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SGLT2s, insulin among novel agents in the diabetes pipeline

Issue: January 2013

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It has been established that poor glycemic control is associated with microvascular and macrovascular complications, increasing morbidity and mortality among patients with diabetes. With as many as 25.8 million patients diagnosed with diabetes, researchers are now investigating an array of mechanisms to treat the disease. Endocrine Today spoke with researchers about novel sodium-glucose cotransporter 2 inhibitors and the latest insulin therapies, as well as the potential for additional agents in the diabetes pipeline.

Sodium-glucose cotransporter 2 inhibitors (SGLT2s) have entered the limelight in the past couple of years as a novel class of agents that have been shown to effectively control blood sugar levels without causing adverse events such as weight gain or hypoglycemia.

Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center and the Audie L. Murphy Memorial VA Hospital in San Antonio, told Endocrine Today that there are three core defects in type 2 diabetes: insulin resistance in muscle and liver, and beta-cell failure.

 

Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center and the Audie L. Murphy Memorial VA Hospital in San Antonio, said initial studies showed blocking SGLT2 increased glucose excretion in rats.

Photo courtesy of   Ralph A. DeFronzo, MD reprinted with permission.

“Many years ago, using initial studies carried out in rodents, we showed that if you were to treat rats with drugs that blocked glucose reabsorption in the proximal tubule block SGLT2, rats markedly increased their excretion of glucose and blood sugar levels dropped,” DeFronzo said.

In a review published in the Journal of Clinical Pharmacology, Raktim Kumar Ghosh, MD, of Maulana Azad Medical College at Bahadur Shah Zafar Marg in New Delhi, India, and colleagues discuss this effect of SGLT2s.

“The therapeutic potential of SGLT2 inhibition was established with the discovery of familial renal glucosuria (FRG), owing to a defect in SGLT2 expression in the kidney. Normal renal function, absence of hypoglycemia, and electrolyte imbalance in FRG validate SGLT2 inhibition as a potential therapeutic target in diabetes. The selective inhibition of SGLT2 does not hamper glucose transport in other major organs of the body such as the brain, liver, and muscle,” Ghosh and colleagues wrote.

“Their mechanism is very unique; mainly working on the kidney. Some of these agents also work on the SGLT1 receptor in the gastrointestinal tract,” Robert R. Henry, MD, chief of the Section of Diabetes, Endocrinology & Metabolism at the San Diego VA Medical Center and professor of medicine at the University of California San Diego School of Medicine in San Diego, told Endocrine Today.

Robert R. Henry

Henry said there will likely be more scrutiny for approval of the SGLT2 inhibitors due to their being a new class of anti-diabetic compounds with a novel mechanism of action.

Data on dapagliflozin

Although it has been approved in the European Union for monotherapy in metformin-intolerant patients, dapagliflozin (Bristol-Myers Squibb, AstraZeneca) was denied approval by the FDA in the United States in January 2012. Six months prior, the advisory committee recommended against the approval of the drug at a July 2011 meeting by a 9-6 vote due to concerns of potential breast or bladder cancer risks found in the 11 phase 3 clinical trials.

In the 11 randomized controlled trials, researchers found nine cases of bladder cancer in patients receiving dapagliflozin compared with one case in control groups. The incidence of breast cancer was similarly elevated, with five cases occurring in the treatment arm vs. one case in the control group. A separate FDA review of the data linked dapagliflozin to a fourfold increased risk for breast cancer and fivefold increased risk for bladder cancer. One probable case of drug-induced liver injury was also cause for concern.

“The issue of hepatotoxicity is always one that is a little concerning to me,” committee member Doris B. Strader, MD, associate professor of medicine at the University of Vermont, said during the meeting. “This is only one case, but it does raise some issues about monitoring. … We can’t dismiss breast and bladder cancer as minor or irrelevant.”

Optimism, however, remains. At the American Association of Clinical Endocrinologists 21st Annual Scientific and Clinical Congress Meeting in May, Elise Hardy, MD, a director of clinical research at AstraZeneca, presented new data on dapagliflozin. Hardy said the drug was linked to weight loss in patients with type 2 diabetes despite varying age, sex, baseline HbA1c, BMI, estimated glomerular filtration rate and duration of diabetes.

According to data, dapagliflozin reduced HbA1c from 0.23% to 0.89% at the end of 6 months of a multicenter trial of 270 patients with type 2 diabetes. Moreover, a 2.2-kg to 3.2-kg weight loss over 6 months and a reduction in BP of 4 mm Hg to 2 mm Hg were reported. Also, dapagliflozin displayed similar effects compared with metformin and sulfonylureas, and the side effect profile was well tolerated compared with sulfonylureas in other studies.

“In my opinion, the drug should’ve been approved in the US as well,” DeFronzo said. “However, the FDA has asked for additional data, and we hope that at some point, the drug will be approved.”

Impact of canagliflozin

On Jan. 10, the Endocrinologic and Metabolic Drugs Advisory Committee recommended approval for canagliflozin tablets (Invokana, Janssen). Similar to dapagliflozin, canagliflozin is a member of the SGLT2 inhibitors. It has been developed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

According to data from the Canagliflozin Cardiovascular Assessment Study (CANVAS) presented at the 48th European Association for the Study of Diabetes Annual Meeting in October, adverse events, including genital mycotic infections, increased urination and hypotension, were more common in the treatment groups compared with placebo. The incidence of hypoglycemia was also higher with canagliflozin 100 mg and 300 mg vs. placebo (49% and 48% vs. 37%).

Patients in the canagliflozin 100-mg group experienced reductions in body weight of –1.9% and patients in the 300-mg groups also experienced reductions in body weight of –2.4% compared with placebo (P<.001). Additionally, the 100-mg group had a decrease in fasting plasma glucose of –1.25 mmol/L, whereas the 300-mg group experienced a –1.61 mmol/L decrease (P<.001), according to a press release.

“Effective management of type 2 diabetes in patients with elevated CV risk and other comorbidities can be challenging because these patients are often more susceptible to complications of the side effects of antihyperglycemic therapy. The results from this substudy suggest that canagliflozin could provide an important new treatment option for higher-risk adult patients with type 2 diabetes,” David R. Matthews, FRCP, professor of diabetes at the Oxford Centre for Diabetes, Endocrinology and Metabolism and co-lead investigator of the CANVAS trial, said in a press release.

DeFronzo said he and other researchers are hopeful that canagliflozin will be favorably viewed.

“Canagliflozin doesn’t have the imbalance in breast or bladder cancer, and the drop in the HbA1c looks very similar compared with dapagliflozin,” DeFronzo said.

Research on empagliflozin

During the EASD annual meeting in October, Boehringer Ingelheim and Eli Lilly released results from a pooled analysis of phase 2b data for their SGLT2, empagliflozin. Researchers collected data from two randomized, double blind, placebo-controlled trials that evaluated the safety and efficacy of empagliflozin alone (n=408) or as add-on therapy to metformin (n=495) in adults with type 2 diabetes.

According to data, 152 patients were assigned to empagliflozin 10 mg, 152 were assigned empagliflozin 25 mg and 153 were assigned placebo. After the 12-week study, mean systolic BP decreased by 3.8 mm Hg in the empagliflozin 10-mg group and by 4.5 mm Hg in the 25-mg group vs. 1.2 mm Hg in the placebo group.

Furthermore, empagliflozin was well tolerated, the researchers said. Adverse event rates were similar among treatment and placebo groups (34.2% and 31.6% in empagliflozin 10-mg and 25-mg groups, and 34.6% in the placebo group). Similar to dapagliflozin and canagliflozin, the most common adverse events included urinary tract and genital infections.

“The drug will be approved for monotherapy, but I seriously doubt it is going to replace metformin as a first-line drug,” DeFronzo said. “The beauty is that it works on the kidney and can be added to any other drugs that are out there because it works by a totally different mechanism.”

Researchers anticipate that the current data will be submitted to the FDA and Europe for approval sometime in 2013.

Focus on insulins

Nearly a century after its introduction, insulin is still a fundamental treatment for diabetes. Long-term data from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial released in July laid to rest the concern that insulin may have an atherogenic risk, Endocrine Today’s Chief Medical Editor and AACE president, Alan J. Garber, MD, PhD, said.

Alan J. Garber

“There is no evidence for that [risk], and ORIGIN supports the notion that insulin glargine (Lantus, Sanofi-Aventis) at least is not associated with substantially increased risk for soft tissue cancers,” Garber said.

Looking ahead, he said there are three insulin therapies currently in the pipeline from Novo Nordisk, one from Sanofi-Aventis and one from Boehringer Ingelheim/Lilly.

“Insulin degludec is ultra long-acting basal insulin with reduced rates of hypoglycemia and greater flexibility in dosage timing,” Garber said.

In November, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 8-4 for the approval of Novo Nordisk’s insulin degludec and insulin degludec/aspart for the treatment of type 1 and type 2 diabetes. At the time of the approval, 41 studies of insulin degludec and 21 studies of insulin degludec/aspart had been completed. Six additional studies of degludec and two of degludec/aspart were ongoing.

Insulin degludec was related to improvements in FPG compared with other insulins and demonstrated statistical significance in five of the nine trials. Similarly, in all five insulin degludec/aspart phase 3 trials, the drug, whether given once or twice daily, was noninferior to other insulins in the primary endpoint of reducing HbA1c. Garber said degludec/aspart will produce a remarkable improvement in rates of hypoglycemia compared with the use of analogue premixed insulins.

“Finally, there will be a concentrated form of insulin degludec, a U-200 form of insulin degludec (Tresiba, Novo Nordisk) available for patients who require higher doses of insulin. It’s produced better, with absorption kinetics, ease of use, and simplification of the number of injections per day,” he said.

According to Garber, Sanofi-Aventis is developing a U-300 form of insulin glargine that is an ultra concentrated form of basal insulin. This is also useful for patients who require higher doses of insulin, he said.

“There is some suggestion that the pharmacokinetic of U-300 glargine may be different than the conventional U-100 glargine and may have longer activity and a flatter pharmacokinetic curve,” Garber said.

Additionally, Boehringer Ingelheim/Lilly is developing ultra long-acting basal insulin that depends upon pegylation of their traditional analogue, insulin lispro (Humalog).

“Pegylations of proteins have been used for years to prolong time action curves of injectable proteins such as interferon, and pegylation of lispro does the same with insulin. Only preliminary data have been released thus far about the drug. However, it does appear to have a long half-life and, interestingly, may also be associated with some weight loss rather than weight gain, which is the traditional outcome with other insulins,” Garber said.

He added that rapid-acting insulins are on the horizon as well. Halozyme Therapeutics is currently developing the combination of the hyaluronidase enzyme — rHuPH20 — with mealtime analogue insulin. The goal is to create a combination that has a rapid absorption rate and faster onset, with a shorter duration of insulin action compared with analogues currently on the market.

Obesity therapies

Additional therapies such as weight-loss medications have the potential to enter the arena of diabetes treatment, Zachary T. Bloomgarden, MD, Endocrine Today Editorial Board member and clinical professor of medicine at Mount Sinai School of Medicine in New York, told Endocrine Today.

Zachary T. Bloomgarden

“First of all, the entire field of obesity therapy is almost certainly a great way of treating diabetes, and it has not really been explored, which is a curious paradox,” Bloomgarden said.

Citing the failed rimonabant (Zimulti, Sanofi-Aventis), Bloomgarden said its HbA1c-lowering properties were much better than many drugs available today.

“The cannabinoid receptor antagonist was removed because of the possibility of emotional instability, which may or may not have been a real issue. It was actually a marvelous diabetes drug and brought HbA1c down,” Bloomgarden said.

Two drugs approved last year by the FDA, lorcaserin (Belviq, Eisai) and phentermine-topiramate (Qsymia, Vivus), have been shown to reduce weight. With these approvals and more to come in the pipeline, coupled with the growing popularity of bariatric surgery, Bloomgarden said he wonders why there has not been pharmaceutical research into the use of these two agents as glucose-lowering approaches for patients with diabetes and weight issues.

Endocrine Today Editorial Board member Michael Kleerekoper, MD, MACE, said the available therapies for diabetes are effective, but there is some concern.

Michael Kleerekoper

“I am confident that all available therapies for diabetes are very effective, and those in development will also be proven effective,” Kleerekoper, a professor in the department of internal medicine and section chief of the endocrinology division at the University of Toledo College of Medicine, told Endocrine Today.

However, he added that clinicians have trouble deciding which drug is best for each patient.

“While all available diabetes therapies are well studied, too many non-endocrine colleagues do not spend enough time advising patients about attention to diet and lifestyle as essential components of diabetes management,” Kleerekoper said.

Kleerekoper added that there is no clear indication of which of the 10 available FDA-approved therapies for diabetes (excluding insulin) is best suited to indvidual patients.

“That said, I cannot foresee how this could ever be derived without extremely large clinical trials involving some or all of the available therapies. Such trials are unlikely,” Kleerekoper said.

The road ahead

“Another area that is interesting is G protein-coupled receptor 119 (GPR119) agonists,” Bloomgarden said.

According to a review article published in American Health Drug Benefits, Quang T. Nguyen, DO, of the Carson Tahoe Physician Clinics and University of Nevada School of Medicine in Reno, and colleagues said the physiologic role of GPR119 remains unknown. However, upon activation by an agonist ligand, GPR119 has increased cyclic AMP and induces insulin release.

“Overall, GPR119 agonists, by activating several complementary pathways, may provide a mechanism for glucose control in patients with type 2 diabetes,” the researchers wrote.

Bloomgarden said GPR119 would have the potential for increasing glucagon-like peptide 1 production and separately potentiating insulin secretion.

“It may not work. It might just be a ‘fancy’ sulfonylurea, but it might be a very good drug, and if you have an oral drug that acted like a GLP-1 injected drug, that would of course be a potentially important new approach,” Bloomgarden said.

Another area of interest includes anti-inflammatory drugs. These agents have modest effects on lowering blood sugar and improving insulin sensitivity, he said.

“There are a number of other drugs related to gut peptides that are being explored that look very interesting,” Bloomgarden said. “Also, it turns out that a glucagon blocker is extremely effective in lowering blood sugar but has very major side effects in raising cholesterol and causing weight gain. This is interesting because we don’t often think of glucagon as part of the body’s weight reducing mechanism. We think of glucagon as something that’s bad and increases blood sugar, but maybe we’re missing part of the picture.”

Other promising treatments for diabetes include protein tyrosine phosphatase 1B inhibitors, he added. However, more time and research are warranted to determine the potential for all of these therapies.

“None of these drugs, of course, will cure diabetes. The smart doctor will learn how to use the different classes of drugs in combination because they have different mechanisms of action,” DeFronzo said.-by Samantha Costa

Perspective

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Kwame Osei, MD, FACE, FACP

Is there room for more incremental benefit?

Over the past 2 decades, we have made tremendous progress in developing new classes of drugs that are very unique. The current literature shows that HbA1c has improved from 9.1% to 8.1% in the country. Most importantly, we have reduced the life expectancy gap from 20 years to 10 years in patients with diabetes. Indeed, the mortality attributed to diabetes has also been reduced by 42% in the patients with diabetes.

The ultimate question is to understand what has contributed to these impressive gains and the associated cost.  First, we have developed oral diabetes drugs that are literally focused on the fundamental pathophysiology of type 2 diabetes. The development of GLP-1 analogues and DPP-IV inhibitors has become a great addition to our therapeutic armamentarium.  In addition, the understating that it takes multiple targets to achieve an acceptable HbA1c plays into this therapeutic and management concept.

In this regard, the recent introduction of another target — the kidney — as key player in the pathogeneses of hyperglycemia and its treatment is another new and novel approach. Although, these SGLT2s are not currently approved in the US, barring any major catastrophe, it is hopeful that they will be on the market in couple of years. There is no doubt these drugs can fulfill the goals of developing new oral agents for normalization of HbA1c, physiologic regulation of glucose and weight loss (or with neutrality) without hypoglycemia. Furthermore, they can be combined with several oral agents and insulin.

Apart from developing new oral agents, there are several new insulins that have been approved and approaching marketing and some in development. These new insulin are targeted as peakless basal insulins with extended and prolonged duration action. These are presumed to be the true basal with flattened plateau. These new insulins include degludec, a pegylated and higher concentrated insulins. The true values and benefits of this novel insulin are yet to be investigated.

The major debate in the future for most and all of us are: 1) what are the incremental glycemic benefits and safety?; 2) whether these drugs would improve mortality; and 3) the cost of the new discoveries. The increasing vigilance of FDA and demand for true safety of new drugs is welcome but could delay the introduction of new drugs onto the market. The demand for cardiovascular safety and cancer signal on oral diabetes medications hopefully can guide us in the right direction and avoid delay in detection of such signals. Regarding the new insulins, developing new and novel concentrated insulin and extended release insulins would be the way of the future. Most importantly, the best anti-diabetic medications will not benefit our patients if they cannot afford them. Thus, clearly, the third-party payers and pharmaceutical companies need to strike a balance between affordability and profitability. These important issues need to be carefully studied in the coming years.

Kwame Osei, MD, FACE, FACP

Endocrine Today Editorial Board member;Ralph W. Kurtz professor of medicine and exercise physiology; Director of the Diabetes Research Center at The Ohio University Wexner Medical Center

Disclosures: Osei reports no relevant financial disclosures.

Perspective

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Muhammad A. Abdul-Ghani, MD, PhD

Should we treat type 2 diabetes or its symptoms?

Type 2 diabetes is a systemic metabolic disease characterized by multiple metabolic defects, and it is associated with significant morbidity and mortality primarily due to microvascular and macrovascular complications. Although hyperglycemia is a sine qua non in type 2 diabetes and is the major risk factor responsible for microvascular complications, it is only one symptom of diabetes. Individuals with type 2 diabetes also manifest major abnormalities in lipid metabolism and hypertension.

Moreover, hyperglycemia has only a little role in the macrovascular risk in type 2 diabetes. Thus, focusing the therapeutic efforts of the disease on lowering the plasma-glucose concentration is not only incompatible with the modern concept of medical practice, which aims at identifying the disease etiology and treating it, but also it does not address all of the needs of patients with type 2 diabetes. In addition, therapies which focus on glucose-lowering only (eg, insulin) are often associated with adverse events (eg, hypoglycemia), which confers greater risk to the patient than hyperglycemia itself. Conversely, treatment strategies which aim at correcting the known pathogenic defects characteristics of type 2 diabetes will more safely lower the plasma-glucose concentration, correct other metabolic abnormalities of the disease, and decrease the risk for both microvascular and macrovascular disease.

Muhammad A. Abdul-Ghani, MD, PhD

Associate professor in the diabetes division of the University of Texas Health Center in San Antonio.

Disclosures: Abdul-Ghani reports no relevant financial disclosures.

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