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`DOI: 10.4239/wjd.v5.i5.636
`
`World J Diabetes 2014 October 15; 5(5): 636-650
`ISSN 1948-9358 (online)
`© 2014 Baishideng Publishing Group Inc. All rights reserved.
`
`Treatment of type 2 diabetes, lifestyle, GLP1 agonists and
`DPP4 inhibitors
`
`REVIEW
`
`Gerald H Tomkin
`
`Gerald H Tomkin, Diabetes Institute of Ireland, Beacon Hospi-
`tal, Sandyford, Dublin 18, Ireland
`Gerald H Tomkin, Department of Diabetes and Endocrinology,
`Trinity College, Dublin 2, Ireland
`Author contributions: Tomkin GH solely contributed to this
`paper.
`Correspondence to: Gerald H Tomkin, Professor, Diabetes
`Institute of Ireland, Beacon Hospital, Sandyford, Clontra, Quinns
`Road, Shankill, Dublin 18, Ireland. gerald.tomkin@tcd.ie
`Telephone: +353-1-2390658 Fax: +353-1-2721395
`Received: January 26, 2014 Revised: July 23, 2014
`Accepted: July 27, 2014
`Published online: October 15, 2014
`
`Abstract
`In recent years the treatment focus for type 2 diabe-
`tes has shifted to prevention by lifestyle change and
`to more aggressive reduction of blood sugars during
`the early stage of treatment. Weight reduction is an
`important goal for many people with type 2 diabetes.
`Bariatric surgery is no longer considered a last resort
`treatment. Glucagon-like peptide-1 agonists given by
`injection are emerging as a useful treatment since they
`not only lower blood sugar but are associated with a
`modest weight reduction. The role of the oral dipep-
`tidyl peptidase 4 inhibitors is emerging as second line
`treatment ahead of sulphonylureas due to a possible
`beneficial effect on the beta cell and weight neutrality.
`Drugs which inhibit glucose re-absorption in the kidney,
`sodium/glucose co-transport 2 inhibitors, may have a
`role in the treatment of diabetes. Insulin treatment still
`remains the cornerstone of treatment in many patients
`with type 2 diabetes.
`
`© 2014 Baishideng Publishing Group Inc. All rights reserved.
`
`Key words: Type 2 diabetes; Lifestyle modification; Di-
`peptidyl peptidase 4 inhibitors; Glucagon-like peptide-1
`agonists; Insulin
`
`Core tip: Treatment of diabetes is difficult. Initial suc-
`cess in achieving treatment goals is followed by dete-
`rioration and the necessity for additional treatments.
`Exciting new drugs with new modes of action, have
`stimulated diabetologists to strive for improved control
`in the knowledge that complications will be reduced
`or prevented. Obese patients, who loose weight on
`glucagon-like peptide-1 agonists are usually delighted
`with these drugs but for those who fail to loose weight
`changing to oral dipeptidyl peptidase-4 inhibitors would
`seem a good choice. sodium-glucose transporter-2 in-
`hibitors have the added benefit of being effective even
`if blood sugar is near to target but uro-genital infection
`is a concern.
`
`Tomkin GH. Treatment of type 2 diabetes, lifestyle, GLP1 ago-
`nists and DPP4 inhibitors. World J Diabetes 2014; 5(5): 636-650
`Available from: URL: http://www.wjgnet.com/1948-9358/full/
`v5/i5/636.htm DOI: http://dx.doi.org/10.4239/wjd.v5.i5.636
`
`INTRODUCTION
`Readers interested in diabetes must be sick and tired read-
`ing that diabetes is a global problem of immense size and
`getting worse by the day with predictions that we will all
`have the disease one day! I exaggerate of course but it is
`sad to realise that although we know so much more about
`the condition we have made little progress in reducing or
`conquering the disease. A recent history of diabetes in
`the past 200 years by Polonsky[1] gives an excellent review
`of the history of discovery of so many mechanisms that
`are faulty in diabetes and the number of Nobel prize
`winners who have contributed to such wonderful success,
`yet more and more people are being diagnosed with the
`condition/disease and the consequences are immense
`in terms of suffering and financial cost. One should not
`forget that before the discovery of insulin 90 years ago
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`diabetes was a rapidly fatal disease and there was little
`interest in what we now term type 2 diabetes. Type 2
`diabetes now makes up 90% of all diabetes. Insulin resis-
`tance rather than insulin deficiency is the major player in
`the vast majority of type 2 diabetes and type 2 diabetes
`can be reversed, at least in many patients, with exercise
`and weight reduction. This is not new information but
`was highlighted by Taylor’s group in Newcastle in 2011[2]
`when they did a very simple experiment on patients who
`had diabetes, were obese and managed with tablets. They
`got 13 patients to do what was common practice and
`fashionable 40 years ago. They put the patients on an 800
`kcal diet, a diet that has been proven beyond doubt to
`cause weight loss. Indeed there has never been a report
`of anyone who can maintain their weight on an 800 kcal
`diet. Compliance was checked by urinary ketones and
`weight loss. Eleven of the patients succeeded in finishing
`the eight week diet and lost as much weight as would be
`expected from bariatric surgery. Just like what happens
`following bariatric surgery in patients with type 2 dia-
`betes, the diabetes disappeared and blood pressure and
`lipids improved. Nothing spectacular so far and the study
`would not have been worthy of reporting since all this
`is well known and has been done many times before, as
`Professor Yki-Jarvinen in her leading article in Diabeto-
`logia[3] wrote “the only problem is that in medical school
`and when I was training as an endocrinologist nobody
`told me how to get patients to follow such a diet”. Only
`10% of patients are able to follow dietary restriction
`advice and only the minority take the exercise treatment.
`Worse, of those who do succeed 90% relapse. Indeed this
`is why low calorie diets became unfashionable and large
`type 2 diabetic trials such as the Steino Hospital trial[4]
`did not include weight reduction as part of their proto-
`col. The Newcastle group[2] converted an unoriginal and
`mundane study into a really exciting study by demonstrat-
`ing that liver fat almost disappeared completely within a
`week and this was associated with a very large improve-
`ment in blood sugar and insulin resistance. The rapidity
`of improvement was interesting and the significance of
`the reduction of fat around the beta cell, a new finding
`of uncertain importance. However a plausible theory is
`that fat in the vicinity of the beta cell and in particular
`cholesterol, may be easily oxidised and the release of free
`radicals contributes to damage to the beta cell. In this re-
`gard a gene variant Ckal1, a gene associated with protein
`translation, has been shown to be very sensitive to oxida-
`tion and it is associated with a feeble insulin response[5].
`Beta cells have the ability to regenerate and early and
`intensive reduction in blood sugar has been shown to im-
`prove beta cell function. Hyperglycaemia creates a vicious
`circle-the higher the blood sugar the greater the damage
`to the beta cell and the greater the damage to the beta
`cell the higher goes the sugar. Hence the drive to prevent
`hyperglycaemia by intervention in the pre-diabetes phase
`and to normalise blood sugar in the early stages of dia-
`betes. The final result of the Newcastle group study that
`made me and many others sit up and take notice was the
`
`Tomkin GH. New treatments for type 2 diabetes
`
`demonstration that the beta cell recovered, not partially
`but completely, and even the first phase insulin release
`returned to normal so the patients really did reverse their
`diabetes. This article was of such interest that it made
`headlines in daily newspapers around the world. Patients
`and their relatives, perhaps for the first time, really un-
`derstood the damage diabetes does and gained new hope
`seeing a goal of reversal of diabetes and the possibility
`of discontinuation of diabetes medications. Beta trophin
`has been discovered-a hormone expressed mostly in liver
`and fat that stimulates beta cell proliferation, expands
`beta cell mass and improves glucose tolerance in a mouse
`model[6]. Perhaps an exciting new way to help to reverse
`diabetes in the future?
`The July 2012 edition of the Lancet[7] carried on its
`cover “Physical inactivity: Worldwide”, we estimated that
`physical inactivity causes 6%-10% of the major non-
`communicable diseases. Physical inactivity seems to have
`an effect similar to that of smoking or obesity. Min Lee et
`al[8] examined how much disease could be averted if inac-
`tivity were eliminated. Diabetes, as expected, is one of the
`major diseases the authors looked at. They concluded that
`not only did physical inactivity account for 6%-10% of
`the major non communicable diseases but this unhealthy
`behaviour causes 9% of premature mortality. There is
`good evidence to demonstrate that overweight or obese
`children who become obese as adults are at increased risk
`of diabetes whereas overweight or obese children who be-
`came non-obese by adulthood are not[9]. More importantly
`many studies have shown that educational interventions in
`physical activity have actually been successful and indeed
`more successful than interventions for obesity. Heath et
`al[10] in the same issue of the Lancet, examined interven-
`tions from around the world and demonstrate that the
`literature is convincing in demonstrating that behavioural
`and social approaches are effective. The improvements are
`seen among people of various ages and from different so-
`cial groups, countries and communities. The authors make
`the point that although individuals need to be informed
`and motivated to adopt physical activity, the public health
`priority should be to ensure that environments are safe
`and supportive of health and wellbeing.
`Since we know so much about the risk of developing
`diabetes, it should be possible to have treatment to pre-
`vent diabetes in many patients. The diabetes prevention
`program outcome study[11] has been recently published.
`This ongoing study demonstrated a clear reduction in
`diabetes incidence in participants randomly assigned to
`a lifestyle intervention or metformin during the inter-
`vention period. The authors end by stating that their
`data “support early and aggressive measures for long
`term prevention of diabetes in people at risk”. Inten-
`sive lifestyle intervention has been shown to slow the
`decline in mobility in overweight adults with diabetes[12].
`A disappointing result has recently come from the Look
`AHEAD study[13]. The study was designed to test the
`hypothesis that an intensive life style intervention for
`weight loss would decrease cardiovascular morbidity and
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`Tomkin GH. New treatments for type 2 diabetes
`
`mortality in over weight patients with type 2 diabetes.
`More than 5000 patients took part in the study and the
`median follow-up of the study was for 9.5 years, weight
`loss was modest in the intervention group (6% vs 3.5% at
`the end of the study). Alas there was no reduction in the
`rate of cardiovascular events. The study results are per-
`haps not surprising in that significant weight reduction is
`unachievable in most patients but does suggest that we as
`physicians should accept that most patients are unable to
`loose weight and should not be made to feel guilty about
`this. On the other hand to continue to engage the patient
`in meticulous control of blood pressure, lipids and blood
`sugar, together with cessation of cigarette smoking, a
`healthy diet and exercise, are of proven benefit.
`Casazza et al[14] have written an excellent article enti-
`tled “myths, presumptions and facts about obesity”. The
`definition of a presumption was a belief in the absence
`of supporting scientific evidence; a Myth was defined as
`a belief persisting despite contradictory evidence. Facts
`were suppositions backed by sufficient evidence to con-
`sider them proven for practical purposes. The authors
`note that sometimes action is taken by policy makers in
`the absence of strong scientific evidence “This principle
`of action should not be mistaken as justification for
`drawing conclusions”. The myths examined were: (1) that
`small sustained changes in energy intake or expenditure
`will produce large long term weight changes; (2) Setting
`realistic goals for weight loss is important otherwise pa-
`tients will become frustrated and loose less weight; (3)
`Large rapid weight loss is associated with poor long term
`weight outcomes as compared with slow gradual weight
`loss; (4) It is important to assess the stage of diet readi-
`ness in order to help patients who request weight loss
`treatment; (5) Physical education courses in their present
`form play a part in reducing childhood obesity; (6) Breast
`feeding is protective against obesity; and (7) A bout of
`sexual activity burns 100-300 cal for each participant.
`A stepwise approach to the management of diabetes
`has become a fashionable concept in recent years with
`many published paradigms of the steps which are vari-
`able and often contradictory or display so many different
`stairways that they become very confusing. The first step
`depends on getting the patient at the very beginning of
`their path, that is in the pre-diabetes stage but even then
`they may have already suffered from macrovascular and
`microvascular damage[15-18]. There is little dissention in
`advising the lifestyle changes but, should metformin also
`be used or should one wait and see the effect first of the
`lifestyle changes? Information on this point is available,
`for example in the trial by Snehalatha et al[19] 2009. There
`seemed to be no advantage to add metformin to life
`style changes so perhaps metformin should be reserved
`for those patients who are unable to adhere to life style
`changes?
`Once diabetes has been diagnosed can one wait and
`see the result of life style changes or should one aggres-
`sively control blood sugar? High glucose is toxic to the
`beta cell. Exciting new information suggests that the
`
`beta cell may dedifferentiate under high glucose attack by
`causing reduction in a key transcription factor, Fox 01.
`This dedifferentiation results in the production of inac-
`tive proinsulin and an increase in glucagon[20]. Intensive
`insulin therapy at diagnosis of type 2 diabetes has been
`shown to reverse diabetes. Weng et al[21] studied 382 pa-
`tients and had divided them into 3 groups. Continuous
`insulin infusion, multiple injections or oral agents were
`used to achieve rapid normalisation of hyperglycaemia.
`Treatment was stopped after normoglycemia was main-
`tained for two weeks. After a year 51% and 44% of the
`insulin treated patients were in remission where as only
`26% of the patients in the oral agent group had gone
`into remission. The evidence to support early and aggres-
`sive treatment for type 2 diabetes has not been widely
`accepted. The reasons are probably due to a shortage of
`personnel to manage patients. In my country there is a
`long waiting list to be seen in a diabetic clinic and general
`practitioners are usually unhappy about starting insulin.
`The better understanding of the beta cell pathology of
`diabetes should persuade physicians to adopt a more
`urgent approach to diabetes management in the future.
`A systematic review and meta-analysis on short term
`intensive insulin therapy in type 2 diabetes gives further
`support for the ability of this treatment to modify disease
`progression[22].
`
`BARIATRIC SURGERY
`Bariatric surgery for obese type 2 diabetes has been re-
`fined over the last few years. Laparoscopic surgery has
`made operation on morbidly obese patients who have
`diabetes, and indeed those who do not have diabetes,
`much safer and very often will reverse the diabetes. The
`operation has been shown to reduce cardiovascular risk.
`As with all operations the experience of the surgeon and
`indeed the surgical unit plays a very important part in
`outcome. A Cochrane review[23] in 2009 concluded that
`bariatric surgery is more effective than conventional treat-
`ment in achieving and in sustaining weight loss in people
`with obesity. Improvements in health related quality of
`life and obesity related co morbidities including type 2
`diabetes, dyslipidaemia and sleep apnoea are further ben-
`efits. A very good review of the subject has recently been
`written by Dixon et al[24].
`Mingrone et al[25] in 2012 published a single centre
`non-blinded randomised controlled trial to examine the
`difference in outcome between surgery as compared
`to usual medical therapy. Surgery was either gastric by-
`pass or bilio-pancreatic diversion. At the end of 2 years
`HbA1c was 6.35% in the gastric bypass group and 4.95%
`in the bilio-pancreatic-diversion group as compared to
`7.69% in the medically treated group. Diabetes remission
`had occurred in 75% of the gastric bypass group and
`95% in the bilio-pancreatic diversion group. No patient
`in the medical group had reversed their diabetes. There
`were no deaths and almost no complications in the surgi-
`cal group[25].
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`In the same edition of the journal Schauer et al[26]
`evaluated the efficacy of intensive medical therapy as
`compared to medical therapy plus Roux en Y gastric by-
`pass or sleeve gastrectomy in 150 obese patients with un-
`controlled type 2 diabetes. The primary end point was the
`proportion of patients with a glycated haemoglobin level
`of 6.0% or less, 12 mo after treatment. Twelve percent of
`the medical group, 42% in the gastric bypass group and
`37% in the sleeve gastrectomy group achieved the pri-
`mary end point. HbA1c was 7.5% in the medical group
`6.4% in the gastric bypass group and 6.6% in the sleeve
`gastrectomy group. No deaths or life threatening com-
`plications occurred[26]. An editorial in the same edition by
`Zimmet et al[27] suggests that the bariatric surgery should
`not be seen as a last resort. More recently Arterburn et
`al[28] did a retrospective analysis to compare rates of dia-
`betes remission, relapse and all cause mortality amongst
`severely obese adults with diabetes who underwent
`bariatric surgery vs non-surgical treated individuals. At 2
`years the surgery subjects had significantly higher diabe-
`tes remission rates 73.7% compared to non surgical sub-
`jects with 6.9%. The surgical subjects also experienced
`lower relapse rates with no higher risk of death[28].
`
`NEW INSULINS FOR TREATMENT OF
`TYPE 2 DIABETES
`Many different regimes have been proposed and indeed
`are in use for the treatment of type 2 diabetes when life
`style and metformin have failed to control hyperglycae-
`mia. A three year efficacy of complex insulins in type
`2 diabetes demonstrated that the addition of a basal or
`prandial insulin based regimen to oral therapy had better
`diabetic control than those who added a biphasic insulin
`regimen[29]. My own feeling is that, as so many patients
`with type 2 diabetes don’t increase their blood sugars
`overnight, attention should be paid to controlling the
`post evening meal rise in blood sugar so that the patient
`goes to bed with a normal blood sugar, long acting in-
`sulins being reserved for those patients in whom blood
`sugars rise overnight. To me it doesn’t make sense to give
`a basal dose of a long acting insulin pre bed with the risk
`of overnight hypoglycaemia to a patient whose blood
`sugar has not been shown to rise overnight. Insulin de-
`gludec is almost identical to human insulin but with the
`last amino acid deleted from the B chain and addition
`of a glutamyl link from LysB29 to a hexadecanoic fatty
`acid[30]. Two phase 3 studies were reported recently[31,32].
`In the first study type 1 diabetic patients (472 subjects)
`were subjected to insulin degludec and 157 to glargine
`insulin[31]. Although there was no difference in HbA1c
`at the end of the study and no difference in overall,
`confirmed hypoglycaemia; overnight hypoglycaemia was
`25% less in the insulin degludec and of course noctur-
`nal hypoglycaemia is what many patients fear most. The
`second study Garber et al[32] reported the effect of the
`new insulin in type 2 diabetic patients vs insulin glargine.
`Again after 1 year there was no difference between the 2
`
`Tomkin GH. New treatments for type 2 diabetes
`
`groups in HbA1c. Overall hypoglycaemia was a little less
`in the insulin degludec group and nocturnal hypoglycae-
`mia was also a little lower (1.4 vs 1.8 episodes per patient-
`year exposure). The authors conclude that the newer
`basal insulins with lower hypoglycaemia events may allow
`more intensive blood sugar lowering treatment. From the
`results presented in their paper, insulin degludec does not
`seem to be the answer. An editorial by Tahrani et al[33] in
`the same edition, ends by saying that insulin degludec is
`not a revolution but an evolution of insulin therapy for
`patients with both type 1 and type 2 diabetes.
`
`SODIUM GLUCOSE CO-TRANSPORT-2
`INHIBITORS
`Glycosuria occurs when the blood glucose reaches a
`threshold of about 10 mmol/L. However some people
`will excrete glucose at much lower levels of blood glu-
`cose (renal glycosuria). The discovery that glucose is
`transported across the proximal tubule membrane by
`sodium/glucose co-transport 2 (SGLT2) and that a
`naturally occurring polymorphism of the gene causes
`renal glycosuria, paved the way for the development of
`SGLT2 receptor inhibitors as a way of promoting renal
`glucose excretion and therefore calorie loss and reduc-
`tion of blood sugar. Two drugs have undergone clinical
`trials dapaglifozin and canaglifozin and have been the
`subject of a meta analysis by Clar et al[34]. The drugs both
`result in blood glucose reduction of about 0.5%-1% with
`some weight loss. Urinary and genital infections were
`more common. Hypoglycaemia did not occur any more
`frequently that placebo. The results of the Cantata-SU
`trial have recently been published[35]. The trial was a 52
`wk study in type 2 diabetes with patients who were inad-
`equately controlled with metformin. Canagliflozin was
`compared to Glimepiride. 1452 patients were randomised
`in a phase 3 non-inferiority, double blind, randomised
`trial. Three hundred mg of Canagliflozin reduced HbA1c
`from a mean of 7.8% to 6.9% (mmol/L) a reduction of
`0.9%. Hypoglycaemia was less common on Canagliflozin
`and there was a 4 kg reduction in weight with a small
`reduction in blood pressure. There was a 0.25 increase in
`LDL cholesterol but also a slight, 0.1% increase in HDL
`cholesterol and a very slight reduction in triglycerides also
`of 0.1%. Genital mycotic infections occurred in 8% in
`men and 14% in women on the 300 mg dose. The study
`suggests that the benefit of the drug is a useful reduction
`in HbA1c and weight reduction. The blood pressure re-
`duction is also of benefit but the rise in LDL might be a
`worry and the mycotic genital infections and urinary tract
`infections might make the drug unacceptable to many
`patients who may have presented with these problems
`when first diagnosed. An editorial in the Lancet where
`the results were published is entitled “SGLT2 inhibitors
`for diabetes: turning symptoms into therapy” and makes
`the point that the place of this class of drugs in the treat-
`ment of type diabetes is still to be decided[36]. There has
`been concern about breast and bladder cancer as well
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`Tomkin GH. New treatments for type 2 diabetes
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`as long-term cardiovascular adverse effects also making
`surveillance mandatory. Another recently published study
`comparing canagliflozin with placebo and sitagliptin pro-
`duced similar results[37]. A randomised, blinded, prospec-
`tive Phase 111 study on dapagliflozin as monotherapy in
`drug naive Asian patients with type 2 diabetes found that
`with the 10 mg dose HbA1c had fallen from a mean of
`8.26% to 7.15% as compared to a fall of only 0.29% for
`placebo(a difference of 0.82%) Genital infections oc-
`curred in 4.5% of patients and Urinary tract infections in
`5.3%[38].
`The role of these drugs in the treatment of type 2 di-
`abetes is not clear at present but the lack of risk of hypo-
`glycaemia and the weight reduction suggest that there is
`a place for them in certain patients who are inadequately
`controlled and in whom an extra 0.5% or more reduction
`in blood sugar would be of benefit in bringing the patient
`into the acceptable blood sugar range.
`
`METFORMIN
`The reason for metformin as first line pharmacological
`treatment is based on many studies suggesting that met-
`formin is weight neutral or associated with very modest
`weight loss as compared with sulphonylureas which cause
`slight weight gain initially. Also, in experimental condi-
`tions reperfusion after myocardial infarction is reduced
`by sulphonylureas. As long ago as 1971 the University
`Group Diabetes Program[39] showed that tolbutamide,
`a first generation sulphonylurea, was associated with an
`increased cardiovascular risk in diabetes. The UKPDS
`trial[40] suggested that metformin has a protective effect
`on mortality. Roumie et al[41] examined the comparative
`effectiveness of sulphonylurea and metformin mono-
`therapy on cardiovascular events in type 2 diabetes mel-
`litius. This was a very large retrospective cohort study
`examining cardiovascular outcomes. The crude rates of
`composite outcome were 18.2 per 1000 person years in
`the sulphonylurea users and 10.4 per 1000 person years
`in the metformin group. A wonderful editorial in the
`same edition of the Annals of Internal Medicine by Nis-
`sen[42] entitled “Cardiovascular effects of Diabetes Drugs;
`Emerging from the dark ages”, likens the dark ages after
`the fall of the Roman Empire to the time between the
`University Group Diabetes Program in 1972[39] which
`showed that treatment for diabetes with phenformin or
`tolbutamide was associated with increased cardiovascu-
`lar risk, and 2012. The article explains why there is still
`uncertainty about the effect of sulphonylureas and car-
`diovascular events. Nissen[42] suggests that the study is
`hypothesis generating rather than definitive and that high
`quality evidence is still missing “Continued darkness is
`not an acceptable option” he concludes.
`
`INCRETINS
`It has been known for many years that intravenous
`glucose will not stimulate insulin secretion to the same
`
`extent as a similar glucose load given orally. It was dis-
`covered that hormones secreted from the intestine in re-
`sponse to a glucose load had the ability to release glucose
`from the pancreas. These hormones were called incretins
`and they are responsible for at least 50% of insulin se-
`cretion following a meal. In 1971 a peptide was isolated
`from the intestine which had the ability to inhibit gastric
`acid secretion and was therefore called gastric inhibitory
`polypeptide (GIP)[43]. GIP was later found to stimulate
`insulin secretion. What was very interesting was that GIP
`would only stimulate insulin secretion in the presence of
`high blood sugar. This finding has implications in treat-
`ment terms since drug that only works with high blood
`sugar would be much less likely to cause hypoglycaemia.
`Patients, their families and of course doctors and other
`health care professionals all fear hypoglycaemia. Garber[44]
`refers to the many hospital visits caused by hypoglycae-
`mia and suggests that minimisation of hypoglycaemia
`should be a goal for treatment of type 2 diabetes. I would
`certainly agree. In a survey insulin accounted for 13.9%
`of overall admissions to hospital from adverse drug reac-
`tions and oral anti-diabetic drugs 10.7%[45].
`Another incretin was discovered in 1985 and called
`glucagon-like peptide-1 (GLP-1)[46]. This hormone was
`also dependent on high blood sugar level for full action.
`Both GIP and GLP-1 act by binding to specific recep-
`tors and so release insulin. GLP-1 has another action,
`it inhibits gastric emptying and this has been of benefit
`in the treatment of diabetic patients because the feeling
`of satiety leads to weight reduction. Another beneficial
`effect of the reduction in rate of gastric emptying is to
`delay absorption of food, a mechanism which improves
`blood sugar excursion. GLP-1 also regulates appetite and
`food intake through its effect the hypothalamus. A recent
`review of the effects of GLP1 on appetite and body
`weight with a focus on the central nervous system has
`been published[47].
`GLP-1 agonists have been shown to stimulate B cell
`growth in animals and cell cultures. In humans it is less
`clear if these drugs can improve insulin output by regen-
`erating the B cell. It seems less likely that the dipeptidyl
`peptidase (DPP)-4 inhibitors could also have an effect on
`B-cell re-growth. However an abstract presented at the
`Annual American Diabetes Association meeting in 2010
`suggested that linagliptin was able to restore beta cell
`function in human isolated islets[48]. Vildagliptin has also
`been shown to improve beta cell function and glucose
`tolerance but also to improve the extensive peri-insulitis
`found in the mouse model examined[49].
`A very interesting effect of GLP-1 analogue therapy
`has been described in obese type 2 diabetic patients. The
`investigators found a reduction in inflammatory mac-
`rophages and a reduction in inflammatory cytokines to-
`gether with an increase in the adipokine adiponectin. The
`researchers had previously described a case of psoriasis
`that was greatly improved by GLP-1 agonist therapy[50].
`The new study does suggest an important beneficial ef-
`fect of GLP-1 analogue therapy that needs further inves-
`
`WJD|www.wjgnet.com
`
`640
`
`October 15, 2014|Volume 5|Issue 5|
`
`Novo Nordisk Exhibit 2368
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`tigation[51]. A good review on the extrahepatic effects of
`GLP-1 receptor Agonists has just been published[52].
`
`DEVELOPMENT OF GLP-1 FOR THE
`TREATMENT OF DIABETES
`Exenatide is a GLP-1 receptor agonist. It is a 39 amino
`acid peptide produced in the saliva glands of the Gila
`monster lizard[53] it has 53% amino acid homology to
`full length GLP-1 and it binds with greater affinity than
`GLP-1 to the GLP-I receptor in GLP-1 receptor express-
`ing cells[54]. DPP-4 cleaves peptides and is responsible for
`the rapid breakdown of GLP-1. DPP-4 does not denature
`exenatide because of the slight amino acid differences and
`in human studies the half life ranges from 3.3 to 4 h[55].
`Exenatide (Eli Lilly) is now in clinical use in many coun-
`tries for the treatment of diabetes. It must be given an
`hour before meals on a twice a day basis. Many trials have
`reported that the drugs cause about a 1% reduction in
`HbA1c and reduction in body weight of 5.3 kg at the end
`of 3 years of treatment[56]. The dropout rate is about 20%,
`many patients refusing treatment because of nausea.
`
`EXENITIDE
`Attempts have been made to prolong the action of exena-
`tide using a polylactide glycolide microsphere suspension
`so that the drug can be given weekly. Kim et al[57], in a ran-
`domised placebo-controlled phase 2 study examined the
`effect of exenatide long acting release, a long acting re-
`lease exenatide formulation, found that a weekly dose for
`15 wk in patients with type Ⅱ diabetes resulted in a 1.4%
`reduction in HbA1c, suggesting that once a week formu-
`lation may be as good as, if not better than, twice daily in-
`jections of exenatide. In particular there were no dropouts
`in the trial due to adverse events. Liraglutide is a long act-
`ing GLP-1 analogue with attachment of a C-16 free fatty
`acid derivative. The free fatty acid derivative promotes
`non-covalent binding of liraglutide to albumen thereby
`increasing plasma half life. A recent study comparing li-
`raglutide once a day with exenatide twice a day found that
`liraglutide improved HbA1c significantly more (-1.12% viz
`-0.79%) and was generally better tolerated[58]. The study
`has demonstrated that glycaemic improvement and weight
`reduction are independent of each other. This fits in with
`other studies which suggest that the weight loss is not, in
`itself