Type 2 diabetes already affects 230 million people and is rising at epidemic levels with a worldwide prevalence of 350 million forecast for 2025. The global population is getting progressively older and more obese, even in developing countries, and that increases cases of Type 2 disease with their attendant long-term sequelae. Cardiac, vascular, renal, neurological and eye problems resulting from uncontrolled Type 2 diabetes, cause disability, unemployment and lead to premature death. The scale of the problem and the burden it will place on health care systems and society is immense, so new initiatives to halt the epidemic will receive a sympathetic hearing.
Despite a plethora of anti-diabetic medicines already available, these are clearly not tackling the problem of uncontrolled diabetes adequately, say diabetologists, and, if anything, control is currently getting worse. The US NHANES data show 45 per cent of people with diabetes were adequately controlled between 1988-94, compared with only one third by the year 2000. Now the target for what represents good control has been lowered so figures could be even more disappointing in future. There has never been a better time to introduce new medicines that can improve on the current range of anti-diabetic drugs, which includes biguanides (metformin), alpha glucosidase inhibitors, sulphonylureas, thiazolidinediones, meglitinides, and insulin. All of these have tolerability problems of one type or another such as gastro-intestinal disturbance, weight-gain, fluid-retention and hypoglycaemic episodes. Furthermore, they do not tackle the need to arrest progress of disease.
Incretin mimetics and enhancers
Drugs that work via the manipulation of incretin hormones GLP-1 (glucagon-like peptide) and GIP (glucose-dependent insulinotropic peptide), that play an important role in diabetes, are set to be the next blockbusters. “The hormones they target are secreted naturally in the gut in response to food with the purpose of regulating activity of both the alpha and beta islet cells of the pancreas,” explained Professor Bo Ahren, a researcher in clinical metabolism at Lund University, Sweden. Normally alpha cells release glucagon to stimulate hepatic glucose production between meals, when blood sugar is low, while beta cells produce insulin when it is high, after eating. Incretin hormones modify the activity of both cell types as appropriate. In diabetes, however, the normal incretin response is lost, GLP-1 secretion is reduced by around 25 per cent, beta cells are reduced in number and are under-active; insulin feedback to alpha cells is diminished so these are persistently overactive. The healthy glucagon-insulin balance is lost resulting in both fasting and postprandial hyperglycaemia.
There are two ways of attempting to restore the correct balance via the incretin response. Incretin mimetics or GLP-1 analogs boost GLP-1 levels artificially to supra-physiological levels while incretin-enhancers inhibit the dipeptidyl peptidase-4 (DPP-4) enzyme - which normally degrades endogenously-produced GLP-1 within a few minutes - so as to prolong its activity. Both drug types are effective in reducing HbA1c.The incretin mimetic Byetta (Exenatide, Lilly), administered by injection, delays gastric emptying and increases satiety leading to weight loss of around 4 to 5 kgs over two years. It reduces HbA1c by around 1%. “Incretin enhancers (DPP-4 inhibitors), administered orally, do not delay gastric emptying, but they boost insulin sensitivity and may preserve beta cell function and increase beta cell mass, according to animal studies,” noted Professor Ahren. Because their mode of action is more physiological and also regulates glucagon as well as insulin, they are weight-neutral and, like the mimetics, do not carry the risk of hypoglycaemic episodes associated with insulin and sulphonylureas.
The first incretin-mimetic, exenatide (Byetta, Lilly) was launched in the US last year and has been enthusiastically received there with demand outstripping supply at one point. In Europe it has received a positive opinion from the Committee for Medicinal Products for Human Use. Byetta normally involves twice-daily injections and achieves satisfactory reductions in HbA1c and weight, but is associated with a high incidence of nausea affecting up to 50 per cent of users. “As time goes on you find people either love it or hate it”, noted Professor Edward Horton of the Joslin Diabetes Center, Boston, US. “Sure, patients lose weight but the more you use it, the more patients you notice developing GI side effects – nausea, vomiting and diarrhoea.”
Other incretin-mimetics are in development, including a long-acting once-weekly injection of exenatide, using slow-release polymeric microspheres being developed by Lilly in collaboration with Alkermes. In a phase II study, the long-acting version achieved reductions in HbA1c over 15 weeks of 1.4% with a 0.8mg dose, and 1.7% with a 2mg dose. Fasting plasma glucose reductions of 2mmols/L, were observed, - better than those seen with the twice-daily injectable. It also caused less nausea but produced a new problem of injection-site reactions.
The real interest in the pharmaceutical industry appears to be in developing the orally-administered DPP-4 inhibitors. Around 30 companies have products in their pipeline with two, Galvus (vildagliptin, Novartis) and Januvia (sitagliptin, Merck) already filed and anticipated to be available in North American and Europe in 2007. Three others, Redona (denagliptin, GSK), alogliptin (Takeda) and saxagliptin (Bristol-Myers Squibb) are currently in Phase III trials, the latter including a massive multicentre US trial of saxagliptin plus metformin in very obese diabetics with a BMI over 40.
Januvia is also in development with two strengths of metformin (500 and 100mg) as combined tablets. Other DPP 4 inhibitors are also likely to include combinations with metformin - the gold-standard first-line therapy with proven ability to reduce cardiovascular events. Prosidion, a company which holds patent rights to DPP-4 inhibitor combinations, has several agreements in place with other companies. Stakes are high in this market so companies are keeping their development plans close to their chests and few details of trial designs have been announced or published. Novartis plans to announce further details late November.
Professor Jens Holst, a Medical Physiologist from Copenhagen University, Denmark, who has done much of the work on the role of DPP-4 in the incretin system, says all the DPP-4 inhibitors have chemical differences but so long as they are highly selective for DPP-4, differences should be of minimal importance. “Unlike the incretin-mimetics in development, which are all very different, the DPP-4 inhibitors are broadly similar with the exception of the biotech company Prosidion’s product PSN 3901 which is administered with every meal, rather than once or twice daily, and will enter Phase IIb next year,” he said.
“If they are not selective and also influence DPP 8 and 9 they may cause some very toxic side effects. So any company that sees the slightest side effect with their DPP-4 inhibitor should give it up right away.” Competition from highly selective DPP-4 inhibitors would render less-selective inhibitors non-viable. Both Galvus and Januvia are highly selective for DPP-4 but there is some indication that others may not have the same specificity, he suggested.
At EASD, both Novartis and Merck presented numerous posters and papers on Galvus and Januvia along with reviews of their clinical trials’ database. Of the two products, Galvus has been more extensively studied. More than 10,000 patients have participated in Galvus trials with 7000 exposed to the drug in more than 60 clinical trials. A further 12 studies in the company’s “GLORIOUS” clinical trial programme are to start next year.
With regard to Januvia, 6700 patients have been studied with 4700 receiving Januvia and around 1100 patients treated for up to one year. A further four studies will begin soon.
Both drugs produce similar drops in HbA1c, achieving reductions of close to 3%, in patients with the highest baseline HbA1c, in combination with other drugs and getting the majority of patients to the <7% target when used in dual therapy. Both have similar good tolerability profiles with regard to weight-neutrality and freedom from hypoglycaemic episodes and other side effects. Small differences, said not to be clinically meaningful have emerged in trials, for example a rise in uric acid and neutrophils with Januvia.
Galvus attenuates side effects of other drugs
When used in combination, Galvus has been able to demonstrate an ability to attenuate the side effects of other antidiabetic drugs and to show superior efficacy among older patients whose diabetes is usually more difficult to control. “This is a population increasingly in need of new diabetes treatments because older people find it difficult to tolerate existing therapies or have comorbid conditions that contra-indicate their use”, commented Galvus’ Global Medical Director Dr Martin Fitchet.
“We saw a mean HbA1c of 6.2% - a level approaching normality – in over 65s treated with Galvus and pioglitazone. We also observed fewer TZD-related side effects when Galvus was combined with pioglitazone,” he added. Peripheral oedema occurred in 9.3 per cent with pioglitazone plus placebo but only 5.1 per cent when combined with Galvus.
“When Galvus was added to metformin, we saw a significantly reduced incidence of GI side effects and a further reduction in HbA1c of 1.3% among older patients. A smaller reduction of 0.9% was observed among under 65s,” Dr Fitchet remarked. Administering the drug to this population was easy, he noted, because no drug-drug interactions have been found and there is no need to adjust the dose for patients with renal impairment or other medical conditions.
One study presented at EASD showed when Galvus was added to insulin in people with poor diabetes control, patients, especially over-65s, experienced fewer hypoglycaemic episodes than with insulin plus placebo. A third of patients were over 65 and saw a highly significant improvement in HbA1c with the combination. Among 45 patients receiving insulin and placebo there were 185 mild hypos and 6 severe ones; but among 33 patients receiving Galvus and insulin, only 113 mild hypoglycaemic events and no severe ones occurred.
In a head to head monotherapy study of Galvus 100mg against the thiazolidinedione, rosiglitazone 8mg, the two drugs were equally effective in reducing HbA1c by 1.8%. Galvus-treated patients saw no weight-gain whilst patients on rosiglitazone gained 1.6kg. The Galvus group responded faster, experienced less oedema and showed an improved lipid profile compared to the rosiglitazone group.
A trend to reduced blood pressure and a significant reduction in postprandial plasma triglycerides and lipoprotein metabolism has also been demonstrated for Galvus.
Merck has apparently not seen some of these bonus points in comparable Januvia trials. For example, in a similar trial where Januvia or placebo were added to metformin, results didn’t show any attenuation by Januvia of metformin side effects. However, the company has scored a point over Novartis in managing to get its drug launched ahead of Galvus, in Mexico. The price has yet to be agreed for use in the state medical service and differs among private pharmacies but could be bought over the Internet from Mexican sources for around $30 per month.
So far DPP-4 inhibitors have been studied in patients with longstanding, difficult to control diabetes, as mono, add-on, or in combination therapy with other anti-diabetic drugs. There are increasing calls to start treatment for Type 2 diabetes with more than one drug, especially if they permit the dose of other drugs to be better tolerated or even increased. “DPP-4 inhibitors would be a good choice alongside metformin, particularly in newly-diagnosed diabetics” commented Professor Emmanuel Bosi of San Raffaele University Hospital, Milan, Italy.
However, Professors Jens Holst and Bo Ahrens along with other scientists who originally discovered the advantages of inhibiting DPP-4, say that ultimately drugs like Galvus and Januvia will best be deployed in patients who have ‘pre-diabetes’, a condition of impaired glucose tolerance where blood sugar is raised but not to diabetes levels. These patients still have sufficient beta cells left to benefit from the DPP-4 inhibitors’ hypothesized ability to improve beta cell function and prevent the progress of disease. By the time diabetes is diagnosed, 50 per cent of beta cells are already lost. With a few more years of clinical experience, the durability of the DPP-4 inhibitors’ effects at reducing HbA1c levels to below target levels will be clear. That will indicate whether or not they do really arrest the decline in beta cell mass and function. The hopes that they can modify disease progression will justify a wider role in early disease, possibly in those at risk not only of Type 2 diabetes but Type 1 also.