Diabetes mellitus is a metabolic disease characterized by persistently high blood glucose levels. It is a lifelong condition and requires clinical intervention, lifestyle modifications and self-management to prevent long-term complications.
Based on the beta cells functioning and insulin release from the pancreas, diabetes is classified as type 1 diabetes and type 2 diabetes. In type 1 diabetes, the beta cells of pancreas are genetically impaired, lacking the ability to produce and release insulin. Such patients are only treated via insulin injections. In type 2 diabetes, functional activity of beta cells is hampered over time depending on a number of factors such as heredity, age, obesity, lack of physical activity and sedentary lifestyle.
This results in a diminished release of insulin from the pancreas, predisposing an individual to type 2 diabetes. Currently, all available antidiabetic or anti-hyperglycemic medications are targeted therapies for type 2 diabetes only.
According to the Center for Disease Control and Prevention (CDC) statistics of 2014, 29.1 million people (9.3% of the population) suffer from diabetes out of whom 21.0 million people have been diagnosed and 8.1 million people (27.8% of people with diabetes) are undiagnosed.
Diabetes is associated with multiple macrovascular and microvascular complications such as heart diseases, kidney impairment or failure, retinal damage (blindness), peripheral neuropathy (numbness in hands and specifically feet), delayed healing of wounds and increased chances of acquiring gangrene on foot in case the toe is injured, resulting in the amputation of the limbs. Diabetic patients need to take care of themselves very seriously as a little careless attitude can result in devastating consequences for their health.
According to the American Diabetes Association (ADA) 2016 recommendations, diabetes management requires screening, diagnostic, and therapeutic actions to favorably affect health outcomes in the diabetic population. The ADA states that diabetes should be diagnosed and screened on the basis of plasma glucose (PG) and glycohemoglobin (HbA1C) levels. The PG levels are measured in three different settings.
Let us now have a detailed look at the anti-diabetic medications and their effectiveness in controlling blood sugar.
Diabetes Treatment: Hypoglycemic Medications
There are various class of hypoglycemic drugs available in the market. These are as under.
Insulin, a hormone, is the mainstay of treatment in type 1 diabetes patients since in such a population, the beta cells of pancreas are destroyed, halting the natural production of insulin hormone. Insulin is administered exogenously in such individuals in the form of insulin pumps. A number of insulin analogues are also available which are classified either as short and rapid acting insulin preparations, intermediate acting and long–acting insulin preparations.
Short acting preparations include regular insulin, insulin lispro, insulin aspart and insulin glulisine. Regular insulin is usually given subcutaneously or intravenously in case of emergencies. Regular insulin, insulin lispro and insulin aspart are pregnancy category B and insulin glulisine is pregnancy category C insulin analog. Insulin lispro, insulin aspart and insulin glulisine, all three are not administered alone but with longer acting insulin preparations to ensure proper glucose control.
Intermediate-acting preparations include Neutral Protamine Hagedorn (NPH) insulin which is administered only subcutaneously and never intravenously. It is useful in treating all forms of diabetes except diabetic ketoacidosis and emergency hyperglycemia. It is used for basal control and is usually administered with short acting insulin preparations for meal time control.
Long–acting insulin preparations include insulin glargine, insulin degludec and insulin detemir. These preparations are also administered subcutaneously.
Like any other medicine, insulin and its analogues also have their side effects which are mainly produced due to hypoglycemia, that is, these side-effects are due to hypoglycemic effect. A patient may experience rapid heartbeats (tachycardia), anxiety, headache, confusion, sweating, light-headedness (vertigo), hypersensitivity (allergic reactions) and lipodystrophy (abnormal fat deposition).
Combination Insulin Preparations:
Recently FDA has greenlighted two novel insulin preparations which will likely be approved and marketed for type 2 diabetes treatment by mid-2016. These include:
- iDegLira – a fixed-dose combination of Insulin Degludec (Tresiba®) and Liraglutide (Victoza®)
- iGlarLixi – combination of Lixisenatide and Lantus®
The only agent that belongs to this class is metformin, which is by far the safest, and most effective and popular one. It acts by increasing the glucose uptake by target tissue, thereby ebbing down insulin resistance. Unlike sulfonylureas, it does not promote insulin secretion and therefore, is devoid of hyperinsulinemia adverse effect. This results in negligible risk for hypoglycemia unless calorie intake is diminished or physical activity is not compensated by food intake.
It is also beneficial in polycystic ovary disease due to its ability to lower insulin resistance. Metformin is currently the standard of care in type 2 diabetes treatment as it helps in weight loss by reducing the food intake.
Studies have shown that metformin administration prior to meals results in reduced calorie consumption and is beneficial in lowering weight in instances where other anti-hyperglycemic therapies fail.
A double-blind study showed that 24 women were able to lose more than 8 kg of weight when they were administered metformin before meals at a dose of 1700 mg. the study revealed that the drug produces its beneficial effects in a dose-dependent manner, that is, the larger the dose, the greater the weight loss. Moreover, the 1700mg dose was found to have the maximal hunger suppressant action.
The contraindications for metformin include kidney or liver disease and diabetic ketoacidosis. The adverse effects are largely gastrointestinal. In patients suffering from cardiovascular conditions such as acute myocardial infarction, exacerbation of congestive heart failure or severe infection, the drug should be discontinued.
The drug should also be used cautiously in elderly patients older than 80 years of age and in those with a history of heart failure or alcohol abuse. Long–term use of metformin may interfere with vitamin B12 absorption. The drug also requires suspension or termination in patients undergoing diagnostic procedures requiring IV radiographic contrast agents.
This class includes glibenclamide, glipizide, glimepiride, tolbutamide, chlorpropamide and tolazamide. This class is also termed as insulin secretagogues because they help in secretion of insulin from pancreatic beta cells and this is their mechanism of action as well. These drugs are only for type 2 diabetes patients in whom the functional activity of beta cells of pancreas reduces with age or disease.
These drugs can either be given as a monotherapy or in combination with biguanides (metformin) or insulin injections to enhance their activity. The most common adverse effects of this class is their propensity to cause weight gain, hyperinsulinemia (increased insulin levels in the blood) and hypoglycemia (decreased glucose levels in blood) which is risk factor for arrhythmias, confusion and in extreme cases, stupor.
However, the ADA has provided tips for managing hypoglycemia by instantly ingesting 15-20 grams of glucose or taking in fizzy drinks, juices honey, sugar, corn syrup, hard candies, chocolates or simple carbohydrates. The association also suggests that patients may take up their meals before the preset time if the meal hour is 1-2 hour ahead.
Moreover, injectable Glucagon kits are available as a specific treatment for insulin-induced hypoglycemia. Glucagon is a glucose releasing hormone that incites liver to discharge stored glucose (from glucose depots in the fat cells) into the blood stream. This helps raise glucose levels in the blood. However, kits are accessible only through prescription and the patient must seek advice from the health practitioner before using one.
This class of agents includes repaglinide and nateglinide. They share common actions with sulfonylureas and for this reason are not used in combination with sulfonylureas due to overlapping actions. This class has a short duration of action and causes rapid onset of insulin release and is thus beneficial in boosting the insulin release immediately after meals.
This prevents the surge in glucose levels in the blood that is associated with intake of meals. Pairing up of this class with metformin or glitazones enhances their activity and the combined therapy is superior to monotherapy in regulating glycemic levels. They should be used cautiously in patients with liver impairment. Weight gain and hypoglycemia are less of a problem in contrast to sulfonylureas.
This class also acts as insulin sensitizers and is commonly knowns as the “glitazones”. Drugs belonging to this class include Troglitazone, Rosiglitazone and Pioglitazone and are dependent on insulin for their action. These drugs improve insulin sensitivity by binding actively to peroxisome proliferator-activated receptor (PRAR) in fat cells (called adipocytes) and reduce the hormones secretion, i.e., adiponectin. Troglitazone has been withdrawn from the market awhile after its introduction due to reports of severe hepatotoxicity-liver damage. Rosiglitazone (Avandia) also experienced the same consequences (withdrawal) as Troglitazone in European and Indian markets after a study.
A meta-analysis, published in The New England journal of Medicine (2007) showed that Rosiglitazone increased the risk of heart attack in patients receiving the drug and about 13,000 lawsuits were filed against the drug manufacturer, the GSK. The FDA responded otherwise, stating that the evidence is not enough yet to lead to the withdrawal of the drug from U.S. markets.
However, the FDA did impose certain restrictions on the sales of the drug, confining them with the prescription from a certified doctor, with the drug being sold from specified pharmacies through mail order and the patients fully informed about the risks associated with the use of drug prior to its initiation. This obviously resulted in a dramatic drop in the sales and in 2010. Once a billion-dollar drug, only 3000 patients were prescribed Avandia in the U.S.
The glitazones have experienced a steep decline in prescription trend since 2008, after the introduction and success of DPP-4 inhibitors which now exclusively hold the largest share in antidiabetics market.
Though Rosiglitazone and Pioglitazone are not associated with liver damage, they are accountable for weight gain, fluid retention, subcutaneous fat, osteopenia and fracture risk. Pioglitazone is responsible for worsening the heart failure and several meta-analyses identified that rosiglitazone can potentially increase the risk of myocardial infarction, bladder cancer and death. They may as well cause headache and anemia.
The use of antidiabetics holds some beneficial role in ovulation anomalies. The glitazones cause resumption of ovulation in anovulatory females and in premenopausal females with polycystic ovary syndrome. Therefore, premenopausal women seeking contraception during Glitazones use should be adequately counseled regarding contraception.
They include acarbose and miglitol. These drugs are directed to be taken before meals since they act by delaying the digestion of carbohydrates and adequately lower the postprandial (after-meal) glucose levels.
These drugs act by inhibiting the enzyme, alpha-glucosidase which is responsible for the breakdown of complex sugars (oligosaccharides) into simple sugars such as glucose. They also inhibit a pancreatic enzyme called amylase to reduce the breakdown of starch into oligosaccharides.
Consequently, the upsurge in glucose levels following meals is blunted. As a monotherapy, they do not cause hypoglycemia but in combination with sulfonylureas, they may develop hypoglycemia.
Patients with inflammatory bowel disease (IBS), ulcer of the colon or intestinal obstruction should avoid using these medications. Other side effects are diarrhea, abdominal cramps and wind in the stomach.
They include exenatide and liraglutide. These drugs are analogs of the incretin hormones and act as GLP-1 receptor agonist or activator. The incretin hormones: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are released by the gut following meals and are 60-70% responsible for postprandial insulin secretion. These are not available as oral drugs but rather administered as injectables in type-2 diabetic patients. They are administered as adjunct therapy in patients in whom other antidiabetic agents fail to control glycemic levels.
These drugs not only improve insulin secretion but also promote beta cells proliferation that are responsible for insulin production and release, slow the process of emptying food from the gut therefore, producing the feeling of satiety and result in a decrease in food intake and also diminish postprandial glucagon secretion. Their use is associated with nausea, vomiting diarrhea and constipation.
Synthetic Amylin Analogue
Pramlintide is the synthetic amylin analogue that is used as a supplement or adjunct to insulin therapy. It is indicated for both type 1 and type 2 diabetes. It helps in delaying the emptying of food from the gut, giving forth to a feeling of satiety. It also abates glucagon secretion.
Pramlintide is administered as an injection prior to meals. When used as an adjunct to insulin therapy, the dose of the latter should be reduced by half or 50% to avoid severe hypoglycemia. Commonly observed side effects are mostly gastrointestinal consisting of nausea, vomiting and anorexia. The drug should not be administered in patients with a history of hypoglycemic unawareness, gastroparesis (delayed emptying of the stomach) and cresol hypersensitivity (a component or ingredient of insulin injection).
Dpp-4 Inhibitors Or Gliptins
Saxagliptin and Alogliptin are antidiabetic medications for type 2 diabetes mellitus (T2DM) that belong to a relatively new class of antidiabetic drugs – the dipeptidyl-peptidase 4 (DPP-4) inhibitors, introduced a decade ago. The first one of this class was sitagliptin that was introduced in 2006, followed by vildagliptin in 2007 and later saxagliptin in 2009, alogliptin in 2010 and linagliptin in 2011.
These drugs are novel agents since they target a new entity, the enzyme dipeptidyl-peptidase-4. This enzyme DPP-4 is responsible for the cleavage or breakdown of specific metabolic hormones – the incretins, which are accountable for the release of insulin from beta cells of islet of Langerhans.
Since, incretins help in the release of insulin from the pancreas, particularly after meals regulating sugar or glucose levels in the blood, their inhibition by DPP-4 enzymes results in increased blood glucose or sugar levels. So this innovative class of drugs targets the DPP-4 enzymes, thereby, increasing the incretin hormone levels and thus regulating glucose levels in type 2 diabetes patients.
Recently, on April 5, 2016, the FDA has updated a drug safety communication regarding gliptins. The FDA has directed the manufacturers to revise the “warning” label of these medications by putting up this safety alert on the labels of these medicines that should advise and instruct the health care practitioners and consumers regarding increased heart failure risk associated with the use of these two drugs in diabetic patients, especially those with pre-existing heart and kidney diseases.
The FDA reported their findings in a safety review that has been performed by evaluating two major clinical trials, conducted in diabetic patients. The trials reported the results, stating that the rate of hospitalization due to heart failure was 3.5% with saxagliptin in patients who received this medication as compared to 2.8% in patients who received a placebo. Similarly, the frequency of hospitalization due to heart failure was 3.9% with Alogliptin in subjects receiving this medication compared to 3.3% in patients receiving placebo.
The FDA has warned patients that in case they experience the symptoms of heart failure with these medicines which include shortness of breath, feeling excessively lethargic, difficulty breathing while lying down or taking a nap and weight gain with edema (swelling) in limbs, toes or ankles and stomach, they should immediately contact their health care provider.
The FDA has also issued a list of medications that contain these drugs either as single agent or in combination with other antidiabetic drugs. The drugs enlisted are Onglyza (saxagliptin), Kombiglyze XR (saxagliptin and metformin extended release), Nesina (Alogliptin), Kazano (alogliptin and metformin) and Oseni (alogliptin and pioglitazone).
Are Gliptins Beneficial As Anti-diabetics?
In 2008, the FDA demanded that all anti-hyperglycemic agents be evaluated for their cardiovascular safety profile. This, obviously applied to gliptins as well. Since, their introduction, the gliptins have been scrutinized under advanced phase clinical trials to assess their safety on a broader or massive scale of population.
Also, certain ambiguities regarding their antihyperglycemic effect and cardiovascular outcomes have clouded their efficacy. For this reason, a number of studies have been carried out in this regard.
One such study was published in The New England Journal of Medicine (NEJM), in 2013 under the title of “Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus” by a number of investigators collectively and is known as SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) study.
The study was conducted as a multicenter, randomized, double-blind, placebo-controlled, phase 4 trial for a period of 2.1 years in 16,492 patients, who were either at risk of developing cardiovascular disease or already had a history of heart disease or had increased blood glucose levels.
The study was executed at 788 locations in 26 countries and was sponsored by pharmaceutical giants such as AstraZeneca and Bristol-Myers Squibb and was designed by Thrombolysis in Myocardial Infarction (TIMI) and Hadassah Medical Organization in partnership with other sponsors who provided the drug. All patients were either 40 years of age or above 40 years.
The study found that glycemic levels significantly improved in saxagliptin group as compared to the placebo. The fasting plasma glucose levels were lower in saxagliptin group and glycated hemoglobin levels were substantially more normal as compared to placebo group.
The difference was 7.7% vs 7.9% for saxagliptin and placebo, respectively. Similarly, the primary –end point for heart failure, non-mortal myocardial infarction and non-mortal ischemic stroke presented themselves in 613 patients (7.3%) as compared to 609 patients (7.2%) in placebo group.
The statistical difference for secondary end points for hospitalization incidence due to heart failure, unstable angina and coronary revascularization was 12.8% for saxagliptin group and 12.4% in placebo group. Renal impairment (composite of number of risk factors) occurred in 194 patients (2.2%) in saxagliptin group and 178 patients (2.0%) in placebo group.
The study inferred that although saxagliptin is a remarkable antidiabetic medication and may be superior to other antidiabetic medications but the incidence of hospitalization due to cardiovascular events and renal impairment is significantly more conjoined with saxagliptin use. The researchers, therefore, stated that this outcome of the drug should be further validated by executing additional or more researches.
However, it has been reported that one half (2.5mg) of the usual dose (5mg) of saxagliptin is very much tolerable in moderate to severe renal impairment (GFR 50ml/ min) and the dose reduction is not required in mild renal impairment (GFR 50 ml/min).
Another study published in the Nature: Review Cardiology under the title “Cardiovascular effects of gliptins” also concluded that though gliptins or DPP-4 have proved miraculously beneficial as anti-hyperglycemics and also improved other risk factors associated with diabetes such as high blood pressure, hyperlipidemia, helped in lowering weight to a modest extent, reduced oxidative stress and attenuated inflammatory markers, their cardio-protective effects still needs to be further evaluated since there is limited data available in this regard.
Moreover, the gliptins have been conjectured to be associated with pancreatic cancer and thyroid cancer which is a rare one.
However, a study published in The Lancet under the research title of “Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomized, double-blind trial” reported that alogliptin did not increase the incidence of heart failure in type 2 diabetic patients with recent acute coronary syndrome.
Moreover, the gliptins are mostly used in combination with metformin, which is the first–line treatment for diabetes and the combination has proved successful in controlling both fasting and postprandial glucose levels (glucose levels after meals).
Furthermore, unlike other antidiabetic classes of medications, the sulfonylureas and thiazolidinediones which are associated with weight gain, the Gliptins or DPP-4 has proved beneficial in this regard as they are helpful in losing the weight.
However, DPP-4 inhibitors are still undergoing phase 4 clinical trials for post marketing surveillance to validate their cardiovascular outcomes in a large number of population subjects.
The question that how do gliptins or DPP-4 inhibitors cause cardiovascular adversities remains yet to be answered as the mechanism is still unknown and further pharmacodynamic studies are required to be carried out in this regard.
Other adverse effects reported with the use of gliptins include hypoglycemia, acute pancreatitis which may lead to pancreatic cancer (still controversial), thoracic cancer (still debatable due to preliminary data) angioedema, drug allergy (hives or urticaria), upper respiratory tract infection, urinary tract infection, shortness of breath and headache.
Diabetic ketoacidosis and lactic acidosis are contraindications for saxagliptin (Onglyza) or saxagliptin-metformin (kombiglyze) use.
Lawsuits On Onglyza And Kombiglyze
Since , the introduction of Onglyza (saxagliptin), it became stupendously popular and by 2011, Onglyza had secured more than 700 million dollars. Last year Onglyza was prescribed more than 1.7 million times for type 2 diabetes in America.
The FDA started reviewing the data on Onglyza from other studies since the publishing of SAVOR study in NEJM in 2013 which reported that patients taking Onglyza were 27% more conjecturable to hospitalization due to cardiovascular events. Up to this time, FDA has received approximately 150 cases, reporting either heart failure or hospitalization due to Onglyza use. 46 deaths have been confirmed with Onglyza use and 113 people reported heart complications.
Lawsuits have been filed against AstraZeneca and Bristol-Myers Squibb as the product is their joint venture. The lawsuits claim that despite knowing the heart risks associated with the drug use, manufacturers paid no heed to this outcome and deliberately portrayed incognizant behavior.
Moreover, they were inconsiderate and irresponsible by not putting up warning label for increased risk of cardiovascular events and waited for FDA reports in this regard. The first lawsuit was filed by the family of Lillie Ree Gibson, in Chicago, Illinois, who was twice hospitalized while on Onglyza prescription for 3 years and eventually suffered a heart attack.
Other Antidiabetics Available
Though, the DPP-4 inhibitors have proven outstanding in maintaining blood glucose levels, the safety profile over long–term use is yet to be determined. For this reason, patients should adhere to the already available antidiabetic medications which belong to different classes based on their varied mechanism of action. These include sulfonylureas, gliptins, alpha-glucosidase inhibitors, biguanides and incretin mimetics. Among these, sulfonylureas are the oldest of all.
Recently, the FDA has also approved a dopamine agonist, bromocriptine, for a new indication as an antidiabetic drug for type 2 diabetes patients. Bromocriptine is otherwise used in Parkinson’s disease, migraine and in hyperprolactinemia – a condition associated with excessive production of milk.
The newly approved novel formulation of bromocriptine is a time-release formulation known by the brand name Cycloset and is approved as a supplementary medication which enhances or boost the anti-hyperglycemic effects of anti-diabetic medications, it is not used as a monotherapy but compliments the anti-diabetic therapy.
Studies have shown that Bromocriptine is effective in reducing the HB A1c levels in type 2 diabetic patients treated with either diet alone or with monotherapy with either metformin, sulfonylurea or thiazolidinediones.
The novel formulation possesses a unique mechanism of action. It aids anti-diabetic medications by alleviating the blood glucose levels and also diminishing the levels of triglycerides and free fatty acids in the blood which are responsible for depositing fat in the arteries, particularly, the coronary arteries.
Thus, they have also proved to be beneficial in cardiovascular conditions as suggested by preliminary studies but the underlying mechanism still needs to be determined. Moreover, the indication in case of cardiovascular events requires a deeper insight as bromocriptine is currently not advised in patients with heart diseases.
The common side–effects associated with the drug are dizziness, dry mouth, congestion in nose, vertigo, constipation and numbness in extremities, however, patients with brain tumor, high blood pressure or with other heart diseases and those taking anti-depressants or anti-fungal drugs should avoid this medication and incase of severity of any side-effect, should promptly seek a doctor’s advice or consultation.
Sodium Glucose Co-transporter (SGLT-2) inhibitors are also a relatively new class of FDA- approved prescription medications that have been approved for type 2 diabetes. This class of anti-diabetic includes medications such as canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance).
This class of medications is directed to be taken in addition to diet and exercise. They are commercially available both as singular–constituent and in combination with metformin. These drugs decrease blood glucose levels via renal (kidney) excretion of sugar by way of urine, that is, glucose is excreted in urine.
However, in December 2015, the FDA has revised the labeling of this class of medications, stating in its “safety communication” that warnings should mention that this class of drug is associated with increased acidity in blood and complicated urinary tract infections.
The side effects associated with the drug include increased incidence of urinary tract infections and hypoglycemia and these side effects are more pronounced in females rather than males.
Statistics On The Use Of Antidiabetics
According to the Journal of Diabetes Care , a study was published under the title of “Use of Antidiabetic Drugs in the U.S., 2003–2012”, Since 2003, the number of adult antidiabetic drug users increased by 42.9% to 18.8 million in 2012.
The statistics displayed the data for 2003 till 2012 , revealing that among all types of antidiabetics prescription in 2012 ,GLP-1 analogues were ranked amongst the top antidiabetics with prescription number of about 120 million, followed by DPP-4 inhibitors with 100 million prescriptions, thiazolidinediones with 80-90 million prescriptions, sulfonylureas with approximately 70 million prescriptions and biguanides with only 20 million prescriptions.
The data displayed monotherapy trends regarding different antidiabetics classes. The prescriptions for combination therapy were 100-120 million.
Among the new antidiabetics, the trend for prescription use of Linagliptin was highest with more than 16 million prescriptions followed by saxagliptin and sitagliptin with 16 million and 10 million prescriptions in 2012, respectively. The prescriptions for Pramlintide, Liraglutide and exenatide were less than 2 million prescriptions in 2012.
According to Organization for Economic Cooperation and Development (OECD) statistics , “The use of antidiabetics has almost doubled in OECD countries between 2000 and 2013”. The statistics of 2013 showed that the consumption of antidiabetics was highest in Finland, Germany and the United Kingdom.
According to global statistics on antidiabetic prescription drug use, Biguanides scored the highest or top position in terms of items prescribed. The statistics demonstrated that 18,100 items of biguanide class were prescribed in England in 2014.
The statistics vary regarding antidiabetic use in each country, probably due to trends in prescription ordering or based on patient characteristics.
Nevertheless, it can be concluded that though, DPP-4 inhibitors have consumed much of the share of anti-diabetic drug markets due to their superiority in effectively controlling and maintaining glucose levels of blood and on other contributing factors that are responsible for insulin secretion or decreasing its resistance along with good control on glucagon secretion, their safety on long-term use still requires validity and thus should be dispensed only when benefits outweigh risks.