recovery of pancreatic beta cell function, independently of the correction of glucose toxicity.