Source: Diabetes Care
Effects of combined ezetimibe and simvastatin therapy as compared to simvastatin alone in patients with type 2 diabetes: a prospective, randomized, double-blind, clinical trial
Ruggenenti P, Cattaneo D, Rota S, Iliev I, Parvanova A, Diadei O, Ene-Iordache B, Ferrari S, Bossi AC, Trevisan R, Belviso A, Remuzzi G, for the Ezetimibe and Simvastatin in dyslipidemia of Diabetes (ESD) Study Group;
Diabetes Care (Jun 2010)
Abstract
Objective: To assess the effects of inhibited gastrointestinal cholesterol absorption in statin-treated dyslipidemic patients.
Research Design and Methods: In a multi-center, prospective, randomized, double-blind, placebo-controlled trial we primarily compared by ANCOVA the effect of 2-month ezetimibe (10 mg/day) or placebo therapy on low-density-lipoprotein (LDL) cholesterol serum levels in 108 type 2 diabetes patients with albuminuria<200 mug/min and total cholesterol concentrations>135 mg/dL despite simvastatin treatment (40 mg/day)
Results: Unlike placebo, ezetimibe decreased LDL cholesterol from 99+/-31 to 66+/-22 mg/dL, total cholesterol from 162+/-36 to 124+/-30 mg/dL and apolipoprotein B from 83+/-22 to 64+/-18 mg/dL (p<0.0001 for all changes vs placebo). Seventy-two and 17% of patients on ezetimibe or placebo achieved LDL levels<70 mg/dL, respectively (p<0.0001). Treatment was well tolerated.
Conclusions: Adding ezetimibe to simvastatin therapy helps improving pro-atherogenic lipoprotein profile in type 2 diabetes patients who fail to reach recommended lipid targets with statin therapy alone.
Wednesday, June 30, 2010
Not strictly diabetes this one - but of interest to endocrinologists:
Source: J Clin Oncol
Oral Bisphosphonate Use and Breast Cancer Incidence in Postmenopausal Women;
Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, McTiernan A, Lane DS, Manson JE, Snetselaar L, Yasmeen S, O'Sullivan MJ, Safford M, Hendrix SL, Wallace RB; Journal of Clinical Oncology (JCO) (Jun 2010)
ABSTRACT
PURPOSE Emerging clinical evidence suggests intravenous bisphosphonates may inhibit breast cancer while oral bisphosphonates have received limited evaluation regarding breast cancer influence.
PATIENTS AND METHODS The association between oral bisphosphonate use and invasive breast cancer was examined in postmenopausal women enrolled onto the Women's Health Initiative (WHI). We compared a published hip fracture prediction model, which did not incorporate bone mineral density (BMD), with total hip BMD in 10,418 WHI participants who had both determinations. To adjust for potential BMD difference based on bisphosphonate use, the hip fracture prediction score was included in multivariant analyses as a BMD surrogate.
RESULTS Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; P<.001; r = 0.43) and breast cancer incidence (P = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; P<.01) as was incidence of estrogen receptor (ER)-positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, P = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; P = .02).
CONCLUSION Oral bisphosphonate use was associated with significantly lower invasive breast cancer incidence, suggesting bisphosphonates may have inhibiting effects on breast cancer.
Source: J Clin Oncol
Oral Bisphosphonate Use and Breast Cancer Incidence in Postmenopausal Women;
Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, McTiernan A, Lane DS, Manson JE, Snetselaar L, Yasmeen S, O'Sullivan MJ, Safford M, Hendrix SL, Wallace RB; Journal of Clinical Oncology (JCO) (Jun 2010)
ABSTRACT
PURPOSE Emerging clinical evidence suggests intravenous bisphosphonates may inhibit breast cancer while oral bisphosphonates have received limited evaluation regarding breast cancer influence.
PATIENTS AND METHODS The association between oral bisphosphonate use and invasive breast cancer was examined in postmenopausal women enrolled onto the Women's Health Initiative (WHI). We compared a published hip fracture prediction model, which did not incorporate bone mineral density (BMD), with total hip BMD in 10,418 WHI participants who had both determinations. To adjust for potential BMD difference based on bisphosphonate use, the hip fracture prediction score was included in multivariant analyses as a BMD surrogate.
RESULTS Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; P<.001; r = 0.43) and breast cancer incidence (P = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; P<.01) as was incidence of estrogen receptor (ER)-positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, P = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; P = .02).
CONCLUSION Oral bisphosphonate use was associated with significantly lower invasive breast cancer incidence, suggesting bisphosphonates may have inhibiting effects on breast cancer.
ADA 2010
The use of Thiazolidinediones in the current clinical context was reviewed in a symposium on the opening day of the 2010 ADA conference in Orlando.
Data suggesting that markers of bone formation are reduced in patients taking Rosiglitazone whilst resorption is unaltered were shown to attendees (Grey et al. JCEM 2007; 92: 1305-10).
More recent data supporting the possibility that this may result in bone thinning with a 2% reduction in BMD after 3 months of therapy with Rosiglitazone in diabetes were also presented (JCEM 2010; 95: 134-142).
Data from PCOS patients were then presented and suggest that a similar phenomenon is observed when this cohort is treated with Pioglitazone, raising the probability that there is a class effect for adverse metabolic activity in bone for the TZD’s.
It was pointed out to delegates that this theoretical risk is supported by data from the ADOPT study where increased fracture risk was observed in TZD treated patients. The RECORD study confirms this finding with the observation of increased long bone fractures, especially in women.
In concluding the presentation of TZD bone data, delegates were reminded that the skeletal risk conferred by TZD therapy was related to duration of therapy.
Data are incomplete, and it is not yet clear whether TZD use in men confers the same fracture risk as occurs in women. However the risk to bone health of long term therapy TZD's should be explained when initiaing this therapy for people with diabetes.
The use of Thiazolidinediones in the current clinical context was reviewed in a symposium on the opening day of the 2010 ADA conference in Orlando.
Data suggesting that markers of bone formation are reduced in patients taking Rosiglitazone whilst resorption is unaltered were shown to attendees (Grey et al. JCEM 2007; 92: 1305-10).
More recent data supporting the possibility that this may result in bone thinning with a 2% reduction in BMD after 3 months of therapy with Rosiglitazone in diabetes were also presented (JCEM 2010; 95: 134-142).
Data from PCOS patients were then presented and suggest that a similar phenomenon is observed when this cohort is treated with Pioglitazone, raising the probability that there is a class effect for adverse metabolic activity in bone for the TZD’s.
It was pointed out to delegates that this theoretical risk is supported by data from the ADOPT study where increased fracture risk was observed in TZD treated patients. The RECORD study confirms this finding with the observation of increased long bone fractures, especially in women.
In concluding the presentation of TZD bone data, delegates were reminded that the skeletal risk conferred by TZD therapy was related to duration of therapy.
Data are incomplete, and it is not yet clear whether TZD use in men confers the same fracture risk as occurs in women. However the risk to bone health of long term therapy TZD's should be explained when initiaing this therapy for people with diabetes.
ADA 2010
Delegates at the ADA were reminded that there is limited data to support the addition of fibrates to statin therapy to enhance the benefit of further cholesterol lowering in people with diabetes.
However the results from the ACCORD study illustrate that in people with the most pronounced lipid abnormalities, there was a strong signal for benefit when fenofibrate therapy was combined with simvastatin.
Moving on to consideration of niacin therapy Dr John Guyton pointed out that increasing HDL levels may confer cardiovascular benefits. The conference was told that whilst many things (including alcohol) increase HDL concentrations, almost all outcome studies have shown that increasing HDL levels with Niacin therapy confer benefit through reduced end points. For instance the Coronary Drug Project and the Stockholm IHD study demonstrated reduced coronary event rates with HDL elevation through Niacin therapy. Other studies have shown reduced atherogenesis (eg. Lee et al. JACC 2009; 54: 1787-94)
Carotid Intimal thickness also benefits with Niacin when compared with Ezetimibe therapy in the ARBITER-6/HALTS (Taylor AJ. NEJM 2009; 361). It should be noted however that Carotid Intimal thickness may not directly equate to cerebrovascular event rates.
Dr Guyton briefly reviewed the data which suggest that “no-flush” Niacin does not raise HDL Cholesterol, and pointed out that the ability to cause flushing is linked to the mechanism through which Niacin benefits the lipid profile.
However, whilst flushing demonstrates tachyphylaxis and will usually resolve, the HDL elevation is durable. He pointed out that it can take 6 months for flushing to fully resolve, but that most patients tolerate this phenomenon as long as suitably warned in advance of starting Niacin.
In concluding delegates were reminded that in terms of consistency of cardiovascular benefit, Niacin is second only to the statins. It was also pointed out that Niacin is the most effective HDL raising agent in use today, and that recent advances may help to reduce flushing in the future.
Delegates at the ADA were reminded that there is limited data to support the addition of fibrates to statin therapy to enhance the benefit of further cholesterol lowering in people with diabetes.
However the results from the ACCORD study illustrate that in people with the most pronounced lipid abnormalities, there was a strong signal for benefit when fenofibrate therapy was combined with simvastatin.
Moving on to consideration of niacin therapy Dr John Guyton pointed out that increasing HDL levels may confer cardiovascular benefits. The conference was told that whilst many things (including alcohol) increase HDL concentrations, almost all outcome studies have shown that increasing HDL levels with Niacin therapy confer benefit through reduced end points. For instance the Coronary Drug Project and the Stockholm IHD study demonstrated reduced coronary event rates with HDL elevation through Niacin therapy. Other studies have shown reduced atherogenesis (eg. Lee et al. JACC 2009; 54: 1787-94)
Carotid Intimal thickness also benefits with Niacin when compared with Ezetimibe therapy in the ARBITER-6/HALTS (Taylor AJ. NEJM 2009; 361). It should be noted however that Carotid Intimal thickness may not directly equate to cerebrovascular event rates.
Dr Guyton briefly reviewed the data which suggest that “no-flush” Niacin does not raise HDL Cholesterol, and pointed out that the ability to cause flushing is linked to the mechanism through which Niacin benefits the lipid profile.
However, whilst flushing demonstrates tachyphylaxis and will usually resolve, the HDL elevation is durable. He pointed out that it can take 6 months for flushing to fully resolve, but that most patients tolerate this phenomenon as long as suitably warned in advance of starting Niacin.
In concluding delegates were reminded that in terms of consistency of cardiovascular benefit, Niacin is second only to the statins. It was also pointed out that Niacin is the most effective HDL raising agent in use today, and that recent advances may help to reduce flushing in the future.
Sunday, June 27, 2010
ADA 2010
In a session discussing the management of insulin resistant people with type-2 diabetes treated with insulin Professor Matthew Riddle reviewed current knowledge of this patient group.
He reminded delegates of the recent publication of the 4-T study (Holman RR et al. NEJM 2009; 361: 1736-47) in which it was demonstrated that even with intensive treatment algorithms about 50% of insulin treated type-2 diabetic patients do not achieve a HbA1c < 7.0%.
He pointed out that attainment of this target is affected by HbA1c at initiation of insulin therapy with fewer patients achieving target if HbA1c is > 8.5% at introduction of injections (Riddle MC et al. Diabetes 2009; 58 (suppl 1) A125).
Data exist which show that attainment of ideal target morning fasting glucose by bedtime basal insulin is possible. However the addition of prandial insulin often fails to maintain post-meal normoglycaemia, and the result is that pre-meal glucose values do not return to target. Furthermore, insulin use in type-2 diabetes is associated with both weight gain and hypoglycaemia.
Thus the hunt is on for a therapy, or combination of therapies which will attain targets in greater numbers, ideally lead to less hypoglycaemia and attenuate weight gain in this already insulin resistant group of patients.
Professor Riddle went on to present some recent data from the INSTEAD study (Riddle MC. Diab Care 2009; 32: 1577-82) which suggest that combining the Amylin analogue Pramlinitide to basal insulin results in less insulin use, equivalent HbA1c reduction and zero hypoglycaemia when compared to the addition of prandial insulin.
He then showed data presented in late breaking abstracts at this year’s ADA meeting which suggest that combining the GLP-1 analogue Exenatide with glargine insulin results in statistically more patients achieving an HbA1c target < 7.0% in the MEXELIN study (Riddle MC et al. 18-LB ADA2010). This exciting data are extended by the observation that adding exenatide to insulin glargine achieved glycaemic targets whilst achieving weight loss and without increased risk of hypoglycaemia (Buse et al. 10-LB ADA 2010).
Whilst we await the publication of ongoing longer term outcome studies investigating the combination of insulin and GLP-1 analogues, these data suggest that there may be efficacy and safety reasons for clinical use of such combinations in overweight insulin resistant patients.
In a session discussing the management of insulin resistant people with type-2 diabetes treated with insulin Professor Matthew Riddle reviewed current knowledge of this patient group.
He reminded delegates of the recent publication of the 4-T study (Holman RR et al. NEJM 2009; 361: 1736-47) in which it was demonstrated that even with intensive treatment algorithms about 50% of insulin treated type-2 diabetic patients do not achieve a HbA1c < 7.0%.
He pointed out that attainment of this target is affected by HbA1c at initiation of insulin therapy with fewer patients achieving target if HbA1c is > 8.5% at introduction of injections (Riddle MC et al. Diabetes 2009; 58 (suppl 1) A125).
Data exist which show that attainment of ideal target morning fasting glucose by bedtime basal insulin is possible. However the addition of prandial insulin often fails to maintain post-meal normoglycaemia, and the result is that pre-meal glucose values do not return to target. Furthermore, insulin use in type-2 diabetes is associated with both weight gain and hypoglycaemia.
Thus the hunt is on for a therapy, or combination of therapies which will attain targets in greater numbers, ideally lead to less hypoglycaemia and attenuate weight gain in this already insulin resistant group of patients.
Professor Riddle went on to present some recent data from the INSTEAD study (Riddle MC. Diab Care 2009; 32: 1577-82) which suggest that combining the Amylin analogue Pramlinitide to basal insulin results in less insulin use, equivalent HbA1c reduction and zero hypoglycaemia when compared to the addition of prandial insulin.
He then showed data presented in late breaking abstracts at this year’s ADA meeting which suggest that combining the GLP-1 analogue Exenatide with glargine insulin results in statistically more patients achieving an HbA1c target < 7.0% in the MEXELIN study (Riddle MC et al. 18-LB ADA2010). This exciting data are extended by the observation that adding exenatide to insulin glargine achieved glycaemic targets whilst achieving weight loss and without increased risk of hypoglycaemia (Buse et al. 10-LB ADA 2010).
Whilst we await the publication of ongoing longer term outcome studies investigating the combination of insulin and GLP-1 analogues, these data suggest that there may be efficacy and safety reasons for clinical use of such combinations in overweight insulin resistant patients.
Diabetes is NOT a cardiovascular disease equivalent and there is limited data to support the <70 mg/dl target for total cholesterol argued Prof Lawrence Leiter from the University of Toronto at the ADA 2010.
He pointed out that there is no study that set 70mg/dl as the cholesterol target and that this is an extrapolated figure based on several other studies.
He reminded the audience of the abundant data that suggest that diabetes is not a cardiovascular disease equivalent and that patients should have a suitable lipid management strategy based on their current total cardiovascular risk.
He reviewed briefly a 2008 meta-analysis published in the Lancet that demonstrated that people with diabetes derive the same overall risk reduction from cholesterol reduction as people without diabetes.
He also reminded the delegates that data from the NHANES population suggest that it is the presence of metabolic syndrome in additon to diabetes which confers increased cardiovascular risk rather than diabetes per se.
In an amusing aside he quoted a 2008 ADA survey which showed that the American population are more afraid of shark bites than diabetes; with 49% afraid of cancer, 12% heart disease, 11% stroke, 4% shark bites and only 3% fearing diabetes!
In concluding Professor Leiter demonstrated data from Framingham and elsewhere which show that the presence of diabetes causes the risk of heart disease to occur some 15 years earlier than would be the case without diabetes in both men and women. Thus he supported the use of an age of 45 years in men with diabetes and 50 years in women with diabetes to define a high cardiovascular risk that would be the trigger for lipid lowering in the absence of any other significant additional risk factor.
He pointed out that there is no study that set 70mg/dl as the cholesterol target and that this is an extrapolated figure based on several other studies.
He reminded the audience of the abundant data that suggest that diabetes is not a cardiovascular disease equivalent and that patients should have a suitable lipid management strategy based on their current total cardiovascular risk.
He reviewed briefly a 2008 meta-analysis published in the Lancet that demonstrated that people with diabetes derive the same overall risk reduction from cholesterol reduction as people without diabetes.
He also reminded the delegates that data from the NHANES population suggest that it is the presence of metabolic syndrome in additon to diabetes which confers increased cardiovascular risk rather than diabetes per se.
In an amusing aside he quoted a 2008 ADA survey which showed that the American population are more afraid of shark bites than diabetes; with 49% afraid of cancer, 12% heart disease, 11% stroke, 4% shark bites and only 3% fearing diabetes!
In concluding Professor Leiter demonstrated data from Framingham and elsewhere which show that the presence of diabetes causes the risk of heart disease to occur some 15 years earlier than would be the case without diabetes in both men and women. Thus he supported the use of an age of 45 years in men with diabetes and 50 years in women with diabetes to define a high cardiovascular risk that would be the trigger for lipid lowering in the absence of any other significant additional risk factor.
Saturday, June 26, 2010
From the ADA 2010: 26th June
In the early morning debate on cardiovascular risk in diabetes, Dr Iskandar Idris (UK) convincingly argued that Diabetes is NOT a cardiovascular disease equivalent.
Presenting data from both his own group and others, he suggested that diabetes is undoubtedly a significant addition to an individuals cardiovascular risk.
However as he went on to point out, it cannot be assumed that all populations carry the same degree of conferred risk. He cited by example data from Indian South Asians (Bulugahapitiya et al. Diab Med 2009; 26: 142) which show that cardiovascular risk is enhanced easily 10 years earlier if diabetes is present than would be the case in a caucasian equlaiavlent population.
Thus whilst arguing for agressive management of cardiovascular risk, Dr Idris was advocating caution in adopting a "one size fits all" approach to managing cardiovascular risk in people with diabetes.
In the early morning debate on cardiovascular risk in diabetes, Dr Iskandar Idris (UK) convincingly argued that Diabetes is NOT a cardiovascular disease equivalent.
Presenting data from both his own group and others, he suggested that diabetes is undoubtedly a significant addition to an individuals cardiovascular risk.
However as he went on to point out, it cannot be assumed that all populations carry the same degree of conferred risk. He cited by example data from Indian South Asians (Bulugahapitiya et al. Diab Med 2009; 26: 142) which show that cardiovascular risk is enhanced easily 10 years earlier if diabetes is present than would be the case in a caucasian equlaiavlent population.
Thus whilst arguing for agressive management of cardiovascular risk, Dr Idris was advocating caution in adopting a "one size fits all" approach to managing cardiovascular risk in people with diabetes.
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