Ranibizumab (Anti-VEGF) for Visional Loss Due to Diabetic Macular Oedema – Results of Two Phase 3 RCT’s
David Boyer
ADA 2011.
Ranibizumab is an injectable antibody.
Diabetic Retinopathy (DR) is present in 28.5% of people with diabetes and is the leading cause of new blindness in people of working age. Whilst laser therapy can halt progression of neovascularization, the benefit treatment for macular edema (DME) is limited.
VEGF is a key mediator in the pathway, which leads to DME. Improved glycaemic and BP control in the UKPDS and lipid control in the ACCORD study have been shown to reduce the risk of progression/development of DR. It is important to recognize however that DR does still occur and the time to refer to ophthalmology is BEFORE any visual loss has occurred. To date, laser photocoagulation has been the only therapy for DME and whilst this reduces further visual loss it does not improve vision.
The RIDE and RISE trials were conducted in USA and S America. They included adults >18 years with a central subfield thickness > 275 micrometers. Primary endpoints were those gaining 3 or more lines from baseline. Secondary endpoints were laser therapy, QALY. Those in both the sham injection and ranibuzimab groups were similar.
Visual outcomes showed significant benefit for both the 0.3 and 0.5mg treatment groups for 3 or more lines of visual improvement. There was a mean 11-12 letter improvement shown in both the RISE and RIDE trials (15 letters = 3 lines). In terms of driving licenses requirement there was an almost doubling in the number of patients who would be allowed to drive. There was benefit irrespective of the HbA1c. There was also a significant benefit of contrast sensitivity.
The National Eye Institute VQF-25 score increased significantly in both trials, which means that patients derived meaningful clinical benefit in vision. It was found that the need for laser therapy was almost non-existent in the treatment groups and that the only group in whom there was worsening of retinopathy was the sham group.
Safety was consistent with all previous trials. There was a tiny increase in TIA but S/E were limited.
Tuesday, June 28, 2011
Utilising Self-Monitored Blood Glucose Data to Further Characterise Glycaemic Control in the ACCORD Trial
Utilising Self-Monitored Blood Glucose Data to Further Characterise Glycaemic Control in the ACCORD Trial
Richard Bergenstal
ADA 2011.
In the ACCORD study there was an increase in mortality related to intensive therapy to control blood glucose. It has been shown that rapid drop in glucose or weight change were not linked to death. There has been evidence published whjich shows that those who experienced 1 or more episodes of severe hypo had increased mortality. What is not clear is the impact of minor hypoglycaemia.
The accumulated SMBG data were analysed to look for minor episodes of hypo. In the intensive group there were 762 versus 683 days (standard treatment group) of SMBG data. In the intensive arm the distribution curve was clearly to the left of the standard treatment group, which is due to a lower glucose throughout the entire 24-hour profiles in the intensive group.
What is also emerging is that when the 24-hour profiles in those who died in either arm are examined there appears to be a greater tendency for the glucose value to drop significantly during the day curve. Analyzed by the number of low blood sugars there were no more lows in those who died versus those who lived. In fact there were more highs in those who died. In the standard arm in those who died there were both more highs and more lows.
Of the standard group who had lots of lows there was a substantial increase in mortality. This suggests that there may be a correlation between swings ion glucose level (from high to low) and mortality. This phenomenon is also seen in the intensive group as those who were swing dramatically above the target glucose were more at risk of dying – ie the more you diverge from the glucose goal you have set, the greater the risk of dying.
In conclusion, severe hypo is a significant risk and mild to moderate hypoglycaemia is probably a risk if the glucose levels are swinging or if the target glucose is in the range set for the standard group (because hypos impleies significant glucose swings).
Richard Bergenstal
ADA 2011.
In the ACCORD study there was an increase in mortality related to intensive therapy to control blood glucose. It has been shown that rapid drop in glucose or weight change were not linked to death. There has been evidence published whjich shows that those who experienced 1 or more episodes of severe hypo had increased mortality. What is not clear is the impact of minor hypoglycaemia.
The accumulated SMBG data were analysed to look for minor episodes of hypo. In the intensive group there were 762 versus 683 days (standard treatment group) of SMBG data. In the intensive arm the distribution curve was clearly to the left of the standard treatment group, which is due to a lower glucose throughout the entire 24-hour profiles in the intensive group.
What is also emerging is that when the 24-hour profiles in those who died in either arm are examined there appears to be a greater tendency for the glucose value to drop significantly during the day curve. Analyzed by the number of low blood sugars there were no more lows in those who died versus those who lived. In fact there were more highs in those who died. In the standard arm in those who died there were both more highs and more lows.
Of the standard group who had lots of lows there was a substantial increase in mortality. This suggests that there may be a correlation between swings ion glucose level (from high to low) and mortality. This phenomenon is also seen in the intensive group as those who were swing dramatically above the target glucose were more at risk of dying – ie the more you diverge from the glucose goal you have set, the greater the risk of dying.
In conclusion, severe hypo is a significant risk and mild to moderate hypoglycaemia is probably a risk if the glucose levels are swinging or if the target glucose is in the range set for the standard group (because hypos impleies significant glucose swings).
A novel GPR40 Agonist (TAK-875) in Subjects with T2 DM
A Randomised, Double Blind, Placebo and Active Controlled, Dose Ranging Study to Determine the Efficacy and Safety of the Novel GPR40 Agonist TAK-875 in Subjects with T2 DM
Prabakar Viswanathan
ADA 2011.
TAK-875 is a potent agonist of GPR40. It has a glucose dependent insulinotropic mechanism. GPR40 in pancreatic cells is coupled with the GQ couplet in the beta cell and modulates signaling within the beta cell.
Of the 426 subjects randomized nearly 90% completed the study. In the TAK-875 group there was equivalence in HbA1c lowering from midway up the dose range when compared with glimepiride 4mg. There was a rapid decline in FBG after initiating treatment and within 4 weeks a significant fall in HbA1c. The fall in HbA1c was equivalent to that seen with glimepiride. By week 12 there was a significant fall in 2-hour BG after an oGTT.
HOMA-b showed similar changes when compared with baseline in the TAK-875 arms and these changes compared with glimepiride. There was no change in body weight in the TAK arms whereas there was a rise in weight in the glimepiride group.
Over the 3 months of the study all doss of TAK-875 there were no significant problems with tolerance.
Prabakar Viswanathan
ADA 2011.
TAK-875 is a potent agonist of GPR40. It has a glucose dependent insulinotropic mechanism. GPR40 in pancreatic cells is coupled with the GQ couplet in the beta cell and modulates signaling within the beta cell.
Of the 426 subjects randomized nearly 90% completed the study. In the TAK-875 group there was equivalence in HbA1c lowering from midway up the dose range when compared with glimepiride 4mg. There was a rapid decline in FBG after initiating treatment and within 4 weeks a significant fall in HbA1c. The fall in HbA1c was equivalent to that seen with glimepiride. By week 12 there was a significant fall in 2-hour BG after an oGTT.
HOMA-b showed similar changes when compared with baseline in the TAK-875 arms and these changes compared with glimepiride. There was no change in body weight in the TAK arms whereas there was a rise in weight in the glimepiride group.
Over the 3 months of the study all doss of TAK-875 there were no significant problems with tolerance.
10-year Cost-Effectiveness of Lifestyle Intervention or Metformin for the Primary Prevention of Type-2 Diabetes Mellitus – An Intent-to-Treat Analysis
The 10-year Cost-Effectiveness of Lifestyle Intervention or Metformin for the Primary Prevention of Type-2 Diabetes Mellitus – An Intent-to-Treat Analysis of Diabetes Prevention
William Herman (on behalf of the DPP/DPPOS group)
ADA 2011.
DPP was run over 3 years and the DPPOS (Diabetes Prevention Program Outcome Study) ran for a further 7-year follow up. A recent intention to treat analysis showed a persistent benefit out to 10 years.
In the lifestyle intervention there was a 31% reduction in risk of developing diabetes versus a 19% reduction in diabetes risk in the metformin treated group. It was postulated that there may be differences in cost effectiveness if diabetes were prevented.
Data on medical and non-medical costs were evaluated in the present study. From the health system perspective there was a substantial additional cost for lifestyle intervention accruing to $4500 over 10 years for lifestyle intervention and $2000 over 10 years for metformin versus $500 for placebo.
The direct medical costs for treatments other than DPP interventions were substantially greater for all 3 groups which by 10 years was an average of $25000 in each group with a trend to the placebo group costing a little more. This additional cost appeared to relate to the use of self monitoring for diabetes that developed in the placebo group. If both the cost of DPP intervention and other health costs were added then it cost more overall to treat the lifestyle intervention group.
Health utility scores however showed a different trend with the lifestyle group achieving substantial gains. Quality adjusted life years were greatest for the lifestyle group and least for the placebo group. Cost per QALY gain in the lifestyle group was $9000 (undiscounted) or $12000 (discounted) over 10 years. The metformin group was cost saving and in health effectiveness terms were in the same league as influenza vaccine whereas lifestyle intervention equated to antihypertensive therapy in terms of QALY gain. The reduced costs of medical care in the metformin group more than offset the cost of the therapy.
William Herman (on behalf of the DPP/DPPOS group)
ADA 2011.
DPP was run over 3 years and the DPPOS (Diabetes Prevention Program Outcome Study) ran for a further 7-year follow up. A recent intention to treat analysis showed a persistent benefit out to 10 years.
In the lifestyle intervention there was a 31% reduction in risk of developing diabetes versus a 19% reduction in diabetes risk in the metformin treated group. It was postulated that there may be differences in cost effectiveness if diabetes were prevented.
Data on medical and non-medical costs were evaluated in the present study. From the health system perspective there was a substantial additional cost for lifestyle intervention accruing to $4500 over 10 years for lifestyle intervention and $2000 over 10 years for metformin versus $500 for placebo.
The direct medical costs for treatments other than DPP interventions were substantially greater for all 3 groups which by 10 years was an average of $25000 in each group with a trend to the placebo group costing a little more. This additional cost appeared to relate to the use of self monitoring for diabetes that developed in the placebo group. If both the cost of DPP intervention and other health costs were added then it cost more overall to treat the lifestyle intervention group.
Health utility scores however showed a different trend with the lifestyle group achieving substantial gains. Quality adjusted life years were greatest for the lifestyle group and least for the placebo group. Cost per QALY gain in the lifestyle group was $9000 (undiscounted) or $12000 (discounted) over 10 years. The metformin group was cost saving and in health effectiveness terms were in the same league as influenza vaccine whereas lifestyle intervention equated to antihypertensive therapy in terms of QALY gain. The reduced costs of medical care in the metformin group more than offset the cost of the therapy.
Long Term, Injection Free Treatment with ITCA 650, Continuous Subcutaneous Delivery of Exenatide via DUROS Device Leads to Sustained Improved Glycaemi
Long Term, Injection Free Treatment with ITCA 650, Continuous Subcutaneous Delivery of Exenatide via DUROS Device Leads to Sustained Improved Glycaemic Control and Weight Loss for 48 Weeks in Metformin Treated Type 2 Diabetes
Julio Rosenstock
ADA 2011.
The DUROS is an implantable device that gives a continuous infusion of exenatide. The present study is a 48 weeks extension of a previously reported (EASD 2010) shorter clinical trial.
The ITCA was implanted every 3 months and is an osmotic mini pump shaped like a rod. A salt tablet at one end absorbs water through a semi permeable membrane at one end of the titanium rod from the subcutaneous tissue and as it swells it causes a piston to move and thus infuse the drug from a chamber beyond the piston. The rod is about 2.5cm long.
The proof of concept study was presented at EASD 2010. There were ITCA 2 doses tested in that trial (20mcg and 40mcg) which were then increased in a randomized way to 20-80 mcg of exenatide daily. The comparator group was exenatide bd subcutaneous injections
Compared to baseline, at 24 weeks there was a sustained but not greater than in the original study reduction in HbA1c of 0.9% in those staying on 20mcg. In those moving from 20-60mcg daily the HbA1 there was a 1.4% reduction in HbA1c thus there was an additional benefit with the higher dose. There was the same initial frequency of nausea in the ITCA and exenatide injection groups but the ICTA group ended up with significantly less nausea as the rates fell whereas they stayed unchanged in the S/C exenatide injection group.
At the end of the 24 week extension patients were offered the chance to sstay involved in an extension trial although this was a non-randomised stage. The HbA1c reduction remained constant out to 48 weeks. Body weight changed from 12-24 weeks while the doses of ITCA infused exenatide were increased. However in the 24-48 week period there was no further reduction in weight, which remained constant.
The data form this series of studies suggest that in phase 3 studies the preferred doe if ITCA infused exenatide should be 60mcg daily as this achieves the best combination of HbA1c and weight reductions.
Julio Rosenstock
ADA 2011.
The DUROS is an implantable device that gives a continuous infusion of exenatide. The present study is a 48 weeks extension of a previously reported (EASD 2010) shorter clinical trial.
The ITCA was implanted every 3 months and is an osmotic mini pump shaped like a rod. A salt tablet at one end absorbs water through a semi permeable membrane at one end of the titanium rod from the subcutaneous tissue and as it swells it causes a piston to move and thus infuse the drug from a chamber beyond the piston. The rod is about 2.5cm long.
The proof of concept study was presented at EASD 2010. There were ITCA 2 doses tested in that trial (20mcg and 40mcg) which were then increased in a randomized way to 20-80 mcg of exenatide daily. The comparator group was exenatide bd subcutaneous injections
Compared to baseline, at 24 weeks there was a sustained but not greater than in the original study reduction in HbA1c of 0.9% in those staying on 20mcg. In those moving from 20-60mcg daily the HbA1 there was a 1.4% reduction in HbA1c thus there was an additional benefit with the higher dose. There was the same initial frequency of nausea in the ITCA and exenatide injection groups but the ICTA group ended up with significantly less nausea as the rates fell whereas they stayed unchanged in the S/C exenatide injection group.
At the end of the 24 week extension patients were offered the chance to sstay involved in an extension trial although this was a non-randomised stage. The HbA1c reduction remained constant out to 48 weeks. Body weight changed from 12-24 weeks while the doses of ITCA infused exenatide were increased. However in the 24-48 week period there was no further reduction in weight, which remained constant.
The data form this series of studies suggest that in phase 3 studies the preferred doe if ITCA infused exenatide should be 60mcg daily as this achieves the best combination of HbA1c and weight reductions.
Role of Newer Antiplatelet Therapies in the Patient with Diabetes - Can we Improve on Aspirin? Stephen Wiviott; ADA 2011.
There is doubt about the safety and efficacy of aspirin in diabetes. Combining clopidogrel with aspirin yields slight added benefit in non-diabetics, but those with diabetes showed no benefit or even a tendency to harm.
Thus in those with diabetes/multiple risk factors there is no evidence that adding clopidogrel adds any benefit beyond that of aspirin alone for primary prevention. That changes for acute coronary syndrome (ACS) or stent thrombosis however.
There is a 2-3 fold increase in stent thrombosis rates in diabetes. In the CURE Trial in ACS there was a significant benefit in favour of adding clopidogrel to aspirin in the medical therapy alone group, and there was a substantial and consistent benefit across all treatment groups in CURE in favour of clopidogrel. This benefit may be increased with Prasugrel (a newer generation agent) which improves benefit especially in those who get no response with clopidogrel. In the TRITON TIMI-38Trial there was a significant reduction in CV death/MI/stroke with an NNT of 43 in the diabetic subgroup.
In TRITON TIMI-38 Prasugrel increased risk of severe bleeding especially in the older patients although the difference did not reach significance. A second newer agent that is in the pipeline is Ticagrelor which has a very rapid onset of action and far greater inhibition of platelets/ It has been studied in the PLATO Trial which showed a significant reduction in MI & stroke. There was also a significant reduction in CV death with this agent.
New agents including a thrombin receptor inhibitor are in trial. The Thrombin Receptor Antagonist (TRA) programme is now running with enrollment complete in 2 trials. There is an increase in overall bleeding and this has led to premature closure of the trials.
In summary the is NO evidence for intensive (combined) anti-platelet therapy in diabetes EXCEPT in acute coronary syndromes as there is an increase in bleeding without benefit on ischaemic events. Newer intensive agents have shown greater reductions in ischaemic events but this is at the expense of increased bleeding rates. Studies of alternate pathways are ongoing.
Assessing the Risk-Benefit Ration of Aspirin for primary Prevention in Patients with Diabetes; Nilay Shah; ADA 2011.
There is no doubt that aspirin confers significant benefit as a secondary prevention agent in diabetes.
However as a primary preventioin agent there is substantial doubt about the efficacy of aspirin. There have been 5 systematic reviews of the benefit of aspirin in diabetes in the last few years. All of these showed that there was a slight (approx. 15-20%) RR benefit for aspirin but this does not reach significance. However in all of these reviews there was a clear and significant increase in the risk of severe bleeding due to aspirin.
This raises the question – can we recommend the routine use of aspirin as a primary prevention agent in diabetes? There are known gender specific differences in the types of event that aspirin prevents (eg MI in men versus CVA in women). The ongoing ASCEND and ACCEPT-D trials are very large and will hopefully give a clearer answer about the use of aspirin as a primary prevention agent and especially those groups who might derive primary benefit from aspirin.
Users of aspirin have better knowledge about the benefits of aspirin whereas non-users have been shown to have greater knowledge about the risks.
Thus there is a knowledge differential related to users versus non-users. Concordance is also a potential issue in patients who already take an average of 4 mediciations for their diabetes, especially as aspiring confers no symptom benefit at the tine it is taken.
Sussman et al (2011) have shown that in 54 million people treated with aspirin there will be a net gain of 670,000 QALY’s, but most of this gain is in those at higher risk 20-30% 10-year risk and there is very limited gain in those at lower (eg 10@%) 10-year risk.
The various guidelines offer conflicting advice and it is important to involve the patient in making a decision about aspirin therapy. For instance in a case with 11% 10 year risk there would be a risk of 3/1000 for sever bleeds and 15/1000 for CVD events prevented. These are NNT of 333 and 66 respectively.
There are limited data specifically related to low dose aspirin which makes it difficult to be exact about risk.
Subscribe to:
Posts (Atom)