Table of Contents  

Ludvik: State-of-the-art and future aspects of the treatment of type 2 diabetes mellitus

Introduction

Type 2 diabetes mellitus is associated with increased morbidity and premature mortality due to macro- and microvascular complications.1,2 In addition, diabetes increases the risk for other diseases such as cancer,3 depression4 and chronic liver disease.5 The global prevalence of diabetes is rising epidemically and the number of diabetic patients will exceed 552 million worldwide by 2030.6 As a consequence, costs related to the treatment of hyperglycaemia, diabetes-associated risk factors and complications cause an enormous economic burden, especially as novel and more expensive agents become increasingly available.

The relationship of glycaemic control to macro- and microvascular complications has been well established2 and has prompted clinical trials to investigate whether or not the improvement of glycaemic control will eventually result in better health-related outcomes. Unexpectedly, the results of various studies have shown some inconsistency. The UK Prospective Diabetes Study (UKPDS)7 could demonstrate that intensive diabetes treatment leading to a haemoglobin A1c (HbA1c) difference of 0.9% compared with standard care significantly decreased microvascular complications. However, the reduction in myocardial infarction was not significant and mortality remained unaffected over the course of the study. In a subgroup of obese patients treated with metformin, myocardial infarction and diabetesrelated as well as all-cause mortality were significantly reduced.8 These results led to the pre-eminent role of metformin as the primary oral antidiabetic drug. When the patients enrolled in UKPDS were followed up after termination of the trial for another 10 years, the reduction in cardiovascular endpoints and total mortality became significant.9 This finding suggests a benefit of early intensified diabetes treatment on subsequent complications in the sense of a legacy effect.

As improvement of glycaemic control is undoubtedly beneficial, the level of the HbA1c target to maximally reduce micro- and macrovascular complications and mortality was still under debate. In order to solve this question, three studies have been performed: Action to Control Cardiovascular Risk in Diabetes (ACCORD),10 Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE).11 The goal of these trials was a HbA1c below 6.0% and 6.5%, respectively. The Veterans Affairs Diabetes Trial (VADT)12 aimed to reach an absolute HbA1c reduction of 1.5 percentage points. These trials could not demonstrate a benefit of strict glycaemic control on cardiovascular endpoints in the intensively treated population. In fact, the ACCORD trial showed a 22% increase in total mortality and was therefore stopped prematurely. The exact mechanism for this surprising finding is not definitely determined, but hypoglycaemia seems a likely candidate for the lack of benefit or even harm of an aggressive diabetes treatment. Since a meta-analysis of these trials including the UKPDS, however, suggests that improvement of glycaemic control is indeed associated with a risk reduction in cardiovascular endpoints,13 the need for optimal treatment of hyperglycaemia is no longer debatable.

Glycaemic target

Regarding the optimal glycaemic level in terms of HbA1c, there seems to be no unique threshold that is applicable for all patients. In-depth analysis of the above mentioned studies suggests individually targeted HbA1c goals for distinct patients' characteristics, which have been recently published in a consensus agreement.14 In general, a target HbA1c level below 7% is recommended in most patients to reduce the incidence of microvascular disease. In newly diagnosed patients, free of significant cardiovascular disease and particularly in those treated with medications without hypoglycaemic potential, a more stringent target of < 6.5% might be appropriate. In patients with advanced disease, longer diabetes duration, complex therapies or diabetes-associated complications a less stringent goal (7.5–8.0%) might be appropriate. Thus, it is of utmost importance to individualize the glycaemic goal and to also consider patients' commitment.

Antihyperglycaemic treatment

Non-pharmacological treatment

Type 2 diabetes mellitus develops in the context of the metabolic syndrome, comprising visceral abdominal fat distribution, hypertension, hyper-/dyslipidaemia and impaired glucose tolerance. The majority of patients with type 2 diabetes mellitus are obese and the earliest pathophysiologically important feature is insulin resistance, which usually precedes the onset of type 2 diabetes mellitus by many years. This leads to an increased demand for insulin secretion which cannot be maintained in patients prone to diabetes. This relative secretory defect of the β-cells prompts a rise in glycaemia and, ultimately, the development of type 2 diabetes. In addition to well-recognized metabolic features of type 2 diabetes mellitus, such as insulin resistance, impaired insulin secretion and increased hepatic glucose production, abnormalities in incretin secretion and renal glucose handling have been identified quite recently in hyperglycaemic patients and serve as targets for therapeutic intervention.15

Lifestyle modification is the mainstay of diabetes treatment, especially considering the eminent role of obesity for the development of insulin resistance. Consequently, weight reduction through an appropriate diet and increased physical activity is of great importance. A moderate weight loss of 5–10% of body weight leads to remarkable improvements in glycaemia, hyperlipidaemia and hypertension.16 There is no definite answer as to the optimal macronutrient composition of different diets. However, there is some evidence that a Mediterranean-type diet with low carbohydrate content could be beneficial in treating17 and preventing diabetes18 as well as delaying the need for pharmacological therapy.19 In addition to diet, a minimum of 150 min of aerobic exercise per week, ideally combined with strength training, is recommended to increase physical fitness, facilitate weight loss and preserve or even increase muscle mass.20

When considering initiation of pharmacotherapy, it is generally advised that any patient presenting at diagnosis of diabetes with a HbA1c of below 6.5% should be treated with lifestyle intervention only. Those patients with an HbA1c above 6.5% should receive metformin as the primary pharmaceutical agent. This recommendation is based on the proven beneficial effects of metformin on cardiovascular endpoints and mortality.8 As additional or alternative medications, a variety of pharmaceutical agents are available (Figure 1 and Table 1) and will be discussed in detail in this review. If HbA1c at diagnosis exceeds 9%, an initial combination therapy of two medications is recommended in order to reach the glycaemic target.14 Insulin therapy can be introduced at any point of time when appropriate (Figure 2).

FIGURE 1

Antidiabetic pharmacotherapy (adapted from21,22,23).

5-2-8-fig1.jpg
TABLE 1

Pharmacotherapy for type 2 diabetes mellitus (adapted from25)

Class HbA1c Hypoglycaemia Advantages Disadvantages
Metformin ↓↓ No Weight neutral, reduction of macrovascular events Contraindications and GI side effects
Alpha-glucosidase-inhibitor No Improved post prandial blood glucose control, weight neutral GI side effects
DPP-4-inhibitor ↓ to ↓↓ No Improved post prandial blood glucose control, possible beta-cell protection New agent (unknown long-term security)
Incretin mimetics ↓↓ No Weight reduction, possible beta-cell protection New agent (unknown long-term security), nausea
Insulin ↓↓↓ Yes No dose upper limit, many types, flexible regulations Weight gain
Hypoglycaemia
Insulin secretagogues
Sulfonylurea ↓↓ Yes Gliclazide and glimepirid are associated with fewer hypoglycaemia and weight gain than glibenclamid Possible weight gain
Glinides ↓ to ↓↓ Yes Improved post prandial blood glucose control Three times a day dosing, possible weight gain
Thiazolidinediones ↓↓ No Possible beta-cell protection, reduction of macrovascular events (pioglitazon) Weight gain, peripheral oedema, fractures in females, bladder cancer

↓ = <1.0% HbA1c reduction; ↓↓ = 1.0–2.0% HbA1c reduction; ↓↓↓ = >2.0% HbA1c reduction; GI, gastrointestinal.

FIGURE 2

Earlier use of combination therapy to improve treating to target. OAD, oral antidiabetic agent (adapted from47,48).

5-2-8-fig2.jpg

Pharmacotherapy

The progressive natural history of type 2 diabetes mellitus and the limited effectiveness of established medications regarding glucose control and durability have prompted the search for alternative treatment strategies. Quite recently, innovative agents such as dipeptidyl peptidase 4 (DPP-4) inhibitors and incretin mimetics [glucagon-like-peptide (GLP)−1 agonists], which act on insulin secretion, glucagon production, satiety and gastric emptying, have extended our armamentarium for diabetes therapy. In the near future we might see the introduction of medications which increase renal glucose excretion [sodium–glucose co–transporter (SGLT) 2 inhibition] and, thereby, improve glucose control markedly over any other class of antidiabetic drugs. Finally, there is an extensive search for medical therapy which not only decreases elevated blood glucose but also influences diabetes-associated risk factors and complications such as chronic inflammation.

Established pharmacotherapy

Figure 1 and Table 1 present an overview of the function, efficacy and safety of established diabetes medications. According to their mechanism of action, the appropriate medications have to be chosen with respect to the predominant metabolic feature. Because of its beneficial cardiovascular effects, however, metformin constitutes the basis of antidiabetic pharmacotherapy. The biguanide metformin activates adenosine monophosphate (AMP) kinase and thereby reduces hepatic glucose production. In addition, it decreases glucose absorption, increases GLP-1 production and improves insulin action.25 Metformin does not cause hypoglycaemia and promotes weight loss. It might lead to gastrointestinal side effects such as diarrhoea and abdominal discomfort and increases the risk for lactic acidosis in patients with impaired kidney function. It should therefore not be used in patients with a glomerular filtration rate (GFR) below 60 ml/min. As metformin reduced the incidence of myocardial infarction and diabetes-related mortality in the UKPDS,8 it is considered as the first-line drug in the treatment of type 2 diabetes. In addition, there is evidence that metformin might lower the incidence of cancer26 and improve survival in type 2 diabetic patients already affected by cancer.27

Glitazones (thiazolidinediones) are activators of the nuclear transcription factor peroxisome proliferator activator receptor (PPAR)-γ and improve insulin sensitivity in skeletal muscle and liver.28 In addition, they increase high-density lipoprotein (HDL)-cholesterol and decrease triacylglycerol plasma levels and microalbumin excretion. They do not carry the risk of hypoglycaemia and there is evidence that they are more durable as regards to glucose control than sulfonylureas and metformin.29 As rosiglitazone has been withdrawn in most parts of the world due to an increased rate of myocardial infarction,30pioglitazone is the only remaining glitazone on the market . Pioglitazone has shown beneficial effects on cardiovascular endpoints in diabetic patients with macrovascular disease.31 Side effects are weight gain, largely due to fluid retention; oedema formation and heart failure; an increase in fractures; and a small, but significant, increase in the risk of bladder cancer.32 The risk of bladder cancer, however, is far outweighed by the beneficial effects on cardiovascular disease. Thus, patients with predominant insulin resistance, little risk for osteoporotic fractures and no history of bladder cancer are considered suitable candidates for pioglitazone treatment.

Sulfonylureas (glibenclamide, glyburide, gliclazide, glimepiride and glipizide) and the short-acting glinides (repaglinide and nateglinide) increase insulin secretion by closure of adenosine triphosphate (ATP)-sensitive potassium channels in the β-cell plasma membrane.33 There is extensive experience with sulfonylureas over the last few decades and they have been proven to exert beneficial effects on microvascular complications.11 There is, however, an increased risk of hypoglycaemia and weight gain and some evidence that they might lead to premature exhaustion of β-cell function.29 Gliclazide causes less hypoglycaemia than glimepiride.34 When compared with metformin, sulfonylureas seem to be associated with a higher risk of cancer22 and increased total mortality.27

The α-glucosidase inhibitors (acarbose and miglitol) slow carbohydrate absorption from the gut and lead to a modest improvement of diabetes control by primarily affecting post prandial glucose levels. They do not cause hypoglycaemia and are weight neutral, but their use is quite limited owing to gastrointestinal side effects such as abdominal discomfort, flatulence and diarrhoea.35 There is some evidence for a cardioprotective effect, presumably due to reduction of post prandial glucose,36 but this finding from a retrospective analysis requires additional confirmation.

Recently, the incretin system has become a major target for diabetes treatment. The major incretin GLP-1 is secreted by the L-cells of the intestine in response to nutrient intake and increases glucose stimulated insulin secretion, suppresses glucagon secretion and thereby hepatic glucose output, slows gastric emptying and increases satiety.37 GLP-1, however, is rapidly degraded by DPP-4. In order to utilize the effects of GLP-1 for the treatment of diabetes, GLP-1-receptor agonists (incretin mimetics) and agents that inhibit the action of DDP-4 (DPP-4 inhibitors or gliptins), have been developed.

DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, and algogliptin) are orally administered and increase the concentrations of endogenous DPP-4 (fourfold) as well as glucose-dependent insulinotropic peptide (GIP), which likewise stimulates insulin secretion.38 The efficacy of the different DPP-4 inhibitors is comparable, decreasing HbA1c levels by 0.6 to 1.0%. There is evidence that metformin and DPP-4 inhibitors act complementarily in increasing GLP-1 levels and, indeed, initial combination therapy with metformin and DPP-4 inhibitors improved HbA1c by 2.4%.39 They do not lead to hypoglycaemia and are weight neutral,40 and are generally very well tolerated. In patients with renal failure, the dose of all DPP-4 inhibitors, except for linagliptin, needs to be reduced because of their predominant renal excretion. DPP-4 inhibitors can be prescribed as initial therapy when metformin is contraindicated or not tolerated and might be combined with all existing established classes of antidiabetic pharmacotherapy. This is, however, different for the individual substances, depending on approval by regulatory authorities.

Incretin mimetics or GLP-1 agonists are injected subcutaneously once (liraglutide) or twice (exenatide) a day, or once a week (exenatide extended-release formulation). Their plasma levels correspond to a 10-fold increase in GLP-1. This makes them more potent in terms of HbA1c lowering (up to 1.8%) and weight loss (up to 4.4 kg).41 They also do not cause hypoglycaemia. The major side effect is nausea due to delayed gastric emptying, which diminishes over time. Comparing liraglutide with exenatide, HbA1c was significantly lower after 26 weeks with liraglutide (1.1% vs 0.79%) with a similar reduction in body weight of around −3 kg. Nausea was less common with liraglutide.42 The extended-release formulation of exenatide, which is injected once weekly, has also proven superior to exenatide twice daily in terms of HbA1c lowering (−1.6% vs −0.9%) and body weight reduction (−2.3 kg vs 1.4 kg). Nausea was less common with the once-weekly formulation (14% vs 35%).43

There are some concerns about an increased risk of pancreatitis; however, to date both classes of drugs are regarded as safe. As activation of GLP-1 receptors in different tissues such as endothelial cells and the heart exert beneficial effects in terms of vascular protection,44 and as GLP-1 agonists – and to a minor degree DPP-4 inhibitors – improve hypertension and lipid levels,45 the results of studies on hard cardiovascular endpoints are eagerly awaited.

Combination therapy

When glycaemia cannot be controlled by lifestyle intervention and metformin alone, a combination therapy with one or two more drugs is warranted in order to achieve the individualized HbA1c target. The choice of the additional medication should be based on the predominant pathophysiological defect, i.e. insulin resistance or defective insulin secretion. If the patient is likely to be rather insulin resistant and presents with visceral obesity, pioglitazone should be preferred, especially in patients with a history of myocardial infarction and stroke according to the results of the PROACTIVE (prospective pioglitazone clinical trial in macrovascular events) study.31 Of course, contraindications such as heart failure and increased risk of bone fractures and bladder cancer need to be taken into consideration. In patients with a predominant secretory defect, DPP-4 inhibitors offer a good choice to stimulate glucose-dependent insulin secretion without the risk of hypoglycaemia and weight gain. In obese patients, co-medication with a GLP-1 agonist has the additional benefit of weight loss and improvement of lipid parameters and hypertension. Combination of metformin with sulfonylureas is inexpensive and a proven alternative; however, this therapy increases the risk of hypoglycaemia and weight gain. If metformin is not tolerated or is contraindicated, treatment can be started with any class of drugs based on the predominant metabolic phenotype. When dual combination therapy is not capable of achieving adequate glycaemic control, another class of drugs can be added to the pre-existing medication (triple therapy). Of course, at any time, insulin therapy can be initiated when appropriate. There is, however, no indication for early insulin therapy to reduce cardiovascular mortality in prediabetic or newly diagnosed diabetic patients, as seen from the ORIGIN (outcome reduction with initial glargine intervention) trial.46

Insulin therapy

The defect in insulin secretion is usually progressive and thus many patients require insulin replacement therapy at some time. Insulin activates the insulin receptor and promotes glucose uptake in muscle and adipose tissue. It has theoretically an unrestrained efficacy to lower blood glucose, which is, however, limited by hypoglycaemia and weight gain.49 There is also some evidence that insulin therapy in high doses and over a long period of time increases the risk of cancer.50 Insulin therapy is usually initiated when the glycaemic goals cannot be achieved by any combination of oral agents or GLP-1 agonists, or in patients with severe hyperglycaemia or signs of catabolic features. Transient insulin therapy is also warranted with major surgery, myocardial infarction, stroke or major illness, when insulin resistance prevails and glucose levels cannot be controlled with current antidiabetic therapy.

Usually, intermediate-acting insulin such as NPH (neutral protamine Hagedorn) insulin or a longacting insulin analogue such as glargine or detemir is added to the existing oral antidiabetic medication. It may be administered before bed-time which has the advantage to suppress hepatic glucose output during the night leading to an improved fasting glucose level. The long-acting insulin analogues carry less risk of night-time hypoglycaemia when compared with NPH insulin, but are more expensive.51 If glucose control cannot be achieved with bed-time insulin therapy throughout the day, the oral antidiabetic medications except for metformin are replaced by meal-time injection of rapid-acting insulin or insulin analogues (aspart, lispro, glulisine). Alternatively, several types of premixed insulin preparations can be used twice or three times a day. They consist of a fixed combination of intermediate insulin and regular insulin or a rapid-acting insulin analogue.52 Although this approach is likewise effective, it allows less flexibility regarding meal size and timing of food intake. Metformin therapy is usually continued as it helps to prevent excessive weight gain.53 In severely insulin-resistant patients requiring large doses of insulin, combination with pioglitazone improves glycaemic control and decreases the insulin dose.54 The increased prevalence of oedema and heart failure with this therapy needs to be taken into consideration. Addition of DPP-4 inhibitors to insulin therapy might decrease HbA1c by 0.6%55 and of GLP-1 analogues by 0.7% compared with placebo with a concomitant weight loss of 2.7 kg.56 Ultralong-acting insulin analogues such as deglutec will be most likely become available in the near future to further decrease the risk of nocturnal hypoglycaemia and allow more flexible administration.57

New medications

Apart from compounds of the established classes of drugs (mostly DPP-4 inhibitors, GLP-1 analogues, glitazones), there are some innovative medications under development or in late-phase clinical trials. They focus on novel targets to lower blood glucose such as the inhibition of SGLT2, or employ innovative mechanisms to act on the liver or to modulate inflammation or peripheral insulin action (Table 2).

TABLE 2

Selected diabetes drugs in development (adapted from58)

Target system Drug class Mechanism of action Cardiovascular effects
Liver Glucokinase activators ↑ Glycolysis Not determined
↑ Glycogen synthesis59
Glucagon receptor ↓ Gluconeogenesis Not determined
antagonists ↓ Glycogenolysis60
Infammation Salsalate NF-kB inhibition61 ↓ Markers of inflammation
Attenuates endothelial dysfunction in HIV-infected patients
IL-1-receptor antagonists Inhibition of cytokine production6264 ↓ Markers of inflammation
Cardiomyocyte protection
Peripheral insulin action SIRT1 activators ↑ Insulin sensitivity of muscle, fat and liver65 Attenuates endothelial dysfunction in animal models
SPPARMs Modulation of PPARγ signalling66 Partial angiotensin I-receptor blockade
↓ Markers of inflammation
↑ Adiponectin
11βHSD1 inhibitors Inhibition of the conversion of cortisone to cortisol in muscle, fat and liver67 ↓ Plaque progression in mice
Improved lipid profile

11βHSD1, 11β-hydroxysteroid dehydrogenase type 1; HIV, human immunodeficiency virus; IL-1, interleukin-1; NF-kB, nuclear factor-kB; PPAR, peroxisome proliferator-activated receptor; SIRT1, sirtuin 1; SPPARM, selective peroxisome proliferator-activated receptor modulators.

New medications in the near future

Sodium–glucose co-transporter 2 inhibition

Sodium–glucose co-transporters activate the transport of glucose across the S1 segment of the proximal convoluted tubule.68 Thus, SGLT2 has an important role for the reabsorption of glucose in the kidney. Inhibition of SGLT2 leads to increased glucose excretion, which is also seen in patients with genetic mutations in the kidney's specific SGLT2 isoform, a disease which is termed renal glycosuria.69 Interestingly, subjects with this mutation have no complications from glucosuria or other metabolic abnormalities. As patients with type 2 diabetes mellitus express higher numbers of SGLT2 and show an increased renal glucose uptake,70 inhibition of SGLT2 might at least in part be considered as a causal diabetes therapy. At the moment, there are various SGLT2 inhibitors in clinical development; and the most advanced – dapagliflozin and canagliflozin – will presumably soon be available.

Dapagliflozin, at a dose of 10 mg per day, lowers HbA1c in patients inadequately treated with metformin by 0.84%.71 Addition of dapagliflozin to glimepiride decreases HbA1c by 0.82%,72 and addition of dapagliflozin to insulin decreases HbA1c by 0.96%.73 From the available studies it seems that dapagliflozin lowers HbA1c regardless of the concomitant medication. In all studies patients lost an average of 2 kg of body weight and systolic and diastolic blood pressure were decreased by 5 and 4 mmHg, respectively. There is no increased rate of hypoglycaemia, and the antihyperglycaemic effect seems irrespective of diabetes duration.74 Not unexpectedly, the rate of urinary tract infections (4.3% vs 3.7% with placebo) and vulvovaginitis and balanitis (4.8% vs 0.9% with placebo) were significantly increased. Regarding cardiovascular safety, a meta-analysis on the available date of Phase II and Phase III studies submitted to the the US Food and Drug Association (FDA) showed a hazard ratio of 0.67 in favour of dapagliflozin. These data are reassuring, but need to be interpreted with caution and have to be regarded as preliminary. In the USA, licensing of dapagliflozin has been put on hold due to an imbalance of bladder and breast cancer in the dapagliflozin group when compared with patients not exposed to the drug. The number of cases is very low, and it seems unlikely that these tumours have developed during the rather short time of exposure. In addition, there is no indication of any mitogenic effect of the substance. Nevertheless, the FDA has requested more safety data with respect to bladder and breast cancer.75 In Europe, dapagliflozin has recently received a positive opinion for approval, which is expected soon. The data on canagliflozin reported so far are quite comparable.76 Taken together, the available data suggest that the addition of SGLT2 might be a promising new approach to decrease HbA1c regardless of concomitant treatment. As potential side effects, urinary tract and genital infections have been reported. Further studies on safety and potential beneficial effects on cardiovascular morbidity will define the role of this new class in the treatment of type 2 diabetes mellitus.

New potential medications in early development

Table 2 gives an overview of some potential new drugs which in part target alternative pathways and are in early development.58

Liver

The liver plays a key role in glucose homeostasis by activating hepatic glucose uptake following food ingestion and providing glucose by glycogenolysis and gluconeogenesis. It thus presents an appealing target for pharmacotherapy.

Glucokinase activators

Glucokinase serves as a glucose sensor in the pancreatic beta cell, regulating insulin secretion, and regulates hepatic glucose disposal. It is therefore tempting to improve glucose control by activation of glucokinase. A recently published study on the administration of the glucokinase activator MK-0941 in insulin-treated type 2 diabetic patients found only a transient decrease of post prandial glucose levels. Unfortunately, the incidence of hypoglycaemias was increased and blood pressure and triglycerides were elevated.77 To date it is not clear whether or not these unfavourable findings are related to the compound itself or the pathophysiologic concept.

Glucagon receptor antagonists

Type 2 diabetes mellitus is associated with increased glucagon levels and diminished post prandial glucagon secretion. As an alternative to incretin-based therapies, glucagon-induced gluconeogenesis and glycogenolysis could also be counteracted by blocking the glucagon receptor.60 In order to avoid a rebound of hepatic glucose output, the effect of the glucagon antagonism must be maintained. This, however, could compromise counter-regulation during hypoglycaemia.

Inflammation

Chronic inflammation is considered to be involved in the pathogenesis of insulin resistance and type 2 diabetes mellitus and might also play an important role for the development of cardiovascular disease.

Salsalate

Activation of NF (nuclear factor)-kB translocation in response to an inflammatory stimulus modulates the expression of genes linked with inflammation and proliferation.58 Salsalate inhibits NF-kB, like aspirin, but carries a lower risk of bleeding. In obese, non-diabetic subjects, administration of salsalate for seven days decreased blood glucose and improved insulin secretion.78

Interleukin-1 receptor antagonists

Interleukin (IL)-1 is a proinflammatory cytokine which inhibits the function of beta cells. High glucose concentrations increase the beta-cell production of IL-1 and promote apoptosis.79 IL-1 blockade with the IL-1 antagonist anakinra improved glycaemia and beta-cell function in patients with type 2 diabetes. This was accompanied by a reduction of inflammatory markers.80

Peripheral insulin action

Sirtuin-1 activators

Sirtuin-1 (SIRT1), which is activated by resveratrol, is a modulator of pathways downstream of caloric restriction. In animal models, small-molecule activators of SIRT1 improved insulin sensitivity in skeletal muscle, liver and adipose tissue, lowered plasma glucose and increased mitochondrial capacity.65 The approach of mimicking the effect of caloric restriction might therefore be a promising effect for the treatment of type 2 diabetes mellitus.

Selective peroxisome proliferator-activated receptor γ modulators

Glitazones are peroxisome proliferator-activated-receptor γ (PPARγ) agonists and improve insulin sensitivity in muscle and liver.28 They are, however, associated with side effects such as fluid retention and weight gain. Selective PPARγ modulators (SPPARMs) activate the receptor distinct from older PPAR activators leading to a differential gene expression.66 They exhibit the beneficial effects of PPARγ agonists without the commonly seen side effects as recently shown by the SSPARM NT131 in a study in type 2 diabetic patients over four weeks.81

11β-Hydroxysteroid dehydrogenase type 1 inhibitors

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) mediates the conversion of cortisone to cortisol in liver and adipose tissue, and thereby increases insulin resistance, gluconeogenesis and glycogenolysis.58 11βHSD1-deficient mice showed improved glucose tolerance, insulin sensitivity and lipid levels.82 Preclinical experiments showed that inhibition of 11βHSD1 decreased plaque progression in mice.67 In human subjects, the 11βHSD1 inhibitor MK-0916 showed modest improvements in HbA1c, body weight and blood pressure in type 2 diabetic patients with a metabolic syndrome.83

Conclusions

Type 2 diabetes mellitus is a chronic disease with an increased risk of morbidity and premature mortality. The incidence of diabetes-related complications is tightly linked to the quality of glucose control and can be decreased effectively by an appropriate treatment with lifestyle modification and pharmacotherapy. The targets for glycaemic control – best expressed by the HbA1c levels – have to be set individually, taking into account diabetes duration, complications, the risk of hypoglycaemia, patient's commitment and life-expectancy. Over the last years new drugs have been developed which might have properties beyond glucose lowering or target different metabolic features. These substances, however, need to prove their safety and efficacy in reducing vascular complications in already ongoing studies. In addition to antidiabetic pharmacotherapy, treatment of concomitant hypertension, hyperlipidaemia and hypercoagulability are of utmost importance to decrease macro- and microvascular complications. Although there is evidence that survival of patients with type 2 diabetes mellitus has improved over the last decade,84 there is still a long way to go in order to win the fight against this epidemic disease, affecting the lives of millions of people and imposing an enormous socioeconomic burden to the societies.

Conflict of interest

Bernhard Ludvik served in advisory boards and as a speaker with or received study grants from Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp and Dohme, Novartis, Bristol-Myers Squibb, Roche, Servier and Boehringer Ingelheim.

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