High blood sugar leads to many long-term complications, including stroke, heart disease, poor circulation, kidney failure and diabetic retinopathy
The rising incidence of Type II diabetes has sparked a real need for more, and more effective, drug treatments for the condition. Growing levels of obesity tie in with this dramatic increase in diabetes, and while about 285 million people were estimated to have the Type II form in 1985, the number was just 30 million or so a mere 25 years earlier.1
The impact on health is not merely the direct impact of the diabetes: high blood sugar leads to many long-term complications. Many of these are cardiovascular, such as stroke and heart disease, and poor circulation in the extremities. Other potential knock-on effects include kidney failure and diabetic retinopathy.
However, thanks to the high-profile problems with rosiglitazone (Avandia), the regulators are demanding ever-larger clinical trials, adding greatly to the development costs and time to market. As a result, it is now common for diabetes drugs to be co-developed by two rival companies to defray the huge expense.
One such drug is empagliflozin, which is being put through clinical trials by originator Boehringer Ingelheim, in conjunction with Eli Lilly.2 The drug inhibits sodium glucose co-transporter-2, or SGLT-2. Found largely in the kidneys, this transporter is responsible for the majority of glucose reabsorption from the urine into the blood, and therefore if it is blocked, this glucose will be eliminated in the urine.
Empagliflozin was found to have good selectivity over other forms of sodium glucose co-transporters. Its safety, tolerability, pharmacokinetics and pharmacodynamics were studied in 78 Type II diabetes patients.3 Subjects were given 10, 25 or 100mg doses of the drug or placebo for 28 days, and exposure increased dose-proportionally, with a linear pharmacokinetic profile. Urinary glucose excretion increased from baseline by 74, 90 and 81g respectively on day 1 across the three dosage groups, and these increases were maintained over the 28-day period. There was almost no difference in the placebo group. Adverse event profiles were similar across all four groups.
In a randomised, placebo-controlled Phase IIb trial, 408 patients who were either treatment naïve or had undergone a four-week wash-out were given 5, 10 or 25mg empagliflozin, placebo or open-label metformin once a day for 12 weeks.4 The empagliflozin group showed dose-dependent reductions in haemoglobin A1c (HbA1c), and fasting plasma glucose also decreased for those in the treatment group. Bodyweight also decreased for these patients. The most commonly reported adverse events included pollakiuria, thirst and nasopharyngitis.
Top-line results of four Phase III clinical trials have also been announced. In all four of these studies, the primary efficacy endpoint of a significant change in HbA1c from baseline compared with placebo was achieved, with single daily doses of 10mg and 25mg.
In one of these trials, 986 subjects were given 10 or 25mg doses as monotherapy or placebo for 24 weeks. In the second, 1,504 patients received 10 or 25mg doses of empagliflozin as an add-on therapy in combination with metformin or metformin plus sulfonylurea, or placebo, again for 24 weeks. The third trial also lasted 24 weeks, with 499 subjects being given 10 or 25mg empagliflozin as an adjunct to either pioglitazone or metformin, or placebo.
Finally, in the 52-week fourth trial 741 patients with renal impairment as well as Type II diabetes were given 25mg doses (for mild, moderate or severe impairment), 10mg if the impairment was mild, or placebo. Adverse event incidence was similar in all groups, although genital infections were more common with empagliflozin, unsurprisingly as glucose is being excreted.
In all, eight Phase III trials are being carried out in nearly 15,000 subjects with Type II diabetes. The companies anticipate filing for approval later this year.
1. S. Smyth and A. Heron, Nature Med. 2006, 12, 75
2. R. Grempler et al. Diabetes Obes. Metab. 2012, 14, 83
3. T. Heise et al. Diabetes Obes. Metab. 2013, Jan 28, epub ahead of print, doi: 10.1111/dom.12073
4. E. Ferrannini et al. Diabetes Obes. Metab. 2013, Feb 8, epub ahead of print, doi: 10.1111/dom.12081