Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits ...long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.
Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of ...glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a “glucose-sensor” or “glucose receptor” in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose “gate-keeper” in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs) may increase insulin secretion from the pancreas and promote glycogen synthesis in the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and a novel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.
Summary The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, ...once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium–glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.
Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular ...complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD.
We did a phase 3, randomised, double-blind, parallel-group, placebo-controlled trial at 127 centres in 15 countries. Patients with HbA1c of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate eGFR ≥60 to <90 mL/min per 1·73 m(2); n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR ≥30 to <60 mL/min per 1·73 m(2); n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA1c, and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501.
In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA1c at week 24 were -0·52% (95% CI -0·72 to -0·32) for empagliflozin 10 mg and -0·68% (-0·88 to -0·49) for empagliflozin 25 mg (both p<0·0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA1c at week 24 was -0·42% (-0·56 to -0·28) for empagliflozin 25 mg (p<0·0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe 16% and 11 serious 12%), 86 (88%) on empagliflozin 10 mg (six severe 6% and six serious 6%) and 78 (80%) on empagliflozin 25 mg (eight severe 8% and seven serious 7%). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe 8% and 23 serious 12%) and 156 (83%) on empagliflozin 25 mg (18 severe 10% and 22 serious 12%).
In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA1c and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment.
Boehringer Ingelheim, Eli Lilly.
SGLT inhibitors in management of diabetes Tahrani, Abd A; Barnett, Anthony H; Bailey, Clifford J
The lancet. Diabetes & endocrinology,
10/2013, Letnik:
1, Številka:
2
Journal Article
Recenzirano
The two main sodium-glucose cotransporters (SGLTs), SGLT1 and SGLT2, provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT1 enables the small intestine to absorb ...glucose and contributes to the reabsorption of glucose filtered by the kidney. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors with varying specificities for these transporters (eg, dapagliflozin, canagliflozin, and empagliflozin) can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine. Results of randomised clinical trials have shown the blood glucose-lowering efficacy of SGLT inhibitors in type 2 diabetes when administered as monotherapy or in addition to other glucose-lowering therapies including insulin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Effective SGLT2 inhibition needs adequate glomerular filtration and might increase risk of urinary tract and genital infection, and excessive inhibition of SGLT1 can cause gastro-intestinal symptoms. However, the insulin-independent mechanism of action of SGLT inhibitors seems to offer durable glucose-lowering efficacy with low risk of clinically significant hypoglycaemia at any stage in the natural history of type 2 diabetes. SGLT inhibition might also be considered in conjunction with insulin therapy in type 1 diabetes.
Summary Background A substantial proportion of patients with type 2 diabetes are elderly (≥65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed ...to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes. Methods In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c ) of 7·0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice–response system, stratified by HbA1c level <8·5% vs ≥8·5% and insulin use yes vs no, block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov , number NCT01084005. Findings 241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74·9 years (SD 4·3). Mean HbA1c was 7·8% (SD 0·8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was −0·64% (95% CI −0·81 to −0·48, p<0·0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75·9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8·6% (14) of patients in the linagliptin group and 6·3% (five) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24·1% 39 in the linagliptin group, 16·5% 13 in the placebo group; odds ratio 1·58, 95% CI 0·78–3·78, p=0·2083). Interpretation In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo. These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients. Funding Boehringer Ingelheim.
Abstract
Objective:
To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with ...metformin.
Methods:
Adults (n = 455) with HbA1c 7.5-11% on stable insulin therapy (30-150 U/day ± metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks. Patients were to maintain stable insulin doses but these could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or substantially increased insulin use were rescued with a flexible insulin regimen and remained in the study. Metformin doses were kept stable. The primary efficacy endpoint was change in HbA1c from baseline to week 24 (or rescue).
Results:
Patients treated with saxagliptin versus placebo had significantly greater reductions in adjusted mean HbA1c (difference: −0.41%, p < 0.0001), postprandial glucose (PPG) 180-minute area under the curve (−3829.8 mg min/dL, p = 0.0011), and 120-minute PPG (−23.0 mg/dL, p = 0.0016) at 24 weeks. Treatment with saxagliptin resulted in similar reductions in HBA1c relative to placebo, irrespective of metformin treatment. At 24 weeks, difference in adjusted mean fasting plasma glucose for saxagliptin versus placebo was −4.02 mg/dL (p = 0.3958); 17.3% and 6.7% of patients in the saxagliptin and placebo groups, respectively, achieved HbA1c < 7%. Mean change from baseline in body weight at week 24 was 0.39 kg for saxagliptin and 0.18 kg for placebo. Hypoglycemia was reported in 18.4% and 19.9% of patients in the saxagliptin and placebo groups, respectively (confirmed hypoglycemia: 5.3%, 3.3%). Other adverse events reported in at least 5% of patients were urinary tract infection (saxagliptin, placebo: 5.9%, 6.0%), influenza (3.0%, 6.6%), and pain in extremity (1.6%, 6.0%).
Conclusions:
Saxagliptin 5-mg once-daily add-on therapy improves glycemic control in T2D patients on insulin alone or combined with metformin and is generally well-tolerated.
NCT00757588
Both angiotensin II–receptor blockers and angiotensin-converting–enzyme (ACE) inhibitors are renoprotective, but direct, long-term comparisons of their use in patients with diabetes have not been ...conducted. This prospective, multicenter, double-blind comparison of telmisartan (an angiotensin II–receptor blocker) and enalapril (an ACE inhibitor) in 250 subjects with type 2 diabetes and early nephropathy found that the two agents were associated with similar decrements in the glomerular filtration rate.
In subjects with early nephropathy, telmisartan and enalapril were associated with similar decrements in the glomerular filtration rate.
In persons with type 2 diabetes mellitus, hypertension and increased urinary albumin excretion are features of diabetic nephropathy. Diabetic persons with this complication are at increased risk for cardiovascular events and, if untreated, have a relentless decline in renal function.
1
Although death from cardiovascular causes commonly occurs before end-stage renal failure, diabetic nephropathy is now the most common reason for renal-replacement therapy, accounting for about half the new cases in the United States.
2
Angiotensin-converting–enzyme (ACE) inhibitors, which competitively block the renin–angiotensin system, decrease glomerular capillary pressure and prevent the progression of microalbuminuria to overt proteinuria.
3
The results of clinical trials . . .
PDF
