Ranibizumab (Anti-VEGF) for Visional Loss Due to Diabetic Macular Oedema – Results of Two Phase 3 RCT's

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.

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).

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.

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.

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.

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.

Platelet Function Testing in Diabetes; Dominick Angiolillo; ADA 2011.

Patients with diabetes are known to have exaggerated platelet reactive function putting them into a higher atherothrombotic risk sub-group.

However it is not known whether there are cohorts of people with diabetes who are at particular risk due to especially exaggerated platelet reactivity. For instance those with kidney disease have higher rates of platelet reactivity and increased atherothrombotic risk. There are also some genetic analysis studies, which suggest that there are subgroups of people with diabetes with specific platelet pathway abnormalities.

This leads to the likelihood that targeting these diabetes specific platelet pathway abnormality may yield benefit.

Platelets have increased reactivity and reduced responsiveness to antiplatelet agents.

Increased reactivity and reduced antithrombotic responsiveness are associated with increased atherothrombotic risk in diabetes

Abnormalities intrinsic to diabetic platelets warrant specific tailored drug regimens

More effective agents would enable more efficient blockade of diabetic platelets

Positioning Insulin vs GLP-1 Agonists in Type-2 Diabetes Insufficiently Controlled on Oral Agents GLP-1 Agonists go First; Tina Vilsbol; ADA 2011.

Treatment for DM2 needs to be targeted at the diabetic phenotype (obese, IR, beta cell dysfunction, reduced beta cell mass, hyper-glucagonaemia, macrovascular risk, progressive disease).

GLP-1 analogues reduce weight, improve glucose-induced insulin secretion, increase beta cell growth and reduce apoptosis, inhibit glucagon, reduce gastric emptying and probably have cardiovascular beneficial effects.

A recent systematic review and meta-analysis including exenatide, exenatide LAR and Liraglutide is presented at the 2011 ADA. Weight loss was common to all trials with an overall average weight loss across the studies included of -2.8Kg. This compared with a rise in body mass in the studies involving insulin as the agent of choice when injection therapy is initiated. The overall difference between GLP-1 therapy vs insulin was 4.53Kg.

Hypoglycaemia risk is an important consideration as it results in reduced QOL for patients and affects concordance. There are also reasonable data to suggest that hypo may be linked to an increased mortality in DM2 when compared to those without hypo. GLP-1 therapy causes significantly less hypo than insulin.

In the recent meta-analysis there was a fall of around 3.5mmHg inSBP and 1.5 mmHg in DBP. Cholesterol also decreased and Liraglutide and Exenatide have been shown to improvesurrogate markers of vascular dysfunction.

Positioning Insulin vs GLP-1 Agonists in Type-2 Diabetes Insufficiently Controlled on Oral Agents The case for: Insulin Goes First; Steve Edelman; ADA 2011.

The approach to patients failing on oral therapies in DM2 should be individualized to the patient. There are clear reasons for using basal insulin – it has been tested much more thoroughly, has been around for 90 years and is much cheaper than GLP-1 analogues. There are many drugs in this time that have fallen by the wayside as their safety profile becomes established through years of clinical use. To prove the difference in knowledge base between GLP-s and basal insuln simply google search for GLP-1 analogue and compare the number of hits with a google search for basal insulin therapy.

In Monnier’s analysis it was the fasting blood sugar that was the largest determinant of HbA1c in patients with higher HbA1c. Thus it makes sense to target FBG in selecting add-in therapy when faced with poorly controlled HbA1c.

In the Treat to Target study there was a fall in HbA1c from 8.6% to 7% and this was a significantly greater fall than GLP-1 analogues have been shown to achieve. In this trial the hypo rate was actually lower than is often suggested.

In the AT.LANTUS study there was a significantly greater HBa1c reduction in the patient driven titration group, and although there was a slightly greater hypo rate, it was only in those categories of hypo that did not have significant clinical impact.

The LANMET study showed that insulin naïve patients starting basal insulin had a fall in HbA1c from 9.5% to 7.1% with the patients self-adjusting to titrate. These changes were achieved without the risk of severe hypo.

In the 3 Amigo studies there was a staring HbA1c of only 8.5% and there was only a 0.8% reduction with a weight loss, which could be considered relatively meaningless. In addition in the exenatide studies about 33-43% of patients reported nausea that leads to vomiting consistently in more than 5%. There is also the issue of acute pancreatitis and c-cell thyroid tumours in GLP-1 therapy which resulted in an FDA warning as recently as 13th June 2011 (http://www.medscape.com/viewarticle/744477 ).

Insulin is also far cheaper NPH insulin costs approx. 10th the price of GLP-1 analogues per month. Basal glargine or detemir cost ½ the monthly price for GLP-1.

ADA Outstanding Scientific Achievements Award Lecture Speaking from the gut – From Gastrointestinal Hormones to Combinatorial Therapy. Matthias Tschop; ADA 2011.

Obesity represents one of societies' most urgent health threats. Thus the discovery that the stomach secreted Ghrelin opposes the effects of Leptin and induces adiposity offered a significant opportunity to intervene in the progress of the obesity epidemic.

However, Ghrelin is actually a food substrate/hormone polymer as shown in rat models that is in reality more involved in the control of lipid metabolism. Thus the search went on for therapy that works in treating obesity.

Research in the field turned to establishing the hormone profile that occurs in bariatric surgery, which has been shown to reduce obesity. Studies in patients with gastric bands (which induce less weight loss than bypass surgery) have demonstrated that the combination of gastric band plus GLP-1 therapy seemed to induce a similar weight loss as bypass surgery.

This observation led to the hypothesis that combining satiety control agents might offer synergistic effects. In rats, a combination of GLP-1 plus diet does not induce the same weight loss as combining GLP-1 with leptin, thus combined drug therapy seems to offer greater weight benefit. There was therefore good theoretical reason to think that combined stimulation of the glucagon and GLP-1 pathways might offer interesting therapeutic opportunities.

This led to the search for novel molecules which combine homology for the receptors for both native hormones. Bio-engineered glucagon-GLP-1 co-agonist resulted. In mice engineered to have no GLP-1 receptors it was shown that there was still weight loss thus establishing that the co-agonist works. The co-agonist was then tested in obese rats and resulted in significant weight loss. The theoretical benefit of co-agonist therapy is that leveraging the synergistic effect of dual stimulation is likely to overcome the side effects that occur if a single agent is used at sufficient dose to achieve the same efficacy as a synergistic co-agonist.

Early studies in humans suggest that glucagon-GLP-1 co-agonist does not result in altered gastric emptying, thus suggesting that the theory may work. However outcome data are needed.

The next step in the pharma R&D cycle was the development of GLP-1 pro-drugs which may induce a slower onset of GLP-1 receptor stimulation and possibly reduce side effects. These agents are now in early trials in animals.

Attention then turns to tri-agonists. The GIP-GLP-1 co-agonists, combined with glucagon agonists yielded significantly greater weight loss and this experimental observation has led to a recent tri-agonist peptide development. There is clearly much research still to be done, but the latest tri-agonist seems in early studies to induce weight loss at almost homeopathic doses thus there is much hope for a new class of obesity management agents.

Looking to the future there is growing interest in non-labile steroid-peptide hybrids, which combine GLP-1-estrogen in a non-labile stable hybrid. The importance of this approach is that there are neurons in the hypothalamus which control appetite and have both GLP-1 and estrogen receptors. Targeting agents that only release the estrogen when GLP-1 binding has occurred avoid the toxic side effects of estrogen. In early rat studies it appears that this approach achieves substantial weight loss without side effects in the trial animals.

Update on Sensor Technology – What do we have and What Does the Future Hold? Boris Kovatchev; ADA 2011.

The most recent advance in sensor technology is the addition of a near closed loop system from Medtronic and Animas (the latter having just received a EU license). The STAR 3 study (NEJM 2010) shows that sensor augmented insulin pump therapy achieves long-term improvement in glycaemic control.

New generation CGM sensors are smaller, have longer lifespan and in laboratory settings at least appear to offer good accuracy.

De-noising CGM data by removing spikes and artefacts yields about 30 greater accuracy. It is then important to recalibrate CGM senors as they are prone to drift during their lifespan in-situ – doing this improves accuracy by about 26%. Dual sensor arrays’ using more than 1 sensor yields a synergistic benefit which increase accuracy of glucose estimation. Dual sensor arrays also offer real time detection of failure of one unit and may thus improve safety and reduce the impact of patient/human factors in using CGM.

The future holds integrated pump & CGM systems. This closure of the loop requires a control system with a built in algorithm. It also requires that the closed loop devices are small, portable and safe.

Newer agents in diabetes: ADA symposium Sunday 26th June 2011; ADA 2011.

SGLT-1 & SGLT-2

SGLT-1 and SGLT-2 inhibitors block glucose uptake in the gut and glucose re-uptake in the renal tubule respectively. In rats phlorizin is a potent SGLT-1 inhibitor, but is a very potent SGLT-2 inhibitor. Thus either by reducing glucose acquisition or increasing glucose excretion the plasma glucose can be reduced and this has been demonstrated in rats. In humans the role of the SGLT receptor has been established through observation of familial renal glycosuria. Side effects in clinical practice can include diarrhea in SGLT-1 inhibition if CHO is eaten. Thus research is focusing on SGLT-2 inhibitors which are currently in phase 3 trials with limited side effects reported in the present session

Bile Acid Sequestrants (BAS)

Bile acids act as signaling molecules in the gut through the FXR receptor, which acts to reduce bile acid synthesis, thus creating a negative feedback loop. If a sequestrant is added this increases synthesis and as this utilizes LDL cholesterol it reduces LDL-c. In studying the effects on LDL-c it became clear that there is an effect on glucose homeostasis that improves glycaemia. This effect may be mediated via the activation of TGR-5 receptors in the gut due to stimulation by the sequestered bile acids in the gut. In turn activated TGR-5 receptors increase native GLP-1 secretion. It has been shown that the glucose effect is due to an almost complete suppression of glycogenolysis and that BAS reduces glucose independent of FXR. Initial lab work in rats has suggested that bile acids bound to BAS activate TGR-5 that increases GLP-1 release. Thus it appears that the effect of BAS is mediated via GLP-1. The addition of exendin9 (a GLP-1 inhibitor) completely removes the reduction of glycogenolysis that occurs with BAS, whereas exendin-4 (a GLP-1 agonist) mimics the BAS effect. BAS also appears to reduce insulin levels and improve insulin resistance although the mechanisms are not clear.

Selective PPAR Agonists

PPAR receptor family are steroid hormone nuclear receptors. Adverse effects of PPAR agonists include increased CV risk – rosiglitazone, bladder cancer – pioglitazone and increased bone turnover. Alteration of the drug moiety allows an uncoupling of the effects of the PPAR agonists and results in a class of PPAR modulators . Selective PPAR modulators (SPARM’s) are the result.

Agents may have more impact on the PPAR alpha versus PPAR gamma receptor with the present PPAR gamma agonists having limited PPAR alpha effect. However it has been established that Troglitazone (the first licensed PPAR gamma agonist) has equal effects on both alpha and gamma receptors. There are several alpha/gamma agonists under development with Aleglitazar being most developed. It is not known whether there may be problems with weight gain, or bone fracture with these newer agents. The ALECARDIO study in Acute coronary Syndrome suggest that there is probably limited cardiovascular risk with Aleglitazar however. There is emerging evidence that the fat content of the diet may also be important in modulating the effect of gamma agonists with high fat diet resulting in phosphorylation of the gamma receptor and thus an alteration in PPAR activation.

A few unknown areas persist. For example pioglitazone has a number of active metabolites one of which may cause bladder cancer, and CVD concerns persist. It is not yet clear whether any of these issues may also affect the SPARM’s. It is also not clear whether the known side effects are related to the Thiazolidinediones (TZD) and not PPAR activation per-se. Thus the potential for non-TZD SPARM’s to add significant benefit in diabetes remains of interest despite current concerns about side effects with rosiglitazone and pioglitazone.

Next Generation

(Fatty Acid Elongases, 11 Beta HSD-1 inhibitors, GPRs) and some others

There are 100+ target agents being pursued for diabetes management at the present time.

Elongase-6 – This is an enzyme present in the liver. Expression is increased wherever there is increased lipogenesis. Thus it may be over-expressed in consumption of fatty foods. In animal models there was a small reduction in weight with an increased deposition of shorter chain fatty acids in liver in treated animals. There was also a change in insulin secretion with reduced insulin secretion but reduced area under curve for glucose in the same animals suggesting an effect on insulin resistance.

11 Beta HSD-1 - This is one of the enzymes involved in the steroidogenesis pathway, and it is thought that the deposition of omental fat in central obesity increases cortisone to cortisol conversion by 11 Beta HSD-1 activation in metabolically active fat. This in turn will lead to insulin resistance through a cushingoid effect. Inhibition of this enzyme reduced fasting glucose, and there is some evidence that the effect is greatest in those with most central obesity.

G-protein Coupled Receptors – There are a host of G-protein Coupled receptors which mediate signaling in the beta cells. One study of the GPR activator shows reduced HbA1c in animals. In a phase 2 clinical trial in DM2 there was a dose dependent decrease in plasma glucose and 2 hour glucose in OGTT without any augmentation of insulin secretion. A late breaking abstract at the ADA suggests that patients who received a GPR for 12 weeks showed changes in glucose metabolism.

GLP-1 receptor activators – these drugs in animals induce GLP-1 receptor activation in a similar way to that seen with GLP-1 analogues. In patients a dose dependent reduction in OGTT stimulated glucose rise was shown.

Joint GLP-1 and GIP receptor agonists – There is evidence that combined stimulation of GLP-1 and GIP receptors is synergistic in glucose lowering. Agents are in development that offer the potential of combined GLP-1 and GIP agonism.

Fully Closed Loop Insulin Pumps – Where Do We Stand? Ed Damiano; ADA 2011.

An update on progress with dual hormone (insulin and glucagon) closed loop pumps.

Initial trials in 2008-2009 used 2 pumps attached to patient with glucose sampling every 5 minutes for 27 hours.

Infusions were controlled via an algorithm on a laptop. 3 large unannounced standardized meals were given with no rescue snacks. There were significant rises after the meals but mean glucose was well within range and hypos were not a problem. The data suggests that there is a huge variability between subjects in insulin lispro absorption, but also that there is up to 50% variability in insulin absorption in individual subjects. It is noteworthy that there was no “sensor lag” in these studies as these were all based on real time venous glucose. In the same trial the accuracy and reliability of a variety of glucose sensors was also investigated and the Navigator was found to be better in both domains.

A 2-day feasibility trial was repeated using the Navigator as the glucose sensing mechanism with the added complexity of unannounced exercise (the other sensors were also attached and investigated although Navigator drove the system). What was shown was thatplasma glucagon was on average at the very low end of the normal physiological range implying that insulin-dosing calculation was good. Exercise induced fall in glucose was generally controlled well with the dual hormone closed loop. Next study will run in 2011-2012 and run a mobile dual hormone pump which will receive CGM every 5 minutes and study a 5 day period with the patient ambulant. The portable dual hormone pump is in development based on iPod Tough as the controller linked to insulin Omnipod and should be ready by late 2011. The study subjects will be chaperoned by a CGM nurse but be free to wander around the MGH campus to mimic real life. More information is available at: www.artificalpancreas.org

The Banting Memorial Lecture 2011: Hyperinsulinaemia – Cause or Consequence? Barbara Corkey; ADA 2011.

Globalization and changes in diet and lifestyle have led in the past half-century to a dramatic change in the metabolic diseases faced by people. The additives that go into much of the food consumed have never been formally assessed for effect on health.

There is evidence to suggest that hyperinsulinaemia itself may be a contributor to insulin resistance thus stimulating a vicious spiral of leading to diabetes. However, it is known that Free Fatty Acids (FFA) such as MOG can stimulate increased insulin secretion in response to glucose as can artificial sweeteners. Both are found in modern foods. For example saccharin can cause enhanced 48-hour insulin secretion in response to glucose. Iron has a similar effect.

This leads to a question as to whether these non-food compounds cause increased insulin secretion through a direct effect on the pancreas. MOG has not been shown to increase calcium modulated insulin secretion in beta cells, but appears to generate this effect through generation of reactive oxidation species (ROS) in the mitochondria in pancreas. This is known to increase oxidative stress and therefore potentially damage in cells. The biological benefit of this mechanism is that increased ROS also occurs in the presence of normal food substrates and therefore allows their metabolism. Indeed the addition of ROS scavengers reduces basal insulin secretion, thus food stimulated ROS is a necessary component in insulin secretion. However the addition of non-food compounds to modern food leads to an unnecessary ROS generated increase in insulin. Red wine acts as a minor ROS scavenger and thus reduces MOG induced, ROS stimulated insulin secretion in trials. LC-CoA stimulates insulin secretion by FFA, and it has been shown that inhibition of LC-CoA reduces insulin secretion. The exact effect of MOG and other food additives on this pathway is not yet clear.

Thus there seems to be a clear link between Redox status between the cytosol and mitochondria and insulin secretion.

Increased redox in adipocytes is also noted in circumstances that increase insulin secretion and leads to lipid synthesis. Scavenging ROS reduces lipid deposition and suggest that there is a common factor that links insulin secretion and insulin resistance, which is independent of hyperglycaemia – in other words changes in ROS and Redox, may lead to both insulin resistance and hyperinsulinaemia.

In conclusion there is emerging evidence that alterations in redox due to dietary content may be more influential in the causation of insulin resistance than was previously supposed. In addition similar mechanisms may independently trigger increased insulin secretion. This leads to the hypothesis that it may be dietary factors and not hyperinsulinaemia alone that cause insulin resistance and ultimately type-2 diabetes. Further research in this field is needed and in particular a clear understanding of the full impact that modern foodstuffs may be causing should be developed.

The Challenges of Treatment Decisions in Older Diabetes Patients; Philip Levin; ADA 2011.

Data presented by Darius Lakdawalla in the preceding session suggest that if present trends continue, 1/3 of the population over 50 years in the USA by 2050, will have diabetes. This implies that ½ of all healthcare spend will go to people with diabetes by the middle of the 21st century.

Thus in the next few decades physicians will have to face increasingly complicated therapy decisions in elderly people. There is also a relative lack of evidence about the best diabetes treatment algorithms in older people.

The ACCORD, ADVANCE and VADT studies did not show significant benefits in many diabetic complication domains for intensive therapy and this has added to the complexity of decision-making. For instance tight glycaemic control in the elderly will increase hypoglycaemia risk and hence potentiate falls. The potential to increase mortality through intensive control demonstrated in the ACCORD trial is still an open question. What this means for the clinician treating these patients is that there is an uncertain risk of doing more harm than good.

The evidence relating to which therapy is best to achieve improved glycaemia without increasing risk of adverse events is also variable. For instance, some studies suggest that adding basal insulin is better than increasing sulphonylurea dose, other do not. As cognitive impairment and dementia develop, there is evidence that the risk of hypoglycaemic events increases significantly to a peak of 27% in insulin treated over 75 year old patients.

These and other data suggest that for combined endpoints there is an argument in the over 70’s for setting an HbA1c target of less than 8.0% and that tight glycaemic control to less than 7% may increase morbidity and mortality in this age group.

Overall mortality risks are lowest between HbA1c 6-9% in the elderly and whilst this should be considered, other factors including falls risk and cognitive impairment should also be taken into account when setting individual glycaemic targets.

Beyond Recent Trials: The Next Frontiers in Diabetes Management; Caroline Blaum; ADA 2011.

Diabetes patients are a large and heterogeneous group. It is not clear if current pharmacotherapy and clinical services can handle the complexity of diabetes patients or whether this therapy can prevent or mitigate disability in older people.

The health and retirement study (HRS) has provided an insight into the percentage of people with various diseases that correlate to diabetes. For example, in the 51-60 years old age group diabetes is linked to cognitive impairment, which is absent in those without diabetes. In the group a decade older the same phenomenon is found with falls, and it is only in the very elderly that the effect of diabetes appears to go away. Thus diabetes exaggerates the effect of aging in terms of “geriatric conditions” until people are very elderly.

Between 1995 and 2006 in the HRS there was an increase in doctor visits and recorded co-morbidities. In this time ADL dependencies declined for those aged 80-90 years. However there was no reduction in ADL disability rates in people with diabetes who were in their seventies. In general, diabetes management improved during the period of this study which suggests that improved diabetes management did not improve ADL outcomes in the 70-80 years old age group.

There is some emerging evidence that in a more elderly group, steep declines in systolic and diastolic blood pressure may be linked to the risk of death. Thus there may be a case to reduce antihypertensive medication in the elderly if there are any concerns about medication side effects.

Redesigning Clinics to Deliver Geriatric Diabetes Care; Medha Munshi; ADA 2011.

Older people present a heterogeneous mixture in illness, functionality and socioeconomics. In these patients, diabetes increase the risk of comorbidity and also of “geriatric syndrome”. In turn this increases the impact of comorbidities and also reduces the effectiveness of diabetes management.

Thus care needs to address reducing barriers to improved health but also to address issues such as cognitive impairment and impaired activities of daily living (IADL). Assessment should include health literacy, cognition, depression, medication adherence and functional ability.

There is a significant deterioration in glycaemic control in people with cognitive dysfunction, and also a higher incidence of depression in diabetes. IADL are reduced in depressed elderly and this need to be taken into account in care planning – for instance concordance with therapy can be very poor and may require 3rd party drug administration to ensure good glycaemic and blood pressure management.

Continuous glucose monitoring (CGM) may have a greater role than is currently recognized in the elderly with DM as it can often detect unrecognized hypoglycaemia. In turn the consequent reduction in falls and fractures may more than outweigh the cost of CGM. There is also a significant benefit to be gained if telemonitoring and telecare can be introduced to enable the clinical team to continue to observe these patients between clinic visits. Setting individual glycaemic goals improves glycaemic control in 32% and reduces hypoglycaemia in 19% of elderly diabetic patients.

Setting up good diabetes care for the elderly requires careful consideration of the goals of treatment and is fundamentally a balance that should maintain the basic medical ethical principal of “first do no harm”.

Management of Type 2 Diabetes - New and Future developments in Treatment; Cliff Bailey; ADA 2011.

Exenatide LAR (a once weekly GLP-1 analogue) has just been approved for use in Europe. Compared with Sitagliptin and pioglitazone this achieves greater reduction in HbA1c over time, whilst also achieving significantly greater weight loss. Potential gains are persistently increased exenatide levels with the potential for greater therapeutic effect at the expense of a bigger needle and possible enhanced risk of side effects.

Forthcoming there is a hybrid GLP-1 and glucagon receptor agonist. A number of preclinical studies have shown that this approach has interesting potential. As a peptide therapy, this is an injection. However for those who prefer tablets, there are also oral non-peptide GLP-1 agonists in development.

Recently approved DPP-4 inhibitors are Linagliptin and Alogliptin which have altered pharmacodynamics, but generally the same capability as present DPP-4 agents.

Glucokinase activators in development will potentially reduce hyperglycaemia with modulated hypoglycaemia risk. The GPR119 agonists also offer potential as they will increase GLP-1 production and insulin secretion whilst reducing glucagon secretion. Additionally, selective inhibition of glucocorticoid effect may offer an interesting therapy in type 2 diabetes and agents are under investigation using 11beta- HSD1 inhibition.

INT131 is a selective PPAR gamma modulator that will alter the co-activators that come into play in this field of therapy, and thus reduce HbA1c whilst also reducing current side effects. There are also insulin receptor activators and sensitisers under investigation at present.

SGLT-2 co-transporter inhibitors are now available and reduce the re-uptake of glucose in the proximal tubule in the kidney and increase glucose elimination in the urine. This can eliminate >180 grams of glucose per day. In clinical trials in this class, dapagliflozin added to metformin offers sustained improvement in HbA1c reduction.

Finally new analogue insulins are about to become available. Degludec is an ultra-long acting insulin analogue that can be given just three times per week in DM2. Added to metformin in DM2 it shows the same efficacy as glargine without the need for as many injections.

Thus there is a plethora of new agents coming in type 2 diabetes management and generalists and specialists will have much to learn if they are to stay ahead.

Effect of Early Intensive Multifactorial Therapy on 5 year CVD outcomes in DM2 Detected by Screening (ADDITION-Europe Study); Torsten Lauritzen; ADA 2011.

The ADDITION study is a study of people with screen detected DM2 in a multicenter European design. The aim was to evaluate a intensive multifactorial CVD intervention in primary care early into the course of DM2.

A stepwise screening programme was targeted at people with high diabetes risk in general practice. Target population was nearly 400,00 people aged 40-69 years. About 70,000 high risk people screened and identified just over 3000 people with DM2. Patients were randomized to routine care or intensive treatment.

In the intensive group there was a target driven protocol if HbA1c > 6.5% increase glycaemic treatment. Target BP <135/85 and target Total Cholesterol 3.5 mmol/l.

Around 1,350 patient in each arm, mean age about 57 years and > 90% Caucasian. Almost 100% 5 year follow up was achieved.

At baseline about 45% were on BP lowering drugs. At 5 years almost twice as many were on BP lowering drugs, but more so in intensive group. About 12% on stating at baseline but far more at 5 years with around 70% with a similar pattern to BP drugs. This resulted in significantly greater reductions in BP and Cholesterol in the intensive group at 5 years.

Primary endpoints were CVD events. There was a NS 17% risk reduction in favour of intensive treatment at 5 years. Intensive glucose management was NOT associated with increased risk of mortality.

Mortality in both groups was low and only slightly higher than the general population. Comparison with the Michigan CVD mortality model suggests that compared to a model without treatment there was a significant reduction in mortality in both routine and intensive groups.

In conclusion it is possible to screen for DM2 in primary care and this improves early detection and CVD risk intervention. In the present study both routine and intensive groups sustained significantly reduced mortality when compared with a mortality model without treatment intervention. There was a non-significant 17% reduction in CVD mortality if intensive risk factor intervention is initiated early in DM2.

Effect of Early Intensive Multifactorial Therapy on 5 year CVD outcomes in DM2 Detected by Screening (ADDITION-Europe Study); Torsten Lauritzen; ADA 2011

The ADDITION study is a study of people

with screen detected DM2 in a multicenter European design. Aim to evaluate a intensive multifactorial

CVD intervention in primary care early into the course of DM2. A stepwise screening programme was targeted

at people with high diabetes risk in general practice. Target population was nearly 400,00 people

aged 40-69 years. About 70,000 high risk

people screened and identified just over 3000 people with DM2. Patients were randomized to routine care or

intensive treatment. In the intensive

group there was a target driven protocol if HbA1c > 6.5% increase glycaemic

treatment. Target BP <135/85 and

target Total Cholesterol 3.5 mmol/l.

Around 1,350 patient in each arm, mean age about 57 years and > 90%

Caucasian. Almost 100% 5 year follow up

was achieved.

At baseline about 45% were on BP lowering

drugs. At 5 years almost twice as many were on BP lowering drugs, but more so

in intensive group. About 12% on stating

at baseline but far more at 5 years with around 70% with a similar pattern to

BP drugs. This resulted in significantly

greater reductions in BP and Cholesterol in the intensive group at 5 years.

Primary endpoints were CVD events. There was a NS 17% risk reduction in favour

of intensive treatment at 5 years.

Intensive glucose management was NOT associated with increased risk of

mortality. Mortality in both groups was

low and only slightly higher than the general population. Comparison with the Michigan CVD mortality

model suggests that compared to a model without treatment there was a

significant reduction in mortality in both routine and intensive groups.

In conclusion it is possible to screen for

DM2 in primary care and this improves early detection and CVD risk

intervention. In the present study both

routine and intensive groups sustained significantly reduced mortality when

compared with a mortality model without treatment intervention. There was a non-significant 17% reduction in

CVD mortality if intensive risk factor intervention is initiated early in DM2.

Glycaemic Control in Type-1 Diabetes and Heart Failure: The Lancet/ADA Symposium, Marcus Lind, ADA 2011.

Heart failure mortality remains 20% at end of year 1 and 50% by 5 years and accounts for 2% of US hospital admissions. However with modern management mortality is improved.

Diabetes is linked to heart failure through CVD and is increasing rapidly leading to the question: is there a risk that heart failure mortality will increase over the next few years.

Meta-analysis of trials (Turnbull Diabetologia) have shown no link between glycaemic control and HF in DM2. There are similar no studies of note in DM1.

The present study was designed to relate glycaemic control to hospitalization with HF in DM1. 20,985 adult DM1 patients in the NDR 1998-2003. Followed until end of 2009. MI and other CVD morbidities were included. Poisson regression was used.

Mean age 38.6 years, HbA1c 8.2% and median follow up was 9 years. 3% of the patients were hospitalized with HF. General population admission rate with HF for this age group was 0.1% There was a clear correlation between HbA1c and risk of hospitalization in the study group.

Hazard Ratio for HF admission per percentage rise in HbA1c was 1.3 when corrected for other factors. Other key risks identified were age HR 1.64, diabetes duration HR 1.34, and smoking HR 1.9.

This was a non randomized study thus cannot say whether reduced HbA1c reduces HF risk, but it is representative of a long term DM1 population in real life practice.

In conclusion HF is a major complication in DM1 that may be worth screening for. Good glycaemic control may reduce admission with HF but there are other risk factors (eg. Age, BMI, smoking, diabetes duration).

Steps to Control Obesity, diabetes and hypertension: Does Industry have a role?

Steps to Control Obesity, diabetes and hypertension: Does Industry have a role? The Lancet Lecture;
Dr George Mensah
Cardiology and Diabetes at the Limits, Cape Town, Feb 2011.

In the past 30 years, the distribution curve for BMI has moved dramatically to the right in the USA and many parts of the world. This means that there is a pandemic of diabetes and all of the corresponding non-communicable diseases (NCD) that this will cause.

The role that the developed world and its commercial companies can play was highlighted.

The following slides (entitled “Michael Angelo’s David returns after a short visit to the USA” brought much amusement):

http://www.flickr.com/photos/kristadawn/2422391654/

The factors driving the obesity epidemic were explored and some further detail can be found at www.foresight.gov.uk.

The speaker is now a VP for PepsiCo having enjoyed a distinguished career as a cardiologist and working at the CDC in Atlanta (USA). He pointed out that good companies can still make money by selling the right things and this is the philosophy which is now being adopted by the IFBA Alliance https://www.ifballiance.org/.

There seems to determination though. The PepsiCo goal is to reduce the “Triple S” (Sodium, Sugar and Saturated Fats) by 25%, 25% and 15% over the next few years. This may seem a small drop in a vast ocean, however it should be noted that through altering the production of Walkers Potato Crisps in the UK alone, PepsiCo have already achieved a reduction in the overall UK saturated fat intake of 40, 000 tons. This is no mean feat!

In concluding Dr Mensah quoted an old African proverb –it seems very pertinent to the issues the food industry faces in 2011:
“If you want to go somewhere fast – go alone”
“If you want to go somewhere far - go together”