Dipeptidyl Peptidase-4 Inhibitors in the Elderly: More Benefits or Risks

Dipeptidyl Peptidase-4 Inhibitors in the Elderly: More Benefits or Risks?
Mar 15, 2012 6:15 PM
Abstract
Several studies have shown a high prevalence of type 2 diabetes mellitus (T2DM) in the elderly, characterized by a paucity of symptoms, which represents an obstacle for an early diagnosis. Frequently, T2DM in the elderly is diagnosed when a complication occurs, among which are cognitive disorders and/or affective disturbances. Moreover, hypoglycemia is a frequent side effect of therapeutic treatment with insulin, sulfonylureas or glinides, while other treatments (metformin, acarbose, thiazolidinediones, glucagon-like peptide-1 [GLP-1] receptor agonists, and dipeptidyl peptidase-4 [DPP4] inhibitors) are capable of reducing hyperglycemia without inducing hypoglycemia. Thus, considering that older persons are a very heterogeneous group of individuals, management of T2DM in the elderly is challenging but there are no available specific treatment goals or treatment algorithms for older diabetic patients. Metformin is the recommended first-line therapy in all T2DM patients. When metformin is not sufficient to achieve the desired therapeutic targets, a second drug can be added. Available options include sulfonylureas, meglitinides, alfa-glucosidase inhibitors, pioglitazone, insulin, GLP-1 receptor agonists, and DPP-4 inhibitors. The most intriguing therapy for older patients is the one based on the so-called incretins, i.e., gastrointestinal hormones that, mainly secreted in the postprandial phase, stimulate insulin secretion and inhibit glucagon secretion. The two most important human incretins are GLP-1 and glucose-dependent insulinotropic peptide (GIP). These hormones potentiate the acute effects of glucose on pancreatic alfa and beta cells, thus stimulating insulin secretion, and only GLP-1 inhibits glucagon secretion in a glucose-dependent manner (that is, only when glucose levels are increased); as a result, they reduce hyperglycemia with virtually no hypoglycemic risk. Due to their characteristics, DPP-4 inhibitors seem to be particularly interesting as potential agents for the treatment of older patients with T2DM.

Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease

Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease; Tobaru T, Seki A, Asano R, Sumiyoshi T, Hagiwara N; Heart and Vessels (Mar 2012)
We evaluated the effects of adding ezetimibe to statin therapy in hypercholesterolemic patients with coronary artery disease (CAD) who could not achieve the target cholesterol levels recommended in the 2007 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases on statin monotherapy. Ezetimibe (10 mg) was added to basal statin therapy for 12 weeks in 35 patients with hypercholesterolemia and a history of CAD who had not achieved their target cholesterol level with statin monotherapy. Changes in serum lipids, obesity markers, an oxidative stress marker, inflammatory markers, and laboratory values were investigated. Total cholesterol (from 200.6 ± 30.4 mg/dL in week 0 to 173.4 ± 33.3 mg/dL in week 12, P<0.001), low-density lipoprotein cholesterol (LDL-C) (121.3 ± 29.4 vs. 94.6 ± 30.4 mg/dL, P<0.001), and remnant lipoprotein cholesterol (6.4 ± 3.5 vs. 5.3 ± 3.0 mg/dL, P<0.05) all decreased significantly after addition of ezetimibe. The LDL-C/high-density lipoprotein cholesterol ratio also decreased significantly (2.5 ± 0.8 in week 0 vs. 1.9 ± 0.7 in week 12, P<0.001). The percentage of patients achieving the target LDL-C level (<100 mg/dL) increased significantly (70.8 % in week 4 and 65.4 % in week 12, P<0.001). There were no significant changes in the obesity or oxidative stress markers and high-sensitivity C-reactive protein (an inflammatory marker). However, another inflammatory marker (tumor necrosis factor-α) was decreased significantly by ezetimibe (1.36 ± 1.06 in week 0 vs. 0.96 ± 0.24 in week 12, P = 0.042). In conclusion, when ezetimibe was added to basal statin therapy, serum lipids improved significantly and the rate of achieving the target cholesterol level increased. Thus, ezetimibe efficiently decreases LDL-C and might prevent arteriosclerosis in hypercholesterolemic patients with CAD when added to basal statin therapy.

New Data on Risks when Renin Inhibitor Aliskiren is Used With ARBs, ACE Inhibitors

New Data on Risks when Renin Inhibitor Aliskiren is Used With ARBs, ACE Inhibitors
The US Food and Drug Administration (FDA) is warning of possible risks when using blood pressure medicines containing aliskiren with angiotensin converting enzyme(ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or renal impairment.

These drug combinations should not be used in patients with diabetes. In addition, a new warning is being added to avoid use of these drug combinations in patients with renal impairment.

The labels for aliskiren-containing drugs are being updated based on preliminary data from the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) study. In ALTITUDE, the risks of renal impairment, hypotension, and hyperkalaemia in a group of patients taking aliskiren plus an ARB or ACE inhibitor increased relative to a group of patients taking an ARB or ACE plus placebo.

The preliminary data from ALTITUDE also demonstrated a slight excess of cardiovascular events (death or stroke) in the aliskiren group. However, the FDA has reached no definite conclusion regarding an actual link between these drugs and death or stroke.

The FDA will evaluate the final trial results as well as results from other aliskiren trials and will communicate any new information when it becomes available.

The following recommendations are being added to the drug labels for aliskiren-containing products as of 4/20/12:
• A new contraindication against the use of aliskiren with ARBs or ACE inhibitors in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalaemia.
• A warning to avoid use of aliskiren with ARBs or ACE inhibitors in patients with moderate to severe renal impairment (ie, glomerular filtration rate <60 mL/min).

Aliskiren and valsartan (Valturna) should not be used in patients with diabetes. This drug will no longer be marketed after July 2012.

The purpose of ALTITUDE was to determine whether aliskiren plus conventional treatment reduces death and disease caused by the heart, the circulatory system, and the kidney. Patients with type 2 diabetes with renal disease were randomised to aliskiren 300 mg daily (n = 4,283) or placebo (n = 4,296). All patients were receiving concomitant therapy with an ARB or an ACE inhibitor.

The primary efficacy outcome was the time to the first event of the primary composite endpoint, which consisted of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalisation for heart failure, onset of end-stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least 1 month.

After a median patient follow up of about 27 months, the trial was terminated early for lack of efficacy. Greater risks of renal impairment, hypotension and hyperkalaemia were observed in the aliskiren group compared with the placebo group.

SOURCE: US Food and Drug Administration

Consumo de fibratos y elevación de creatinina en ancianos

There was no apparent effect on the need for dialysis or on mortality, however. Dr. Garg and colleagues think this may be "because increases in creatinine levels from fibrate use do not represent true kidney injury." Indeed, they note that fibrates may have long-term renal benefits.

That said, they conclude: "Until we have a better understanding of the underlying mechanism by which fibrates increase serum creatinine level and its long-term renal effects, we believe that, when fibrates are prescribed to older patients, it would be prudent to start the prescription at a low dosage and arrange for close monitoring of renal function, as has been done in clinical trials."

SOURCE: http://bit.ly/IyES9C

Which is the preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?; Mallat SG; Cardiovascular Diabetology

Which is the preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?; Mallat SG; Cardiovascular Diabetology 11 (1), 32 (Apr 2012)

ABSTRACT: Hypertension is a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminuria and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.

Lipid-Altering Efficacy of Ezetimibe/Simvastatin 10/20 mg Compared to Rosuvastatin 10 mg in High-Risk Patients with and without Type 2 Diabetes Mellitus Inadequately Controlled Despite Prior Statin

Source: Cardiovasc Ther. Lipid-Altering Efficacy of Ezetimibe/Simvastatin 10/20 mg Compared to Rosuvastatin 10 mg in High-Risk Patients with and without Type 2 Diabetes Mellitus Inadequately Controlled Despite Prior Statin Monotherapy; Vaverkova H, Farnier M, Averna M, Missault L, Viigimaa M, Dong Q, Shah A, Johnson-Levonas AO, Brudi P; Cardiovascular Therapeutics 30 (2), 61-74 (Apr 2012) Aims: This post hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) or rosuvastatin 10 mg (ROSUVA) in uncontrolled high-risk hypercholesterolemic patients with/without type 2 diabetes mellitus (T2DM) despite statin monotherapy. Methods: Patients (n = 618) at high risk for coronary vascular disease with elevated LDL-C ≥100 and ≤190 mg/dL despite use of statins were randomized 1:1 to double-blind EZE/SIMVA 10/20 mg or ROSUVA 10 mg for 6 weeks. Patients were classified as having T2DM based on ≥1 of the following: diagnosis of T2DM, antidiabetic medication, or FPG ≥126 mg/dL. This analysis evaluated percent changes from baseline in lipids among patients with (n = 182) and without T2DM (n = 434). Results: EZE/SIMVA was more effective than ROSUVA at lowering LDL-C, TC, non-HDL-C, and apo B in the overall study population and within both subgroups. Numerically, greater between-treatment reductions in LDL-C, TC, non-HDL-C, and apo B were seen in patients with T2DM versus those without T2DM. A significant interaction (P= 0.015) was seen for LDL-C indicating that patients with T2DM achieved larger between-group reductions versus those without T2DM. Conclusions: Switching to EZE/SIMVA 10/20 mg versus ROSUVA 10 mg provided superior lipid reductions in patients with/without T2DM.

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