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On March 4, 2018   /  Uncategorized  

Abstract

To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.

Keywords: Type 2 diabetes mellitus, Treatment, Oral antidiabetic agents, Injectable antidiabetic agents, Older people, Renal impairment, Future treatments

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a disease that affects more than 400 million people around the world. In 2040, there will be more than 640 million people with diabetes worldwide[1]. The prevalence of T2DM is expected to double within the next 20 years, due to the increase of the age, obesity and the number of ethnic groups of high risk in the population[2], with significant increases in cardiovascular disease[3], end-stage renal disease (ESRD)[4], retinopathy and neuropathy. Additionally, to achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin (HbA1c) significantly decreases risk of macrovascular and microvascular complications[4]. However, only about 50% of diabetic patients reach their HbA1c target[5]. Algorithms for the treatment of diabetes highlight the need for good glycaemic control to reduce the development or progression of diabetes complications. In recent years has increased the number hypoglycaemic agents available for the treatment of T2DM. A recent position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) on a patient-centered approach in the management of patients with T2DM[6] gives an overview on how different conditions and co-morbidities may influence the choice of different hypoglycaemic agents. The ADA/EASD suggests that initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial[7], but for many patients is a complication keep long term, due to differing experiences or perceptions[8]. In general, drug therapy includes not only initial hypoglycaemic agents, but other intensification strategies to maintain glycaemic control over time, often requiring several drugs with different mechanisms of action[9]. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients.

This article reviews current and future treatments for patients with T2DM, its use in clinical practice and in special situations such as kidney failure and elderly patient, with an emphasis on agents introduced within the last decade. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM.

LIFESTYLE CHANGES

Dietary intake and physical exercise are the two main determinants of the energy balance[10], and they are considered as a basic base in the treatment of patients with diabetes. Adequate rest is also very important for maintaining energy levels and well-being, and all patients should be advised to sleep approximately 7 h per night[9]. Evidence supports an association of 6 to 9 h of sleep per night with a reduction in cardiometabolic risk factors[11], whereas sleep deprivation aggravates insulin resistance, hypertension, hyperglycaemia, and dyslipidaemia[12]. On the other hand, a screening of patients with suspected obstructive sleep apnoea should be performed, and refer them to a sleep specialist for evaluation and treatment[9].

Although the pharmacological options are each time more extensive and they offer more therapeutics possibilities, especially in the T2DM, the interventions in the life style are essentials in the approach of these patients and they are needed to get the therapeutics goals[13].

Diet

When nutritional intervention is contemplated, the co-morbidities that can coexist in a diabetic patient also have to be considered. The recommendations on dietary aspects can contribute to achieve the desired blood glucose, blood pressure, lipid profile and weight[10,14], as well as improve sleep apnoea, depression and quality of life related to health; in addition, it has been observed that the incidence of urinary incontinence in women is reduced[15-18].

Numerous randomized controlled trials have demonstrated the metabolic benefits of nutritional recommendations in reducing HbA1c; being variables the results got depending mainly on the length of the disease[19,20].

Energetic contribution: Total caloric intake diet will depend on several factors, being determining the presence of overweight or obesity. Body mass index (BMI) is a tool commonly utilized in clinical practice to classify patients and it is calculated by the following equation: [weight (kg)/height (m2)] (Table ​1).

Table 1

Classification of degree of obesity by body mass index

Most T2DM patients have some degree of overweight or obesity[21]. It has been connected to insulin resistance and defects in insulin secretion. These alterations favour the appearance and worsening of diabetes[22], so in these cases in addition to an adequate distribution of macro and micronutrients, we should look for as a main objective a weight reduction by reducing the caloric intake. To achieve this objective, it has been proposed that the caloric intake of the diet prescribed to a diabetic patient with obesity should contain between 500 and 1000 kcal less of its energy needs[23]. This weight reduction will improve the insulin sensitivity, being a favourable factor to improve the glycaemic control parameters[24]. In the case of patients for whom there is no excess weight, the diet should be isocaloric.

There are different formulas for calculating baseline energy needs of people (Table ​2). To these basal needs, a factor depending on the physical activity must be added. The randomized trial LOOK AHEAD, showed that weight loss after an intervention in lifestyles, improve blood pressure, and blood glucose control and lipid profile[25], especially in patients with a recent diagnosis of disease[3]. When this study was prolonged, it was found that intensive nutritional intervention did not provide an improvement in the rate of cardiovascular events or weight loss when it is compared against a standard nutritional intervention[26].

Table 2

Different formulas for calculating baseline energy needs of people

Macronutrient distribution: There is not enough evidence to suggest an ideal percentage in the distribution of carbohydrates, lipids and proteins. There are several studies that have sought to distribute the best ratio macronutrients without finding valid results, and several dietary patterns that have been analysed as the Mediterranean diet, vegetarian or vegan diet, Dietary Approaches to Stop Hypertension (DASH), low-fat diet and low carbohydrates diet observing a modest effectiveness of managing diabetes. The benefits happen only when they are accompanied by a lose weight so more studies are needed[27].

Carbohydrates: Although there is no consensus on the percentage of carbohydrates that people with diabetes should eat, it has been shown that the amount and the type of carbohydrates are the main determinants for glycaemic control. Counting carbohydrates has proven to be very important in all patients. It allows a better adjustment of the postprandial blood glucose for those who take insulin. With this method, patients consumed a known amount of carbohydrates divided among different meals and calculated it in grams of carbohydrates per portion (Table ​3). This type of measurement is more important in patients with basal-bolus treatment or with continuous insulin infusion[28].

Table 3

Glycaemic index, glycaemic load and carbohydrates portion

It is preferable that the intake of carbohydrates comes from products such as fruits, vegetables, legumes, whole grains and dairy vs those involve the added contribution of salt, fat or simple sugars[10].

Index and glycaemic load: There is large confusion in the interpretation about the effect of the diet with low glycaemic index and there is not unanimity in the results of the different studies. Even though these diets are recommended by some associations because there are studies in which have been observed a better glycaemic control when it is compared above all with high glycaemic index food[29], there are articles that have questioned this assertion. They based this divergence on: The different definition of glycaemic index, they do not take into account the fiber contribution, and the different glycaemic response to the same food in different individuals. They consider that cannot be determinate that the observed effect is exclusively due to the food’s glycaemic load[30] (Table ​3).

Fiber: Dietary fiber intake, especially the fiber that provide the natural resources, has shown that improve the control of cardiovascular risk factors, and improved the glycaemic control, turning into a lower risk of cardiovascular mortality in people with diabetes[27,31]. However, some studies have shown that the effect on diabetes has a modest significance and it is achieved with high amounts of fiber a day but this is far away from a real consumption in daily life (greater than 50 g/d)[32].

Generally, and taking into account the modest beneficial effects on cardiovascular risk factors, in diabetic patients is suggested a consumption of fiber and whole grains at least similar to that recommended for the general population; about 25 g/d for women, and 38 g/d for men or 14 g per 1000 kcal[28].

Sucrose and fructose: Contrary to what one might think sucrose intakes of 10%-35% of total energy do not have a negative effect on glycaemic or lipid responses when sucrose is substituted for isocaloric amounts of starch[33]. Consume free fructose (naturally occurring from foods such as fruit) did not get worsen the glycaemic control more than other forms of sugar, although it should avoid further intake of 12% of daily calories[28]. Restriction is advised of these sugars in the diet to avoid excessive caloric intake that can contribute to weight gain if are taken in large quantities. Moreover, sugary drinks contain large amounts of fast absorbing carbohydrates and have demonstrated a cardiovascular risk and diabetes increase in the healthy population that consumes them. Especially harmful when are sweetened with fructose free. Although there are not many studies in diabetic patients, there is no reason to think they will not have the same consequences. Therefore, the consumption of these drinks is contraindicated[34].

Non caloric sweeteners: Opposite of natural simple sugars there are sweeteners with lower calorific value. Most are artificial. They do not have caloric contribution, except aspartame (containing 4 kcal/g), and do not increase blood glucose. These sweeteners can be used by diabetic patients. If they are employed to replace glucose, bring the benefit of reducing the kilocalories in the diet[35].

Proteins: It is interesting to make a differentiation between diabetic patients with and without kidney disease. In people without kidney disease, protein intake usually recommended is between 15%-20%; however, reviewing scientific studies no firm conclusion could be reached with respect to this issue. In the literature we can find different randomized clinical trials faced on this issue results. On the one hand there are studies that demonstrate that if 28%-40% of the energy of the diet is taken as proteins there is an improvement of the HbA1c, triglycerides, total cholesterol and/or LDL cholesterol[36], while others studies have not shown a benefit in any of these aspects[37]. In patients with kidney disease, whether if we refer to micro or macroalbuminuria, reducing protein intake below the usual has been undergone various tests and meta-analysis and the evidence has not shown that improve glycaemic control, cardiovascular risk factors or renal disease progression following low-protein diets[27]. With regard to the origin of proteins, there is no difference between animal and vegetable origin in relation to proteinuria[28].

Finally, the proteins in patients with T2DM, although they do not have effect on blood glucose control itself, seems to increase the insulin response so it is not advisable to use proteins in situations of hypoglycaemia.

Fat: Epidemiological studies have related fats with the risk of developing obesity and cardiovascular risk[38]. As in the rest of immediate principles there is no optimal fat proportion and, as a general rule, the recommendations for the general population (between 20%-35%) are applied for diabetic patient, paying special attention if the patient is overweight, then the percentage should be at the lower limits. Despite these recommendations, diabetic patients often take more fat than the recommended[39].

We can distinguish between saturated and unsaturated fats (monounsaturated and polyunsaturated). In addition, has to be specified that trans fatty acids may be a type of unsaturated fat but with harmful effects on the body for its different structure. Distinguish between these types is important because it has been demonstrated that the quality is more relevant than the amount of fat consumed.

There are few studies in diabetic patients about consumption of saturated fatty acids or cholesterol; in this regard the recommendations for patients with diabetes are the same as for the general population: A contribution of saturated fat < 10%, with a minimum intake of trans fatty acids and with a contribution of cholesterol < 300 mg/dL[10] preferably choosing monounsaturated and polyunsaturated fatty acids (including omega-3 fatty acids). Some studies, that have studied the Mediterranean dietary pattern, have demonstrated that monounsaturated fatty acids can improve cardiovascular risk factors and glycaemic control[40], especially if they are replaced with saturated fatty acids.

Omega-3 fatty acids: Although there are unlike results, in general we cannot say that omega-3 supplements have shown clear cardiovascular benefit[41]. However, consumption of products high in omega-3 can be positive in preventing cardiovascular disease[42].

Alcohol: Alcohol should be drunk in moderation and it should not exceed one serving per day for women, or two servings per day in the case of men. To avoid excess of energy when they are consumed, this contribution must be exchanged for other products. This moderate consumption does not harm the glycaemic control but rather in some studies has been found the contrary, with moderation can improve glycaemic control and reduce cardiovascular events.

Despite the above facts, it is very important to note that alcoholic beverages may contribute to the appearance of late hypoglycaemia especially in patients in treatment with hypoglycaemic drugs, so we should warn the patient to pay attention to any symptoms of hypoglycaemia[28].

Sodium: The recommendation for the general population to reduce sodium intake to less than 2300 mg/d shall also apply to patients with diabetes mellitus. When these also have hypertension, which is very common, reduced sodium intake should be individualized[43].

Specific supplements: The potential benefits of dietary supplements for diabetic patients with various specific nutrients have been subjected to trials. In despite of this, reliable data has not been observed to confirm benefits in glycaemic control supplementing because of supplement the diet with antioxidants as vitamin and carotenes, micronutrients such as chromium or other herbs. The recommendations of vitamins and minerals are not different from the general population, they are provided by a varied diet[38].

Exercise

The physical activity and exercise are one of the basic strategies in the treatment of diabetes. Promoting exercise, within a specific plan, provides in general terms multiple benefits: Increased insulin sensitivity in tissues, improvement of glycaemic control[44], benefits in lipid profile and blood pressure, maintenance or weight loss, cardiovascular benefits, better quality of life, psychological well-being and improvement of depression[10].

Benefits of glycaemic control: In some studies it has observed a significant decrease in HbA1c in patients with T2DM who do exercise. The difference in the degree of improvement observed in the different studies will depend on the characteristics of the patient and the type of training, thus, it is more effective when training programs are based on aerobic exercises of programs based on muscle strength in isolation[45].

Other benefits: The physical exercise also brings improvement in other metabolic parameters. It helps control cardiovascular risk factors (dyslipidaemia, hypertension, weight maintenance, psychological benefits, reduces mortality, improvement cardiorespiratory fitness and peripheral neuropathy[10,45].

Types of exercise: Both aerobic and resistance exercises have demonstrated benefits in people with diabetes through increased glucose uptake and decreased insulin resistance.

Though aerobic exercise in isolation seems to get better benefits that resistance exercise[45], in patients with diabetes is recommended the combination of both types because the effect is greater than if each one is performed in isolation[46,47].

This type of training has been traditionally recommended for patients with T2DM. A frequency of at least 3 d per week is recommended, preferably if it can be increased to 5 d with no more than two consecutive days between periods of activity, because the increase of the sensitivity and the glucose tolerance is maintained for about 12-24 h. It should be done with moderate intensity which is 40%-60% of maximum aerobic capacity. This corresponds to 55%-69% of maximum heart rate according to age (maximum heart rate = 220-age)[47]. Another method for measuring the intensity can be the subjective perception of the effort that assigns values to 20 points according to the patient judgment about the activity performed (Table ​4). A moderate-intensity exercise can also be an activity that can be conducted while maintaining an uninterrupted conversation.

Table 4

Relationship between maximum oxygen consumption, % of maximum heart rate and subjective perceived exertion

The effect of exercise in T2DM is clearly related to the volume done, thus, in different societies, it is recommended at least a minimum of 150 min per week[43,47]. Despite following the same recommendations, it has recently published a review where it is expounded that shorter performance exercises, with reference to the accumulated time during the week, keeps some benefit although this is less[48].

This type of exercise should be performed 2-3 times a week on non-consecutive days. For optimal gains in strength and insulin action, training should be moderate (50% of 1 repetition maximum) or vigorous (75%-80% of 1 repetition maximum). Each session should include from 5 to 10 exercises involving the use of large muscle groups. Ten to fifteen repetitions of each exercise (30-45 s) have to be made. Between each series should be left between 1-2 min for the recovery. Supervision by a professional can ensure an appropriate enforcement and progression of the exercise that optimized the benefits and reduce the risk of complications[47].

Although they have not demonstrated benefits in glycaemic control, these exercises are also recommended and can be very useful in older patients with T2DM[49].

Unstructured physical activity: It is also recommended to advise patients to increase energy expenditure in activities of daily life. It requires an increase of unstructured physical activity (walking more in the day, climb the stairs...)[50].

Prescription of a specific plan: Exercise should be prescribed individually for each patient and taking into accounts the characteristics of the person. Initially, the guidelines should recommend a slow progression and, if it is necessary, the patient has to start with low volumes of work. Recommendations should take into account the type of diabetes and the treatment utilized, the possibility that patients have diabetic foot, retinopathy, neuropathy, nephropathy or some degree of cardiovascular risk[49]. Training plans that are supervised by professionals have proved to be more effective as this study have demonstrated. In it, is compared a supervised program against a general advice, and although in both an increase in physical activity is observed, some better effects in HbA1c and cardiovascular risk factors in the supervised group have been seen[51].

Before starting the exercise would be advisable to pre-clinical evaluation, paying special attention to physical ability, complications of diabetes and comorbidities that constrain the realization of physical activity. For patients at high cardiovascular risk or for those who start high-intensity exercises, the ADA recommends performing an effort test with a grade of recommendation C[47].

Exercise and diabetes complications: The presence of diabetes complications involves a number of considerations at the time of writing prescriptions of physical exercise in these patients.

The physical exercise has proved benefits in reducing the appearance of peripheral neuropathy[52]. When it is already present, it is recommended to avoid exercises that cause impacts of repetition in the lower extremities and especially in patients with foot ulcers and wounds[53]. Furthermore, recent studies have demonstrated that moderate intensity walking do not increase the risk of ulcers.

In respect of the weight-bearing exercises, it can be performed while there are no ulcers or foot lesions. In any case it should pay attention and examine the feet and always wear suitable shoes.

The presence of retinopathy advises against the practice of physical activities that increase intrathoracic pressure (Valsalva manoeuvre), or high-intensity exercises by the risk of retinal detachment or intravitreal haemorrhage. The exercises with low and moderate intensity (walking, swimming...) are perfectly authorized and they can be done safely. Contact exercises like boxing should be avoided because of the risk of impact[50].

Exercise for diabetic patients is beneficial at any stage of renal function. In epidemiological studies it has been shown to improve renal function. Promotes muscle strengthening in case of kidney failure that helps to counteract sarcopenia, and improves various parameters in patients on dialysis, so with supervision and restraint exercise is recommended and although they have been transient increases in microalbuminuria with sessions of exercise (because of increasing blood pressure) is not considered as a marker of persistent microalbuminuria[50].

Physical activity has many beneficial cardiovascular effects but must take into account some considerations when there is vascular disease. Patients with diabetes that present a moderate or high cardiovascular risk should be included in supervised cardiac rehabilitation programs, because exist an association with mortality. In addition, during the exercise there is an increased activity of the sympathetic nervous system and catecholamines and decrease vagal tone[47,50].

In people with peripheral arterial disease benefits from the practice of sports aerobics and resistance also exist because of the improvement of the mobility, functional capacity, pain tolerance and quality of life[47].

Moderate physical exercise can improve the autonomic nervous system both in patients with autonomic neuropathy and those who do not have it[54], however it may represent a prescription limitation because it may favour silent ischemia, doubling mortality, impairing exercise tolerance and decreasing the maximum heart rate and thus a prior cardiovascular study is recommended[55].

Exercise with uncontrolled blood sugar

Hyperglycaemia: In T2DM is very strange developing a true insulin deficiency, as in type 1 diabetic, so if the patient feels well is not necessary to postpone the exercise by hyperglycaemia, although they must ensure an adequate hydration state[56].

In non-diabetic person with aerobic exercise the increase of the glucose uptake is offset with similar increase of the hepatic glucose, but in diabetic person the muscle uptake is greater than the liver’s production although the risk of hypoglycaemia is minimal if hypoglycaemic drugs are not taken[47]. However, if in addition to the effect of exercise add up the effects of hypoglycaemic drugs, we recommend a series of precautions mainly based on carbohydrate intake and adjust drug doses. If the levels before exercise are less than 100 mg/dL should take a supplement of 15 g of carbohydrates before exercise. This measure should only be recommended if blood glucose lowering drugs (secretagogues or insulin) are taken. If the control is with other drugs, supplements are not required if the exercise is less than an hour[56]. It is important to note that regardless of the initial levels, if the exercise is prolonged a monitoring could be required and also intakes over the same period.

Before physical activity, to prevent the appearance of hypoglycaemia during exercise, doses of drugs such as insulin secretagogues or insulin (especially the latter) can be decreased. These measures can be associated with dietary measures mentioned above. During the hours after exercise glucose needs increase, so after exercise delayed hypoglycaemia can happens. This hypoglycaemia should be expected and may require reducing the dose of drugs after exercise and/or increase the intake after it[47].

ORAL AGENTS

Metformin

Metformin is considered the agent of first line for treatment of T2DM, in the absence of contraindications[6,13,57].

Mechanism of action[58]: Metformin can change the composition of gut microbiota[59] and activate mucosal AMP-activated protein-kinase (AMPK) that maintain the integrity of the intestinal barrier. These effects, in combination with the activation of AMPK[60] in hepatocytes appear to be the mechanism by which metformin decrease lipopolysaccharide (LPS) levels in circulation and in the liver.

After being delivered to the liver from the intestines, metformin can inhibit gluconeogenesis through four different mechanisms[61]: (1) by activating hepatic AMPK through liver-kinase B1 and decreased energy charge (9, 10); (2) through the inhibition of glucagon-induced cAMP production by blocking adenylcyclase (11); (3) in high concentrations (5 mmol/L) inhibit NADH coenzyme Q oxidoreductase (complex I) in the mitochondrial electron transport chain (12) to reduce ATP levels and increase AMP/ATP ratio. This increased ratio should activate AMPK; and (4) the inhibition of mitochondrial glycerol phosphate dehydrogenase (mG3PDH)[58], will affect transport of NADH from the cytoplasm into mitochondrion, suppressing gluconeogenesis process from lactate.

Also, metformin works through the Peutz-Jeghers protein LKB1. LKB1 is a tumour suppressor, and activation of AMPK through LKB1[62] may play a role in inhibiting cell growth.

Indications and contraindications: Metformin is the drug of first-line for many patients with T2DM. It decreases fasting blood glucose by approximately 20% and HbA1c by 1.5%. It can be given in combination with sulfonylureas, glinides, alpha-glucosidase inhibitors, insulin, thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonist (RA-GLP1), dipeptidylpeptidase 4 inhibitors (iDPP4), and sodium-glucose co-transporter 2 inhibitors (iSGLT2). Metformin is contraindicated in patients with factors that predispose to lactic acidosis. The predisposing factors are: A renal function damaged, concomitant liver disease or excessive alcohol intake, unstable or acute heart failure and personal history of lactic acidosis.

The precise serum creatinine and estimated glomerular filtration rate (eGFR) limits for the use of metformin remain uncertain. In the metformin prescribing information is contraindicated when creatinine level is above 1.4 mg/dL in woman and 1.5 mg/dL in men, and with eGFR < 60 mL/min. However, in observational studies of T2DM patients and eGFR 45-60 mL/min, improved clinical outcomes have been reported. Nowadays[63-65], in patients with eGFR above 45 mL/min, metformin can be utilized. The absolute contraindication is with GFR < 30 mL/min. With eGFR 30-45 mL/min, in clinical practice, currently we reduce metformin dose by a half. It is very important to advise patients with eGFR 30-60 mL/min to stop taking metformin if they develop any condition associated with dehydration, sepsis or hypoxemia. Also metformin should be stopped prior to intravenous iodinated contrast.

Side effects: The most frequents are gastrointestinal, such as anorexia, nausea, abdominal discomfort and diarrhoea; they are usually mild and transient. Also, metformin reduces intestinal absorption of vitamin B12.

Less common is lactic acidosis. In a review[66] of 347 randomized trials and prospective cohort studies, there were no cases of lactic acidosis. However, is very important because of the high case-fatality rate. Predisposing factors are all situations that predispose to hypoperfusion and hypoxemia (sepsis, heart failure, dehydration, acute or progressive renal impairment).

Cardiovascular effects: Metformin does not have adverse cardiovascular effects, and it appears to decrease cardiovascular events as we saw in UKPDS, and during the post-interventional observation period of the UKPDS, in which reductions in the risk of macrovascular complications were maintained in the metformin group.

Metformin also has a lipid-lowering activity, and it result in a decrease in free fatty acid concentration, serum triglyceride, small decrease in LDL cholesterol and a modest increase in HDL cholesterol.

Cancer incidence: Observational data suggest that metformin decreases cancer incidence[67,68]. In different meta-analyses in T2DM patients, use of metformin compared with non-use or with use of other diabetes treatment, was related with a reduced risk of all cancers and lower cancer mortality[69,70]. The majority of the trials were not designed to explore cancer outcomes, so we must be prudent in the interpretation of their results.

Insulin secretagogues: Sulfonylureas and meglitinides

Sulfonylureas and meglitinides or glinides (insulin secretagogues) are two different classes of oral hypoglycaemic drugs but they have a common mechanism of action, and both stimulate pancreatic beta cells to release insulin.

Sulfonylureas are a classic first or second-line therapy for patients with T2DM[71], and since their introduction to clinical practice in the 1950s they have been widely utilized[72]. They are utilized as a reference to compare the efficacy and safety of other hypoglycaemic drugs excluding insulin.

Meglitinides stimulate insulin release through similar mechanisms but they have a different subunit binding site, with a more rapid absorption and more rapid stimulus to insulin secretion. However they require more frequent dosing[73].

Mechanism of action: Both sulfonylureas and glinides base their mechanism of action in increasing insulin secretion, which is regulated by ATP-sensitive potassium channels (KATP potassium channel) located in the membrane of pancreatic beta cells[74]. Although the receptor’s binding site is different for sulfonylureas and glinides, they both induce channel closure and cell depolarization leading to an increase in cytoplasmic calcium level and consequently insulin secretion[37].

Pharmacokinetics: Differences in pharmacokinetic and binding properties of insulin secretagogues result in the specific responses that each drug produces. Sulfonylureas can be divided into first- and second-generation agents. Glyburide (known as glibenclamide in Europe), glipizide, gliclazide and glimepiride are second-generation sulfonylureas[57]. New generation agents are more potent and have fewer adverse effects[37]. Although second-generation sulfonylureas are equally effective, there are differences in absorption, metabolism, and duration of action as well as in effective dose; for example, glyburide has active metabolites that can prolong his action.

There are two different glinides: Repaglinide and nateglinide. Repaglinide is a member of the meglitinide family different from the sulfonylurea. Nateglinide is a derivate of phenylalanine and it is structurally difference from sulfonylureas and meglitinide. They both cause less hypoglycaemia and less weight gain due to their shorter half-life and a different sulfonylureas receptor binding site, leading to faster absorption and a more rapid stimulus to insulin secretion[37].

As a result of their pharmacokinetics, the major effect of sulfonylureas is the reduction of fasting plasma glucose concentrations, whereas meglitinides mainly reduce postprandial glucose[75].

Advantages and effectiveness: Sulfonylureas and meglitinides can be effective when employed as monotherapy, or in combination with other oral hypoglycaemic drugs or insulin. Sulfonylureas are the most cost-effective glucose-lowering agents, have been on the market for a long time[37], and are widely utilized because of their long term efficacy and safety history, low cost and extensive clinical trial data demonstrating good glucose-lowering efficacy[76,77]. The glucose-lowering effectiveness is said to be high for sulfonylureas (expected HbA1c reduction 1.0%-1.5%) and generally lower for meglitinides (0.5%-1.0%)[9,57].

In the Consensus of ADA/EASD 2015 sulfonylureas and glinides appear as an alternative to metformin when metformin is contraindicated or not tolerated, and they represent an alternate treatment option in double and triple therapy[57], whereas in the Consensus of the American Association of Clinical Endocrinologist (AACE) 2016, sulfonylureas and glinides appear as the last alternative both in monotherapy and combined treatment[9].

Side effects: Loss of efficacy, hypoglycaemia and weight gain represent the main problems related to the use of these drugs.

Over time insulin secretagogues lose effectiveness (secondary failure), caused by an exacerbation of islet dysfunction with beta cell failure[78,79]. As a result, the percentage of patients maintaining adequate glycaemic control decreases progressively. Although this effect may also be related to disease progression, it has shown an increase in secondary failure than other agents[80].

Weight gain can be via many of the same mechanisms that are triggered by insulin therapy, and it has been observed in different studies[81,82]. However, metformin might counter the weight gain effect when used in combination[81,83]. Different generations of sulfonylureas have shown to cause weight gain and its magnitude appears to correlate with the propensity to cause hypoglycaemia. It may also occur with meglitinides as they have similar profiles[76], but it seems to occur in a lesser extent due to their short action[78].

Hypoglycaemia is the most common adverse effect[83,84], especially with long-acting sulfonylureas (such as glyburide/glimepiride)[85]. New generation sulfonylureas have shown to have a significantly lower risk of hypoglycaemia. Meglitinides generally have less risk of hypoglycaemia[37], thus being useful for individuals in whom the goal of avoiding hypoglycaemic events is important.

The risk factors for hypoglycaemia are inconsistent eating patterns in older individuals (meglitinides can be useful in these patients), malnutrition, alcohol ingestion, renal insufficiency, hepatic failure, hypothyroidism or drug interactions[86,87]. The risk of hypoglycaemia, as well as considerations of the risk-to benefit-relationship, is particularly relevant in older individuals where results from trials have suggested that aggressive control may not have significant benefits and may present some risk[6].

Cardiovascular disease: Sulfonylureas have been associated with increased cardiovascular risk, especially when it comes to glyburide/glibenclamide. Some studies[88,89] support this association, which can be explained by the interference with ischemic preconditioning, a protective autoregulatory mechanism in the heart. However, other studies like UKPDS, ADVANCE and ACCORD and many meta-analyses failed to proof an increased risk in cardiovascular mortality or morbidity[76]. Therefore, it remains unclear whether sulfonylureas are associated with an increased cardiovascular risk but as glibenclamide may indeed be when compared with other sulfonylureas, clinicians should consider possible differences in risk of mortality if a sulfonylurea is to be utilized.

Other considerations: Most insulin secretagogues undergo significant renal clearance except for meglitinides, and the risk of hypoglycaemia is higher in patients who have chronic kidney disease (CKD) especially with glyburide/glibenclamide which has a prolonged duration of action and active metabolites[58]. In patients with liver disease, sulfonylurea is not specifically contraindicated and meglitinides can also be employed. When liver disease is severe, insulin secretagogues have an increased risk of hypoglycaemia and should be avoided[57,90].

Sulfonylureas have several drug-drug interactions as they are metabolized by cytochrome p450[84]. Repaglinide with gemfibrozil is contraindicated because of its higher risk of hypoglycaemia.

Alpha-glucosidase inhibitors

There are three currently available agents, acarbose, miglitol and voglibose[37]. Their properties are different from other antidiabetics owing to its unique mode of action. Acarbose has been used for over 20 years in the treatment of hyperglycaemia[91].

The alpha-glucosidase inhibitors reduce postprandial triglycerides but their effect on LDL and HDL cholesterol levels and fasting triglycerides is insignificant and inconsistent[75,92]. Alpha-glucosidase inhibitors rarely induce hypoglycaemia, because these agents do not stimulate insulin release, and do not significantly affect body weight[82].

Acarbose has demonstrated to have beneficial effects by reducing the risk of cardiovascular disease and slowing the progression to diabetes in patients with impaired glucose tolerance[93,94].

Mechanism of action: Alpha-glucosidases are enzyme complexes located in the brush border membrane of the small intestine and hydrolyse oligosaccharides into monosaccharides[95]. Alpha-glucosidases inhibitors are structurally similar to natural oligosaccharides with higher affinity for alpha-glucosidases[91], and they produce a reversible inhibition of membrane-bound intestinal alpha-glucoside hydrolase enzymes. This cause delayed carbohydrate absorption and digestion, and results in a reduction in postprandial hyperglycaemia. The undigested carbohydrates in the lower parts of the small intestine increase plasma RA-GLP1 levels[95]. Because reduced blood glucose concentrations, alpha-glucosidase inhibitors do not enhance insulin secretion[91,95].

Efficacy: In general, alpha-glucosidase inhibitors have modest HbA1c lowering effects. In the Consensus of ADA/EASD 2015, alpha-glucosidase inhibitors are not included in the algorithm due to their lower efficacy and limiting side effects compared to other options[57], whereas in the Consensus of AACE 2016, alpha-glucosidase inhibitors appear only before sulfonylureas and glinides as monotherapy and combined treatment[9].

Side effects: The side effects are mainly gastrointestinal and include flatulence, diarrhoea and abdominal pain. These symptoms are usually mild, but they may reduce compliance and they are the most common reason for discontinuation treatment[94,95]. These symptoms occur when undigested carbohydrates arrive to the colon and as a result, there is a fermentation by bacteria in the large bowel and intestinal gas production[91]. For this reason, they are contraindicated in patients with chronic intestinal disorders associated with impaired digestion or absorption, and with conditions that may worsen when an intestinal gas increase appears (hernias, intestinal obstruction and intestinal ulcers). Treatment should be discontinued immediately if there is or is suspected ileus or sub ileus. To maximize the potential for these agents to be well tolerated, start with a low dose and increase slowly[37].

Alpha-glucosidase inhibitors are not recommended for patients with creatinine clearance < 25 mL/min and they can produce asymptomatic elevation of liver enzymes, for this it is necessary a control of liver enzymes[96]. In hypoglycaemia (when it is associated with sulfonylureas, glinides and insulin), like inhibitors of α-glucosidase delay absorption and digestion of sucrose, patients must take glucose.

Thiazolidinediones

Two TZD are currently available in United States: Rosiglitazone and pioglitazone. In Europe, since 2010, rosiglitazone was suspended by the European Medicines Agency, based on the overall risks of rosiglitazone exceed their benefits. French and Germany Medicines Agencies also discontinued pioglitazone in 2011.

Mechanism of action: TZD increase insulin sensitivity by acting on muscle, adipose tissue and liver to increase glucose utilization and decrease glucose production. TZD bind to peroxisome proliferator-activated receptors (PPARs). PPAR-γ is found predominantly in central nervous system, macrophages, vascular endothelium, adipose tissue and pancreatic beta-cells. The concentration of PPAR gamma is increased in the skeletal muscle of obese and diabetic patients[97]. In the central nervous system PPAR-gamma activation mediates weight gain by stimulating increased feeding[98]; this is, in part, the reason for weight gain associated with TZD.

PPAR-alpha is found predominantly in liver, skeletal muscle, heart and vascular walls. Rosiglitazone is purely PPAR-gamma agonist, while pioglitazone has also some PPAR-alpha effects; therefore they have different effects on lipids. Pioglitazone produces a more favourable lipid profile: LDL-cholesterol remained constant during treatment while rosiglitazone raises them; in addition decreased more triglyceride levels than rosiglitazone. HDL-cholesterol increased more or less 10% with both of them.

TZD also may improve blood glucose levels by preserving pancreatic beta-cell function. They are probably similar in efficacy to metformin in monotherapy but we don’t usually choose them because of their adverse effects and cost. Also, they are effective in combination therapy, but again, we typically prefer combination with other drugs with less adverse effects. TZD should not be given to diabetic patients with a history of heart failure or low bone mass.

The ratio between benefit and risk at cardiovascular system of rosiglitazone and pioglitazone remains unclear. Meta-analyses and observational studies (RECORD study, BARI 2D, PROactive trial) suggest caution with rosiglitazone use and also with pioglitazone.

Side effects

Weight gain: The weight gain is the result of diverse mechanisms as: Fluid retention, the activation of PPAR-γ in the central nervous system (which increases feeding) and the up regulation of genes that facilitate adipocyte lipid storage (in part weight gain may be also a result from the proliferation of new adipocytes[99]). It’s time and dose dependent.

Heart failure: PPAR-γ is more abundant in the collecting tubules of the nephron; the PPAR-gamma stimulation (induced by TZD treatment) activate sodium reabsorption in the luminal membrane of the collecting tubule cells[100], leading to a fluid retention that may lead to the precipitation of heart failure or worsening it. Peripheral oedema occurs in 4%-6% of patients in treatment with TZD, and this percentage is higher in patients with heart failure history. Because of the risk of heart failure the American Heart Association and the ADA published a consensus statement in 2003[101].

Because of their mechanism of action (they improve blood glucose by increasing insulin sensitivity) TZD monotherapy cause hypoglycaemia less frequently than sulfonylureas or insulin.

In preclinical studies pioglitazone increased bladder tumours in rats. Latter the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) saws more cases of bladder cancer: 14 vs 5, in the treatment group[102]. In an analysis of an ongoing 10-years observational study, there wasn’t a significant association between pioglitazone and cancer[103], but the risk of bladder cancer was significantly increased in those with the longest exposure and highest cumulative dose. Using data from the Adverse Even Reporting System of the United States FDA, again risk of bladder cancer was higher with pioglitazone[104]. Because of these in 2011 German and French Medicines Agencies suspended the use of pioglitazone.

Decrease bone density and increase fracture risk. The activation of PPAR-gamma has been demonstrated to down regulate components of the IGF-1 system, and IGF-1 is an important regulator of osteoblast proliferation and differentiation[105]. The absolute increase in risk fracture seems to be small and occurred with both of them, rosiglitazone and pioglitazone; the fractures are more frequently in the distal upper or lower extremities. These treatments should not be utilized in women with low bone density or with risk factors for fracture.

Troglitazone suspended its commercialization due of severe hepatocellular injury[106]. FDA currently recommends periodic monitoring of liver function in patients in treatment with rosiglitazone or pioglitazone.

Dipeptidyl peptidase-4 inhibitors

The incretin agents (GLP1 and GIP), secreted by intestine L cells, increase insulin secretion and inhibit glucagon in response to nutrient inputs. The glucoregulatory effects of incretins are the basis for treatment with inhibitors of DPP4 in patients with T2DM. Agents that inhibit DPP4, an enzyme that rapidly inactivates incretins, increase active levels of these hormones and, in doing so, improve islet function and glycaemic control in T2DM.

iDPP4 are used as monotherapy in patients inadequately controlled by diet and exercise, and dual therapy in combination with metformin, TZDs and insulin. iDPP4 are well tolerated; they have a low risk of producing hypoglycaemia, and maintain the patient’s weight. We have five iDPP: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin and Alogliptin.

Sitagliptin: Sitagliptin, which is approved for the treatment of T2DM in many countries, can be employed alone or dual therapy with sulfonylurea, metformin or TZD or third therapy. The normal dose of sitagliptin is 100 mg once daily; half dose is utilized in patients with an eGFR 30-50 mL/min, and quarter dose in those with an eGFR < 30 mL/min[107].

Monotherapy with this drug there are multiple studies, with significant reduction in HbA1c. The results of a study with sitagliptin monotherapy for 18 wk were: HbA1c significantly decreased with sitagliptin 100 and 200 mg compared to placebo (low HbA1c vs placebo: -0.48% and -0.60% respectively). Sitagliptin also significantly reduced fasting blood glucose vs placebo. Patients with baseline HbA1c higher (> or = 9%) had greater reductions in HbA1c subtracted sitagliptin placebo (-1.20% for 100 mg and -1.04% in the case of 200 mg) than those with HbA1c < 8% (-0.44% and -0.33%, respectively) or > or = 8% to 8.9% (-0.61% and -0.39%, respectively). Sitagliptin had a neutral effect on body weight[108].

In dual therapy studies the results confirm that sitagliptin was as effective as glipizide in patients inadequately controlled with metformin. In one of them the following results were found a year: From a mean baseline of 7.5%, HbA1c changes from baseline were -0.67% at week 52 in both groups, confirming non-inferiority. The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were -0.56 mmol/L (-10.0 mg/dL) and -0.42 mmol/L (-7.5 mg/dL) for sitagliptin and glipizide, respectively[109]. With sitagliptin were observed less hypoglycaemia and less weight gain than with glipizide.

Vildagliptin: This is an iDPP4 which FDA was not approved so that is not being used in the United States. The usual dose is 50 mg twice daily when utilized as monotherapy, with metformin, or with a TZD, and 50 mg once daily (in the morning) when utilized with a sulfonylurea. No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min). In patients with moderate or severe renal impairment, the dose is 50 mg once daily.

In some studies comparing the efficacy and safety of vildagliptin compared with placebo target the treatment difference (vildagliptin-placebo) in adjusted mean change (AM Delta) ± SE in HbA1c from baseline to endpoint it was -0.7% ± 0.1% (P < 0.001) and -1.1% ± 0.1% (P < 0.001) in patients receiving 50 or 100 mg of vildagliptin, respectively. The difference between treatments in the Delta GPA (GPA) was -0.8 ± 0.3 mmol/L (P = 0.003) and -1.7 ± 0.3 mmol/L (P < 0.001) in patients receiving 50 or 100 mg of vildagliptin, respectively[110].

Saxagliptin: Saxagliptin is approved as a drug for home treatment of T2DM or dual therapy for patients not controlled with a sulfonylurea, metformin or TZD. The dose is 2.5 or 5 mg of saxagliptin once daily. The dose of 2.5 mg is recommended for patients with an eGFR ≤ 50 mL/min and patients taking drugs inhibitors of cytochrome P450 3A4/5 (e.g., ketoconazole), Saxagliptin monotherapy is effective, achieving reductions in HbA1c of 0.5 in naive patients vs placebo[111,112]. There are studies with saxagliptin (2.5, 5 and 10 mg) in dual therapy with metformin showed a statistically significant adjusted mean HbA1c decrease from baseline to week 24 compared to placebo (-0.59%, -0.69%, and -0.58% vs +0.13%; all P < 0.0001)[113]. There are also studies showing the efficacy of sitagliptin in combination with sulfonylureas and TZD.

Linagliptin: The dose of linagliptin is 5 mg once daily. It is eliminated mainly through the enterohepatic system so it is not necessary to adjust the dose in patients with renal or hepatic impairment. Inducers of CYP3A4 or P-glycoprotein (e.g., rifampicin) may reduce the effectiveness of this agent. In patients receiving these drugs should avoid the use of linagliptin.

In a monotherapy study vs placebo, linagliptin achieved a reduction in HbA1c of 0.44% against rising 0.25% with placebo in 6 mo[114]. In a 24 wk study in triple therapy in patients treated with metformin and sulfonylureas that was added linagliptin or placebo, appeared a reduction in HbA1c of 0.72% in the group with linagliptin vs 0.1% in the group with placebo[115].

Alogliptin: The usual dose of alogliptin is 25 mg once daily, with dose reductions to 12.5 mg once daily in patients with creatinine clearance between 30 and 60 mL/min and to 6.25 mg daily in patients with creatinine clearance < 30 mL/min or undergoing dialysis[116].

In a study to twelve weeks in patients treated with metformin with poor control of their diabetes, alogliptin group achieved a reduction in HbA1c of 0.64% compared to an increase of 0.22% in the placebo group[117]. In another 26 wk studies, with alogliptin (12.5 or 25 mg once a day) vs placebo in patients with poorly controlled T2DM on a stable dose of glyburide (n = 500) or insulin (alone or in combination with metformin, n = 390) there were greater reductions in HbA1c in the alogliptin groups (mean change in HbA1c from baseline -0.39, -0.53 and +0.01 percentage points for the 12.5, 25 mg, and placebo groups, respectively, in the glyburide trial, and -0.63, -0.71 and -0.13 percentage points, respectively, in the insulin trial)[118,119].

Side effects: These drugs are considered very safe since both the risk of hypoglycaemia and other adverse effects are rare. All of them at increased risk of hypoglycaemia in combination with sulfonylureas or insulin. In comparative studies have not observed any significant differences between them in the risk of hypoglycaemia. With vildagliptin and alogliptin have been reported cases of hepatic dysfunction unusually still advisable to monitor liver enzymes during the first three months of treatment. If an increase in transaminases of three times the upper limit of normal or greater persists, the drugs should be discontinued.

At present, there is insufficient data to know whether there is a causal relationship between acute pancreatitis and iDPP4[120-123]. They should be discontinued in patients with persistent severe abdominal pain. In patients with pancreatitis should not start these drugs, or if there is a history of this disease.

Commonly reported side effects include headache, nasopharyngitis, and upper respiratory tract infection[124,125]. Some, but not all, studies have reported a slight increased risk of gastrointestinal side effects with sitagliptin[108,109,126].

Cardiovascular effects: Sitagliptin, saxagliptin and alogliptin have been studied for cardiovascular safety. They are TECOS, SAVOR-TIMI and EXAMINE studies respectively, with thousands of patients at high cardiovascular risk with a median follow up of 18 to 36 m.

In the TECOS study with sitagliptin 14735 patients with T2DM and established cardiovascular disease (history of major diseases of the coronary artery, ischemic cerebrovascular disease or peripheral arterial atherosclerotic disease) were randomized a group with sitagliptin and one with placebo, plus other diabetes medications (mainly metformin, sulfonylurea, insulin)[127]. After three years, the primary cardiovascular combined outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) was observed in a similar proportion of diabetics (11.4% and 11.6% in the sitagliptin and placebo group’s human resources, respectively, 0.98; 95%CI: 0.89-1.08). There was no significant difference in any of the individual components of the composite endpoint or the rate of hospitalization for heart failure (3.1% in each group).

In the test with saxagliptin (SAVOR-TIMI), 16492 patients with T2DM and either a history of cardiovascular disease or multiple risk factors for vascular disease were randomized to the branch of saxagliptin or placebo, and other medicines for diabetes (such as metformin, sulfonylureas, insulin). After a two-year follow-up, the first target (combination of cardiovascular death, nonfatal ischemic stroke or nonfatal myocardial infarction) appeared in a similar number of diabetics in proportion, 7.3% and 7.2% in the saxagliptin and placebo, respectively; hazard ratio (HR) 1.00, 95%CI: 0.89-1.12[128]. Significantly more patients in the field of saxagliptin were hospitalized for heart failure (3.5% vs 2.8%; HR = 1.27, 95%CI: 1.07-1.51). It stresses significantly the hospitalization for heart failure in the saxagliptin study[129] increase. However, the possible association between heart failure and iDPP4 has been linked to other epidemiological data and claims data[130,131].

In the EXAMINE trial alogliptin, 5380 patients with T2DM and either an acute myocardial infarction or unstable angina requiring recent hospitalization were randomized to alogliptin or placebo, along with other antidiabetic (mainly metformin, sulfonylureas, insulin)[132]. At 18 mo follow-up, the primary composite endpoint including cardiovascular death, nonfatal stroke, or nonfatal myocardial appeared in a very similar proportion of patients (11.3% and 11.8% in the branches of alogliptin and placebo respectively; HR 0.96, 95% of the unilateral CI: 1.16). In a post hoc analysis of the data, there was no significant difference in the rate of hospitalization for heart failure (3.1% and 2.9% in the branches of alogliptin and placebo, respectively; HR = 1.07, 95%CI: 0.79-1.46)[133].

Sodium glucose co-transporter-2 inhibitor

iSGLT2 inhibit renal reabsorption of glucose, increase its excretion and reduce hyperglycaemia in patients with T2DM. Therefore, reducing the reabsorption of glucose by inhibition of SGLT2 is a new way to treat T2DM. The increase in glucosuria and diuresis produced results in a reduction in weight and blood pressure[134].

Kidneys from healthy people filter approximately 180 g of glucose each day through renal glomerulus and reabsorbed in the then proximal convoluted tubule. This is possible by passive and active co-carriers which are known as glucose transporter (GLUT) and SGLT[135] conveyors. There are two types of SGLT; SGLT1 located mainly in the small intestine and the kidney proximal convoluted tubule, and SGLT2 located only in the proximal tubule (segment 1 and 2), that are responsible for about 90% of glucose reabsorption[7]. The other 10% of the glucose is reabsorbed by SGLT1 in segment 3. SGLT2 inhibitors block the SGLT2 transporter in the proximal tubule, to lower glucose reabsorption and increase its excretion in the urine. Glucose is excreted in the urine and plasma levels are reduced by improving glycaemia figures plasma[136-138]. It is an independent mechanism of insulin, there is low risk for hypoglycaemia, and no risk of fatigue or overstimulation of the beta cells[139]. Due to its mode of action is based on normal glomerular-tubular function; the iSGLT2 efficiency is lower in patients with renal failure[140]. The three most representative drugs family iSGLT2 are: Dapagliflozin, canagliflozin and empagliflozin.

Dapagliflozin: Dapagliflozin was the first iSGLT2 employee, and has many published data from clinical trials. In phase 3 trials comparing placebo for 24 wk and dapagliflozin (2.5, 5 and 10 mg once daily) used alone or added to metformin[141], pioglitazone[142], glimepiride[143] or insulin[144] was observed that HbA1c and fasting plasma glucose in patients with T2DM was reduced. In tests longer-term (102 wk) added to metformin, dapagliflozin resulted in a sustained decrease in HbA1c, glucose fasting blood glucose and weight without increasing the risk of hypoglycaemia in patients with T2DM not controlled on metformin alone[145]. The initial decrease in HbA1c observed at 24 wk with both doses of dapagliflozin (5 or 10 mg) added to metformin was maintained at 102 wk, and was superior to placebo (-0.58%, -0.78% and 0.02% against). Also the low fasting plasma glucose with both doses of dapagliflozin, remained and was higher than placebo (-1.47 mmol/L and -1.36 mmol/L vs -0.58 mmol/L). This drug has studies which compared with patients whose hyperglycaemia glipizide was poorly controlled by metformin[146]. After 52 wk, a drop in HbA1c starting from the baseline of -0.52% is target with dapagliflozin (≤ 10 mg/d) and glipizide (≤ 20 mg/d). Weight reduction was greater with dapagliflozin (-3.2 kg) vs glipizide (+1.4 kg). Dapagliflozin (≤ 10 mg/d) in T2DM patients was non-inferior to glipizide (≤ 20 mg/d) in reduction of HbA1c at 52 wk (both -0.52%). At 4 years the HbA1c reduction is attenuated in both groups, but more in the glipizide vs dapagliflozin (+0.2% vs -0.1%). There were differences in weight change, with weight loss in the dapagliflozin group vs weight gain in the glipizide group (-3.95 kg vs +1.12 kg). In the dapagliflozin group decreases the mean average of systolic blood pressure, but did no change in the glipizide group (difference: -3.7 mmHg)[146].

Canagliflozin: Canagliflozin was the first of this family of drugs approved by the FDA and began its commercialization in March 2013 for use in T2DM. It is an effective drug in monotherapy and after 26 wk of treatment with canagliflozin 100 mg and 300 mg once daily significantly reduced HbA1c (-0.77% and -1.03% respectively) in patients with T2DM not controlled with diet and exercise compared to placebo (0.14%, P < 0.001)[147]. Also, significantly reduced fasting blood glucose, -27 mg/dL to -34 mg/dL with both doses of canagliflozin (placebo = 9 mg/dL, P