Glucose-lowering drugs for diabetes

The drugs that lower blood glucose in diabetes fall into classes that work in different ways: insulin and the conventional agents that raise insulin secretion or sensitivity, the incretin-based drugs built on a gut hormone, and the SGLT inhibitors that act in the kidney, each with its own balance of benefits, side effects and place in treatment.

Insulin

Insulin was the first commercially available antidiabetic agent. ¹ It was first purified from an animal pancreas in 1921 at the University of Toronto by Frederick Banting and Charles Best, with help from John MacLeod and J.B. Collip. ² It was first used to treat a person with diabetes in 1922. ² It has been used to control glycaemia in diabetic patients since 1922. ³ The scientists received a Nobel Prize in 1923, and Eli Lilly received the contract to manufacture insulin. ²

People with type 1 diabetes need daily insulin therapy throughout their lives to survive, because their β-cells have died. ^{4, 5} People with type 2 diabetes can initially control their blood glucose with diet and exercise, and they may need additional help from oral glucose-lowering medication. ⁴ As the condition progresses, insulin therapy might become necessary to maintain blood glucose levels, so many people with type 2 diabetes need insulin as well. ⁴

Conventional treatments and their side effects

As of 2012, the conventional treatments to control hyperglycaemia in diabetes included insulin, insulin analogues, insulin secretagogues and insulin sensitisers. ³ Insulin analogues with improved properties compared with basal insulin had been developed. ³ The long-acting insulin glargine, marketed by Sanofi-Aventis, is injected only once daily, and Novo Nordisk then had the long-acting insulin degludec in clinical trials, where it appeared to have similar properties to insulin glargine. ³ Insulin secretagogues, such as the sulfonylureas and meglitinides, stimulate pancreatic β-cells to secrete insulin. ³ Insulin sensitisers, such as the biguanides (metformin) and the thiazolidinediones, decrease insulin resistance by improving insulin sensitivity. ³ Metformin, together with changes in diet and increased physical activity, was the first choice of medication for type 2 diabetes, because of its glucose-lowering effects, absence of weight gain, relatively few side effects and relatively low cost. ^{3, 6} Additional treatments are needed when metformin fails to control glycaemia. ⁶

The conventional medicines have been useful in controlling diabetes, but many problems remain. ³ Most antidiabetic drugs seek to lower blood glucose by increasing either insulin secretion by the pancreas or insulin sensitivity, so they can lead to potentially fatal hypoglycaemia. ¹ Hypoglycaemia is particularly an issue with sulfonylureas and insulin therapy, and the conventional medicines, especially sulfonylureas, can also cause β-cell destruction. ³ With the exception of metformin, most antidiabetic drugs cause weight gain, an added problem for the many diabetic patients who are obese. ^{3, 7} So drugs were desired that have fewer side effects and do not cause weight gain, or better still produce weight loss. ³

The incretin hormones and GLP-1

Incretin hormones are released from the gut within minutes of a meal and stimulate insulin secretion from pancreatic β-cells. ⁸ In healthy individuals, this incretin effect accounts for 50–70% of the insulin secreted after a meal. ⁸ Two incretin hormones have been identified: glucose-dependent insulinotropic peptide (GIP), released from the K-cells of the intestine, and glucagon-like peptide-1 (GLP-1), released from its L-cells. ⁸ Studies with exogenous incretins showed that GIP does not stimulate insulin secretion in patients with type 2 diabetes while GLP-1 does, so GLP-1 is the focus of drug development. ⁸

When secreted, GLP-1 lowers plasma glucose to normal levels, inhibits glucagon secretion, delays gastric emptying, decreases appetite and increases pancreatic β-cell proliferation. ⁸ It is secreted only when food is ingested, not when glucose is injected intravenously. ⁸ Its intracellular effect is mediated by the GLP-1 receptor, a G-protein-coupled receptor expressed in many tissues. ⁸ GLP-1 has a very short half-life, of about 1.5 minutes. ⁸ The enzyme dipeptidyl peptidase-4 (DPP-4) cleaves its active form, GLP-1(7–36), generating the inactive peptide GLP-1(9–36). ⁸ Giving GLP-1 itself as a therapy is therefore not feasible, because it is rapidly inactivated. ⁸ As of 2012, two incretin-based approaches were being developed for the treatment of diabetes: GLP-1 analogues that activate the GLP-1 receptor and resist DPP-4, and inhibitors of DPP-4 that increase the half-life of endogenous GLP-1. ⁸

GLP-1 receptor agonists

The GLP-1 receptor agonists on the market in 2012 were exenatide, approved in the USA in 2005 and marketed by Amylin Pharmaceuticals as Byetta, and liraglutide, approved in Europe in 2009 and distributed by Novo Nordisk as Victoza. ⁹ Exenatide is a synthetic version of exendin-4, a naturally occurring 39-amino-acid peptide originally isolated from the saliva of the Gila monster lizard, and it shares 53% amino acid sequence identity with native GLP-1. ⁹ Liraglutide shares 97% sequence identity with GLP-1, with one amino acid substitution and an added glutamate-linked fatty acid side chain that promotes albumin binding. ⁹ Exenatide was injected twice daily, and a once-weekly formulation, Bydureon, had recently been approved. ^{9, 10} Liraglutide was injected once daily, a disadvantage compared with metformin, which can be taken orally. ^{9, 10}

Exenatide and liraglutide nonetheless have many advantages over metformin. ⁹ Because their action is glucose-dependent, the receptor agonists do not induce hypoglycaemia, a common problem with the conventional diabetes drugs. ^{9, 6} They promote weight loss, may improve pancreatic β-cell function and may reduce the risk of cardiovascular diseases, whose complications are the most common cause of morbidity and mortality among patients with type 2 diabetes. ⁹ Their ability to promote weight loss is especially interesting because most patients with type 2 diabetes have obesity. ⁶ Clinical trials to 2012 had reported few side effects, mostly nausea and stomach discomfort that tends to resolve after a few weeks of treatment. ⁹ Their long-term safety remained to be determined. ⁹ Tumours had been observed in the thyroid tissue of rodents treated with liraglutide, but whether liraglutide causes thyroid tumours in humans was not yet known. ⁹ The long-term consequences of sustained GLP-1 receptor activation in the human thyroid required further investigation. ⁹ For this reason the receptor agonists were recommended only as second- or third-line therapies in type 2 diabetes, when metformin and other traditional therapies are not effective in controlling the disease. ⁹ In 2012, lixisenatide (Sanofi-Aventis), albiglutide (GlaxoSmithKline), semaglutide (Novo Nordisk), LY2189265 (Eli Lilly) and CJC-1134-PC (ConjuChem) were in clinical development, and clinical trials of taspoglutide (Roche) had been suspended because of safety concerns. ⁹

On 31 January 2020 the European Medicines Agency's human medicines committee recommended granting a marketing authorisation in the EU for Rybelsus (semaglutide) for adults with insufficiently controlled type 2 diabetes, to improve glycaemic control as an adjunct to diet and exercise. ¹¹ Rybelsus is the first GLP-1 receptor agonist developed for oral use, giving patients another option to treat the disease without injections. ¹¹ Semaglutide acts in the same way as the incretin hormone GLP-1: when blood sugar is high, it reduces blood glucose by stimulating pancreatic secretion of insulin and lowering the secretion of glucagon, a hormone that raises blood sugar. ¹¹ Its safety and efficacy were studied in eight clinical trials in patients at various stages of the disease, three of them against placebo, with Rybelsus used on its own, added to standard treatment or compared with an injected GLP-1 receptor agonist. ¹¹ The most common side effects in the trials were gastrointestinal, such as nausea and diarrhoea, and hypoglycaemia may occur when it is used with insulin or a sulfonylurea. ¹¹

DPP-4 inhibitors

DPP-4, the enzyme that degrades endogenous GLP-1, is widely distributed throughout the body, and inhibiting it increases endogenous GLP-1 concentrations two- to three-fold, depending on the inhibitor. ¹⁰ The DPP-4 inhibitor sitagliptin (Januvia, Merck & Co.) was approved by the FDA in 2006, followed by saxagliptin (Onglyza, Bristol-Myers Squibb), vildagliptin (Galvus, Novartis), linagliptin (Tradjenta, Boehringer Ingelheim and Eli Lilly) and alogliptin (Nesina, Takeda), which in 2012 was approved only in Japan. ¹⁰

DPP-4 inhibitors are taken orally, an advantage over the GLP-1 receptor agonists, which have to be injected. ¹⁰ Like the receptor agonists, they do not produce hypoglycaemia and might preserve β-cell function. ^{10, 6} They do not affect gastric emptying or decrease appetite, so they do not promote weight loss. ¹⁰ They are, however, considered weight neutral, an improvement over other treatments. ¹⁰ Clinical trials suggest that DPP-4 inhibitors reduce cardiovascular risk, although more studies are needed to clarify the relationship. ¹⁰ Overall they appear less efficient than the receptor agonists at lowering plasma glucose. ¹⁰ The DPP-4 inhibitors on the market differ in potency, metabolism and excretion route, so understanding their pharmacological properties is necessary for choosing the appropriate therapy for each patient. ¹⁰ Their most common side effects are headaches and an increased risk of infections, namely nasopharyngitis and upper respiratory and urinary tract infections. ¹⁰ Because the consequences of long-term DPP-4 inhibition in patients with type 2 diabetes were unknown, DPP-4 inhibitors, like the receptor agonists, were a second- or third-line option used when conventional therapies fail to control hyperglycaemia. ^{10, 6}

The place of incretin-based therapies

In 2012 the incretin-based therapies were second- or third-line therapies in type 2 diabetes, mainly because long-term safety studies of them had not yet been completed. ⁶ Both classes seemed to increase pancreatic β-cell proliferation and to reduce cardiovascular risk. ⁶ They seemed to circumvent the undesirable effects of the conventional therapies, and they could herald a new era in the treatment of diabetes, subject to the outcome of long-term safety studies. ⁷ The promising results obtained in clinical trials to 2012 suggested that they would largely replace conventional therapies. ⁶ The increasing number of therapies had led clinical bodies such as the American Diabetes Association, the European Association for the Study of Diabetes and the National Institute for Health and Clinical Excellence in the UK to develop guidelines to help physicians choose the best treatment for patients. ⁶

SGLT2 inhibitors

As of 2019, the sodium-glucose co-transporter-2 (SGLT2) inhibitors were the most recently developed class of antidiabetic drugs, and they act independently of the insulin pathway. ¹ They include empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. ¹ Canagliflozin was the first to be approved, in 2013, and by 2019 four drugs of the class had been approved by the FDA. ¹ They act in the kidneys, blocking the SGLT2 proteins that are the prime mediators of renal glucose reabsorption in the proximal tubules, and so maintain normal blood glucose by removing excess glucose from the blood. ¹ Unlike other antidiabetic drugs such as the sulfonylureas, they do not affect insulin secretion or action, so they have a low risk of inducing hypoglycaemia. ¹ In clinical trials they reduced fasting blood glucose and HbA1c. ¹ They can cause weight loss and blood pressure reduction, probably by increasing glucose and sodium excretion. ¹ Clinical studies show that, in contrast to other antidiabetic drugs, SGLT2 inhibitors reduce cardiovascular-related mortality risk in patients with type 2 diabetes. ¹

SGLT2 inhibitors may cause urogenital tract infections by increasing urinary glucose, and they may also increase the risk of stroke and diabetic ketoacidosis, although the mechanisms are not fully understood. ¹ Despite the risks of ketoacidosis and urinary tract infections, they can be used in carefully selected patients. ¹ They can be prescribed alone, or with other antidiabetic agents such as metformin for patients who cannot substantially reduce their glucose levels with one drug. ¹ In the future they may be used for diabetic patients with hypertension, but more clinical studies will be needed to verify benefits other than their ability to normalise glucose levels. ^{1, 12}

Sotagliflozin in type 1 diabetes

Despite improvements in insulin, its methods of administration and blood glucose monitoring, a proportion of patients with type 1 diabetes cannot achieve or maintain recommended blood sugar levels with insulin alone. ⁵ Hyper- and hypoglycaemia and weight gain are common. ⁵ So new therapies are needed as an adjunct to insulin, to better manage blood sugar and other cardiovascular risk factors. ⁵

On 1 March 2019 the European Medicines Agency's human medicines committee (CHMP) adopted a positive opinion for Zynquista (sotagliflozin) as an adjunct to insulin therapy to improve glycaemic control in adults with type 1 diabetes who have failed to achieve adequate glycaemic control despite optimal insulin therapy. ⁵ Sotagliflozin is a small molecule that inhibits both SGLT1 and SGLT2: it prevents reabsorption of glucose in the kidneys and delays and reduces glucose absorption in the proximal intestine, which helps lower the blood sugar level. ⁵ It was the second SGLT inhibitor for type 1 diabetes to be recommended for authorisation. ⁵ The opinion was based on three phase 3 studies in 1,853 patients with type 1 diabetes, in which the main benefit of sotagliflozin was improved glycaemic control, and its other effects included reductions in weight, blood pressure and the variability of glucose levels. ⁵ Despite precautionary measures, it considerably increased the risk of diabetic ketoacidosis, a potentially life-threatening complication. ⁵ Because of that risk, the committee recommended limiting its use in type 1 diabetes as follows: ⁵

• Treatment should be considered only in overweight or obese patients with a body mass index above 27 kg/m².
• Sotagliflozin is not recommended for patients with low insulin requirements.
• During treatment, insulin therapy should be continuously optimised to prevent ketosis and ketoacidosis, and the insulin dose should be reduced only to avoid hypoglycaemia.
• Treatment should be initiated and supervised only by specialist doctors.
• Patients should be able and committed to control their ketone levels, and should be educated about the risk factors for ketoacidosis and how to recognise its signs and symptoms.

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