Promising Therapies in Diabetes Mellitus

Diabetes mellitus (DM) results from defects in insulin secretion (type 1) or insulin resistance (type 2). Insulin is used to manage type 1 DM, and oral hypoglycemic agents are used to manage type 2 DM. These therapies are inconsistent in maintaining glycemic control and cause some severe adverse effects such as undue weight gain and hypoglycemia. New and appropriate therapies are needed to overcome these problems. Drugs that are in the pipeline include oral insulins for type 1 DM and incretin mimetics, incretin enhancers, gastric inhibitory peptides, amylin analogues, peroxisome proliferator-activated receptor-α/γ ligands, sodium-dependent glucose transporter inhibitors, and fructose 1,6-bisphosphatase inhibitors for type 2 DM.

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Effects of glycemic load on metabolic risk markers... [Am J Clin Nutr. 2010] - PubMed result

A recent study suggests that diet with a decreased Glycemic Load does not ameliorate metabolic risk markers such as fasting plasma glucose, insulin , serum total cholesterol , LDL-cholesterol , HDL-cholesterol ,triacylglycerol, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein and prothrombotic plasminogen activator inhibitor 1 in overweight subjects. This means that such subjects should concentrate on reducung weight and cholesterol rather than restricting sugar intake. Effects of glycemic load on metabolic risk markers... [Am J Clin Nutr. 2010] - PubMed result

Mediterranean Diet Delays the Need for Drug Therapy in Type 2 Diabetes

Effects of a Mediterranean-Style Diet on the Need for Antihyperglycemic Drug Therapy in Patients With Newly Diagnosed Type 2 Diabetes: A Randomized Trial

Esposito K, Maiorino MI, Ciotola M, et al
Ann Intern Med. 2009;151:306-314

Study Summary

In this randomized controlled trial, 108 subjects with newly diagnosed type 2 diabetes were assigned to a Mediterranean-style diet (MED) while 107 were assigned to a low-fat diet based on American Heart Association guidelines. The MED diet was rich in vegetables and whole grains, low in red meat, had a goal of no more than 50% of calories from complex carbohydrates, and no less than 30% of calories from fat (mainly olive oil). The low-fat diet was rich in whole grains with the goal of no more than 30% of calories from fat and no more than 10% of calories from saturated fat. Both diets restricted energy intake to 1800 calories per day for men and 1500 for women, and each group received equal guidance on increasing physical activity. Subjects were followed for up to 4 years to assess the primary outcome of time to introduction of antihyperglycemic drug therapy. Per protocol, drug therapy was initiated when HbA1c exceeded 7% at 2 consecutive 3-month intervals. Secondary outcome measures included changes in weight, glycemic control, lipid levels, and blood pressure.

Typical of newly diagnosed patients, the study participants averaged 52 years of age, half were men, mean body mass index was about 30 kg/m², and HbA1c was 7.7%. None of these characteristics differed between groups. At the end of the trial, 44% of MED subjects required antihyperglycemic drugs compared with 70% of low-fat diet subjects. The hazard ratio for time to drug therapy was 0.63 (95% confidence interval, 0.51-0.86), a finding that was essentially unchanged after adjustment for change in body weight. Both groups lost weight, and though the MED group lost significantly more in the first year, there was not a statistically significant difference between groups at the end of the trial. Other measures of glycemic control (changes in level of HbA1c, plasma glucose, serum insulin, HOMA insulin sensitivity, and adiponectin) all favored the MED participants. High-density lipoprotein (HDL) cholesterol increased and triglycerides decreased significantly more in the MED group.

Source: http://www.medscape.com/viewarticle/711007?src=mp&spon=22&uac=82830HJ

Oral Insulin

1) The FDA has approved Oral-lyn, an insulin spray treatment for type I and type II diabetes, for its Investigational New Drug program.


The spray delivers prandial insulin orally through a device similar to an asthma inhaler, which sprays it on the inside of the cheek, rather than via injection.

Researchers have spent much time looking for alternative means of dispensing insulin to diabetics, and the IND program allows patients with serious or life-threatening conditions, and without suitable alternative treatment, to access drugs otherwise available only to those in a clinical trial.



2) Oramed has developed a tablet form of insulin in which the hormone's protein structure is supposedly protected by special adjuvants from destruction by gastric juice. The firm just reported positive results from a Phase 2A clinical trial with Type I diabetics.

Mediterranean Diet Lets Diabetics Cut Back on Drugs

Mediterranean Diet Lets Diabetics Cut Back on Drugs - ABC News

Cycloset -a new antidiabetic

The U.S. FDA approved Cycloset, a new quick-release oral formulation of bromocriptine mesylateis, which is the first therapy directly targeting the body’s dopamine activity to improve glycemic control. It is also the only drug to be approved subsequent to the FDA's guidelines that require studies demonstrating that diabetes drugs do not increase cardiovascular risk.

Preclinical studies indicate that while an increase in dopamine activity leads to improvements in diabetes, the time of day of the increased dopamine activity is also important. Studies in diabetic animals have shown that increased dopaminergic activity at a particular time of day is most effective in “resetting” the biological clock neurochemistry to a physiology that improves diabetic dysmetabolism. Taken orally, once-a-day, in the morning, Cycloset provides a single brief pulse of dopamine agonist activity shortly after its administration. Morning Cycloset improves post-prandial (after-meal) glucose without increasing plasma insulin concentrations, and the beneficial effects of Cycloset on post-meal glycemic control in patients with Type 2 diabetes are demonstrable many hours after the drug has been substantially cleared from the circulation, for example at lunch and dinner.

Mechanism: Bromocriptine mesylate, an ergot derivative, is a sympatholytic dopamine D2 agonist that exerts inhibitory effects on serotonin turnover in the central nervous system. It has been proposed that bromocriptine can reverse many of the metabolic alterations associated with obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activitties. Indeed, bromocriptine, if administered systemically or into the cerebral ventricle during the early hours of the light cycle, prevents or reverses seasonal fattening, insulin resistance, and decreased endogenous (hepatic) glucose production in mammals. Moreover, timed bromocriptine treatment decreased body weight and improved glucose tolerance in obese individuals who were instructed to follow a hypocaloric diet . Bromocriptine has also been shown to reduce mean daylong plasma glucose, triglyceride, and free fatty acid (FFA) levels in the absence of a change in body weight in obese nondiabetic women.

Adverse metabolic and cardiovascular consequences of not maintaining circadian rythm

The following studies signify the importance of maintaining a regular routine of sleeping, eating and other daily activities.
In a recent study, Ciprian and colleagues found increased pathological remodeling and vascular injury in mice with aberrant circadian rhythms, Bmal1-knockout and Clock mutant. In addition, naive aortas from Bmal1-knockout and Clock mutant mice exhibit endothelial dysfunction. Akt and subsequent nitric oxide signaling, a pathway critical to vascular function, was significantly attenuated in arteries from Bmal1-knockout mice. The authors concluded that their data reveal a new role for the circadian clock during chronic vascular responses that may be of significance in the progression of vascular disease.
In another study by Scheer et at, Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle—achieved by scheduling a recurring 28-h “day.” Subjects ate 4 isocaloric meals each 28-h “day.” For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling ≈1,000 assays/subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept ≈12 h out of phase from their habitual times, systematically decreased leptin (−17%, P <>P <>P = 0.006), completely reversed the daily cortisol rhythm (P <>P = 0.001), and reduced sleep efficiency (−20%, P <0.002).>
Sources:
Vascular Disease in Mice With a Dysfunctional Circadian Clock
Ciprian B. Anea, MD; Maoxiang Zhang, PhD; David W. Stepp, PhD; G. Bryan Simkins, BS; Guy Reed, MD; David J. Fulton, PhD; R. Daniel Rudic, PhD
From the Department of Pharmacology and Toxicology (C.B.A., M.Z., G.B.S., D.J.F., R.D.R.), Department of Physiology (D.W.S.), Vascular Biology Center (D.W.S., D.J.F.), and Cardiology Division, Department of Medicine (G.R.), Medical College of Georgia, Augusta.
Circulation. 2009;119:1510-1517
Published online before print March 9, 2009, doi: 10.1161/CIRCULATIONAHA.108.827477
Adverse metabolic and cardiovascular consequences of circadian misalignment
Frank A. J. L. Scheer, Michael F. Hilton, Christos S. Mantzoros, and Steven A Shea
Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA 02115
Harvard Medical School, Harvard University, Boston, MA 02115; and
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215
Published online before print March 2, 2009, doi: 10.1073/pnas.0808180106
PNAS March 17, 2009 vol. 106 no. 11 4453-4458

Indian polypill study

The TIPS study was headed by Dr. Prem Pias Dean, SJMCH. Dr. Denis Xavier HOD, Dept of Pharmacology, SJMC And

Dr. Alben Sigamani Trial Manager Division of Clinical Trials St. Johns Research Institute Bangalore.

The concept of Polypill in Cardiovascular Diseases was by Dr. Salim Yusuf (Graduate from St. John's), Now the Director of PHRI Mc. Master university Canada.

The Study was funded by Cadila Pharmaceuticals.

The results of the study are published in Lancet Mar 30th 2009.

This team is now heading forward to conduct one more large clinical outcome based study with polypill, the clinical end points such as All cause mortality and CV mortality. This future study will answer the question such as.

1) Which particular patient can take the poly pill

2) Patient with certain risk factors needs to take which combination of Ploy pill. etc

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60611-5/abstract

Indian scientists discover 'superpill' to combat heart disease Hindu - ‎Mar 31, 2009

'Polypill' could reduce heart disease, stroke: Researchers Calgary Herald

5-in-1 pill passes first major test Times of India

Five-in-one pill cuts heart attack risk Calcutta Telegraph

Vinegar Reduces Post-Prandial Glucose

A mixture of vinegar and olive oil is the traditional salad dressing used in the Mediterranean diet. The consumption of vinegar with meals was used as a home remedy for diabetes before the advent of pharmacologic glucose-lowering therapy. Indeed modern studies indicate that vinegar significantly reduces post-meal glycemia, probably because acetic acid slows gastric emptying and thus delays carbohydrate absorption and improves satiety. Recent studies show that 1 to 2 tablespoons of vinegar, when added to a meal containing high-glycemic-index foods such as white bread or white rice, will both: 1) lower post-prandial glucose by 25% to 35% increase post-meal satiety by more than 2-fold. Thus the addition of vinegar to a standard meal can not only improve the meal-induced oxidant stress by blunting the post-prandial glucose excursion, but also can increase and prolong satiety, which should help to reduce food cravings and lower caloric intake over the subsequent 2 to 4 h. Finally, vinegar with olive oil is generally consumed with green leafy vegetables, which have superior nutrient-to-calorie ratios and very low glycemic indexes.

Sources:

• Östman E, Granfeldt Y, Persson L, Björck I. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr 2005;59:983-988.
• James H. O’Keefe, MD, Neil M. Gheewala, MS and Joan O. O’Keefe, RD . Dietary Strategies for Improving Post-Prandial Glucose, Lipids, Inflammation, and Cardiovascular Health. J Am Coll Cardiol, 2008; 51:249-255, doi:10.1016/j.jacc.2007.10.016

Nuts, Olive Oil, and Fish Oil

Nuts, when consumed with a meal, will significantly reduce the post-prandial glucose excursion by slowing digestion. Recent studies show that almonds, pistachios, or peanuts, when eaten along with high glycemic index carbohydrates such as white bread or mashed potatoes, will reduce the post-prandial glucose area under the curve by approximately 30% to 50%. Importantly, nuts also decrease meal-induced oxidative protein damage because they lower post-prandial oxidative stress and additionally provide antioxidants.
A recent trial randomized 772 subjects at high risk for CAD to a low-fat diet or a Mediterranean-style diet supplemented with either walnuts (30 g/day) or virgin olive oil (1 l/week). This trial found that after 3 months the Mediterranean diets supplemented with either nuts or olive oil produced clinically significant reductions in systolic blood pressure, fasting glucose, and inflammatory biomarkers compared with the low-fat diet.

Epidemiologic studies consistently indicate that consumption of nuts at least 5 times per week will reduce CAD and diabetes risks by 20% to 50%. Tree nuts are comprised predominantly of monounsaturated fats and are a rich source of antioxidants, fiber, phytosterols, magnesium, and folic acid, which might beneficially influence CV risk. Replacing refined carbohydrates with monounsaturated fats (using nuts and/or olive oil) will reduce post-prandial hyperglycemia and hypertriglyceridemia, increase high-density lipoprotein, and decrease oxidative stress . One practical way to accomplish this is to substitute nuts (all of which have very low glycemic indexes) for the sugary and starchy snack foods that are staples in the American diet.

Fish oil (omega-3 fatty acids) lowers post-prandial triglyceride levels by 16% to 40% in a dose-dependent fashion, in part by upregulating lipoprotein lipase activity and accelerating the clearance of chylomicrons. Thus, some of the documented anti-inflammatory and cardioprotective activities of omega-3 fatty acids may be conferred in part by significant improvements in post-meal lipid levels

Source: James H. O’Keefe, MD_^*, Neil M. Gheewala, MS and Joan O. O’Keefe, RD Dietary Strategies for Improving Post-Prandial Glucose, Lipids, Inflammation, and Cardiovascular Health. J Am Coll Cardiol, 2008; 51:249-255, doi:10.1016/j.jacc.2007.10.016

Nonglycemic Effects of Incretins

In addition to their beneficial effects on blood glucose, particularly postprandial glucose, as well as body weight and pancreatic beta cell function, the glucagon-like peptide-1 (GLP-1) receptor agonists (Exenatide, Liraglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (Sitagliptin, Vildagliptin) have other beneficial effects. These effects on blood pressure and blood lipids, although not making incretins suitable as primary therapy, may be important benefits to consider in selecting diabetes therapy, because patients with type 2 diabetes mellitus (T2DM) are at increased risk for cardiovascular disease.

Blood Pressure

GLP-1 receptor agonists and DPP-4 inhibitors produce modest reductions in systolic blood pressure and, in some cases, diastolic blood pressure. The importance of hypertension as a cardiovascular risk factor is well established. As concluded by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, each increment of 20/10 mm Hg above 115/75 mm Hg doubles the risk of cardiovascular disease.

Lipid Profile

the GLP-1 receptor agonists and DPP-4 inhibitors produce significant reductions in the triglyceride level. Exenatide and vildagliptin also produce significant improvements in total, LDL-, and HDL-cholesterol. The benefits on reducing cardiovascular risk by lowering total and LDL-cholesterol and raising HDL-cholesterol are well established. As such, they are important targets for treatment as recommended by the National Cholesterol Education Program Expert Panel - Adult Treatment Panel III

Conclusion

The GLP-1 receptor agonists and DPP-4 inhibitors lower blood pressure and improve the lipid profile, which, although not appropriate as primary therapy, makes them especially valuable treatment options for patients with T2DM. These improvements may help to reduce the risk of cardiovascular events. Various approaches can be taken to initiate and modify GLP-1 receptor agonist and DPP-4 inhibitor therapy to improve efficacy and tolerability based on patient characteristics and concomitant therapies.

References

1. Boschmann M, Engeli S, Dobberstein K, et al. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J Clin Endocrinol Metab. 2008. In press.
2. Viswanathan P, Chaudhuri A, Bhatia R, et al. Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract. 2007;13:444-450.
3. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428.
4. Vilsboll T, Zdravkovic M, Le Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608-1610.
5. Colagiuri S, Frid A, Zdravkovic M, et al. The once-daily human GLP-1 analog liraglutide reduces systolic blood pressure in patients with type 2 diabetes. Paper presented at: American Diabetes Association 68th Scientific Session; June 6-10, 2008; San Francisco, CA.
6. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48:592-598.
7. Chobanian AV, Bakris GL, Black HR, et al; for the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206-1252.
8. Blonde L, Rosenstock J, Sesti G, et al. Liraglutide: superior glycemia control vs exenatide when added to metformin and/or SU in type 2 diabetes. Paper presented at: Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism Annual Meeting; October 15-18, 2008; Montreal, Quebec, Canada.
9. Scott R, Wu M, Sanchez M, et al. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007;61:171-180.
10. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556-1568.
11. Bolli G, Dotta F, Rochotte E, et al. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2008;10:82-90.
12. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes. Diabetes Care. 2007;30:217-223.
13. Grundy SM, Becker D, Clark LT, et al. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed January 20, 2009.
14. Daniel A. Nadeau, MD. Incretin Benefits Beyond Glycemic Control. From Primary Care Education Consortium, Medscape Internal Medicine. Posted 03/19/2009. Available at: http://www.medscape.com/viewarticle/588945?src=mp&spon=18&uac=82830HJ
    

Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension

With the popularity of ACE inhibitors in mind, investigators conducted a systematic review of published studies to determine how effective the drugs actually are in reducing blood pressure. They also examined dose effectiveness, adverse effects, and the role of co-occurring conditions.

The Study Findings

Researchers looked for double-blind studies comparing ACE inhibitors and placebo. All included studies were at least 3 weeks in duration and measured blood pressure as an endpoint at 3-12 weeks. Studies that featured a response-dependent titration of medications were included in the review. Only research that focused on patients with a blood pressure above 140/90 mm Hg was reviewed.

The review included 92 trials with a total of 12,954 participants (mean age, 54 years). Mean baseline blood pressure was 157/101 mm Hg and mean pulse pressure was 56 mm Hg. The majority (75%) of included studies was industry-sponsored, and 82% of the trials examined fixed-dose ACE inhibitors. The duration of trials was generally short, which limited data with regard to adverse events and study withdrawals.

The main potential source of bias in the research was a lack of information with regard to how the studies were blinded. In addition, the reviewers suggested that the researchers could have preferentially selected patients more likely to respond to ACE inhibitors. This selection bias could make ACE inhibitors appear more effective than they truly are.

The studies covered 14 ACE inhibitors. The degree of homogeneity with regard to their efficacy in reducing blood pressure was remarkable. No one medication appeared superior to others.

Overall, ACE inhibitors had a modest collective effect in reducing blood pressure. The mean reduction in systolic blood pressure ranged between 6 mm Hg and 9 mm Hg, and the mean reduction in diastolic blood pressure was 4-5 mm Hg. Less data were available with regard to the blood pressure effects of ACE inhibitors at 1-12 hours after dosing, but the average decrease in blood pressure with ACE inhibitors around their peak concentration was greater than their average efficacy (11.4/6.4 mm Hg).

Dose Effectiveness

The study provided some important information about the relationship between the dose of ACE inhibitors and their effect on blood pressure. Doses lower than the manufacturers' maximum recommended dosage had the same blood pressure-lowering effect as the maximum dose. For example, doses of one eighth to one quarter of the maximum achieved the blood pressure-lowering effect of the maximum dose in 60% to 70% of cases. Half of the maximum dose achieved it 90% of the time. There was no blood pressure-lowering effect at or below one sixteenth of the maximum suggested dose. These data suggest that use of the maximum dosage of ACE inhibitors to achieve greater blood pressure control is usually unnecessary.

The research also identified dosing information for individual ACE inhibitors and suggested that the manufacturers' recommended starting doses of benazepril, moexipril, and ramipril are higher than the minimum dose needed to reduce blood pressure. Conversely, captopril did not appear effective in reducing blood pressure at the manufacturers' recommended starting dose. Most of the maximum blood pressure-lowering effect of lisinopril was achieved at only one eighth of the recommended maximum dose.

ACE inhibitor dosing was also one of the biggest deficits in the current review. It was clear to the review authors that not all data in regard to the efficacy of different doses of ACE inhibitors were published. Instead, the data were supplied to regulators privately to determine the appropriate dosing range of ACE inhibitors.

Only half of trials provided data in regard to the rate of withdrawal due to adverse events. Collectively, there was no difference between ACE inhibitors and placebo in this critical outcome. ACE inhibitors did not significantly affect patients' heart rate.

Addressing Other Health Issues

Physicians might choose ACE inhibitors to treat hypertension for other possible health benefits associated with these medications, especially the potential to prevent type 2 diabetes. ACE inhibitors can have a positive effect on glucose metabolism through multiple mechanisms, and previous research suggested that they could prevent incident diabetes compared with other antihypertensive medications. Specifically, the Captopril Prevention Project demonstrated a 14% relative reduction in this outcome among participants receiving captopril vs a diuretic or beta-blocker. This benefit, associated with captopril, was evident regardless of the baseline risk for diabetes, although the incidence of diabetes was not a primary outcome of the study.

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial directly examined the effect of ramipril vs placebo on the incidence of diabetes. This study examined patients with impaired fasting glucose levels or reduced insulin sensitivity but no history of cardiovascular disease. After a median of 3 years of treatment, ramipril was not associated with a significantly lower incidence of diabetes compared with placebo. Median fasting plasma glucose levels were also similar at the end of the trial. However, ramipril was associated with a higher rate of return to normoglycemia.

Physicians might also consider using ACE inhibitors for hypertension in order to prevent incident heart failure. However, although ACE inhibitors are associated with numerous positive outcomes, including reduced mortality, among patients with known heart failure, little evidence exists that they provide special protection against new heart failure. In a study of quinapril and placebo initiated shortly after myocardial infarction, there was no difference between treatment groups in a composite outcome of cardiovascular death and significant cardiovascular events. Specifically, no difference was found in the risk for heart failure among those patients at high cardiovascular risk. Similarly, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Hearth Attack Trial (ALLHAT), the incidence of heart failure was similar among patients receiving lisinopril and chlorthalidone.

Commentary

Although ACE inhibitors may not provide special protection against diabetes or heart failure among patients with hypertension, physicians should still consider these medications when managing hypertension. In fact, the nature of hypertension management dictates that they have to because most patients require more than 1 medication initially. In a recent study of men receiving care at a Veteran Affairs hospital, 60.4% of subjects with hypertension and significant cardiovascular risk were receiving multiple antihypertensive medications. Nevertheless, only 28% of these same patients had reached their goal blood pressure levels, indicating that they needed titration of their medications, if not the addition of other antihypertensive drugs.

Authors' conclusions

There are no clinically meaningful BP lowering differences between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses. The review did not provide a good estimate of the incidence of harms associated with ACE inhibitors because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Clinical Pearls

• In the current review, ACE inhibitors were associated with an average reduction in systolic blood pressure between 6 mm Hg and 9 mm Hg and in diastolic blood pressure of 4-5 mm Hg;
  
  
• ACE inhibitors achieved most of their power in reducing blood pressure at half of the maximum recommended dose, or less;
  
  
• ARBs provide similar reductions in blood pressure compared with ACE inhibitors; and
  
  
• There is no strong evidence that ACE inhibitors can prevent incident diabetes mellitus or heart failure.

Sources: Medscape Family Medicine Best Evidence Review
Cochrane Database Syst Rev. 2008; (4):CD003823 (ISSN: 1469-493X)
Full text at Cochrane Library

caution against combining the 2 classes of RAS inhibitors

The updated recommendation is based on the results of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), an international study supported by Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and the Canadian Institutes of Health Research. The main results of ONTARGET, published in 2008,^[9] showed that in 25,620 patients with vascular disease or type 2 diabetes, the combination therapy had a greater blood pressure-lowering effect than either telmisartan or ramipril alone, but it did not produce any additional benefit in terms of patient outcomes, and it was associated with more side effects, such as hyperkalemia, hypotension, and renal impairment. The guidelines also note that in patients with stage 3 chronic kidney disease (glomerular filtration rate > 30 mL/min) the ACE inhibitor plus ARB combination reduced urine protein but did not reduce cardiovascular outcomes, and it worsened renal outcomes, including the need for acute dialysis compared with the ACE inhibitor alone.

The only data to support improved patient outcomes with the combination of an ACE inhibitor plus an ARB are in people with heart failure, where, the guidelines note, the combination reduces recurrent hospitalization. Hence, the guidelines advise that the use of combination of ACE inhibitor with an ARB therapy should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. They advise that for people already on the combination and stable, physicians should consider that prescribing 1 of the 2 drug classes alone will reduce cardiovascular events to the same extent and that other therapeutic regimens have the potential to reduce cardiovascular events and blood pressure to a greater degree. Trials are ongoing of a combination of an ACE inhibitor with an ARB in people with chronic kidney disease and diabetes.

Cell-based treatments for diabetes

In Type 1 diabetes mellitus the insulin-secreting b-cells in pancreatic islets of Langerhans are selectively destroyed by autoimmune assault. Because diabetes is caused by the loss of a single cell type it is amenable to treatment by cell replacement therapy. Advances in islet transplantation procedures have demonstrated that people with Type 1 diabetes can be cured by human islet transplantation, but the severely limited availability of donor islets has restricted the widespread application of this approach, and driven the search for substitute transplant tissues. Recent experimental studies suggest that three separate sources of tissue show therapeutic potential – xenografts from other species, tissue stem cells and embryonic stem cells. Of these, xenografts are closest to clinical application but there are still major obstacles to be overcome. Insulin-expressing cells have been derived from a number of different stem cell populations but embryonic stem cells offer the major advantage of being able, in principle, to provide the vast numbers of cells required for transplantation therapy.

For details visit http://www.drugdiscoverytoday.com/echoice/feb2009/Jones.pdf

new approach in type 2 diabetes pharmacotherapy

A relatively new approach in type 2 diabetes pharmacotherapy is the result of understanding incretin physiology. Briefly, after eating a meal, certain gut hormones are released that sensitize the beta cell to secrete more insulin. One of the most important gut hormones is glucagon-like peptide-1 (GLP-1), which goes into the circulation and stimulates insulin secretion in a glucose-dependent manner.

In addition, this pathway has the added benefit of suppressing glucagon secretion, which has a role in the pathophysiology of diabetes. GLP-1 is also involved in slowing gastric emptying and in working on the central nervous system causing early satiety, leading to some beneficial effects in glycemic control. The problem is that GLP-1 is very rapidly degraded through the very important enzyme, DPP-IV. This leads to rapid inactivation of GLP-1, making its use impractical in patients who have type 2 diabetes.

It is also interesting to note that in some animal models, and in in-vitro studies, there are some exciting observations that this pathway may also help beta-cell differentiation. This has been shown to increase beta-cell mass, and the formation of new beta cells, but is not yet proven in humans. It is an exciting new concept that is still being explored.

Coming back to this pathway of GLP-1 degradation through DPP-IV, one of the ways to use this physiologic knowledge is to develop a drug that might block DPP-IV activity, which has been done with the DPP-IV inhibitors. They sustain GLP-1 level in the circulation longer, which then stimulates pancreatic insulin secretion and suppresses glucagon secretion. Another strategy that one can employ is to develop a GLP-1-like substance synthetically that is not recognized by DPP-IV. That is the approach underlying the GLP-1 analogs that are not degraded through this pathway, and you can then use that substance in the treatment of type 2 diabetes.

These are the 2 concepts behind the development of the new drugs. Incretin mimetics, which are analogs of GLP-1, are synthetically produced. Exenatide is one of these drugs used to treat patients with type 2 diabetes. Because of the protein, you have to inject exenatide subcutaneously; you cannot give it orally. Another drug in this class, liraglutide, is under US Food and Drug Administration (FDA) review and might be approved in the near future.

The second way to use this physiology is to develop DPP-IV inhibitors. One such agent, sitagliptin, has been on the market for 2 years. There are several other drugs in this class undergoing clinical trials. This is an important area to pursue, and many of the pharmaceutical companies are trying to develop these agents that will be easy to use in the oral form to improve glycemic control.

exenatide, a twice-daily injection, you can lower A1C by about 0.8% to 1%. The main side effect is nausea, sometimes vomiting. There may be appreciable weight loss, which is a desirable side effect of this drug. We do not have another approved drug yet that improves glycemic control and results in weight loss at the same time. The only medication that came close to it was metformin, but metformin is relatively weight-neutral; it does not cause weight loss in most patients.

Sitagliptin has very similar effects on A1C reduction as exenatide, except it does not cause weight loss. This drug is weight-neutral, but at least it does not cause weight gain. Another advantage of these drugs is that they do not cause gastrointestinal side effects, such as nausea.

Both GLP-1 agonists and DPP-IV inhibitors are being utilized in the strategy of combination therapy to achieve better glycemic control.

Aggressively lowering of blood sugar lead to more deaths

The National Institutes of Health's (NIH) National Heart, Lung and Blood Institute has announced the early cancellation of one part of a major diabetes and cardiovascular disease study after discovering that patients undergoing that treatment were more likely to die from heart attacks and strokes.The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study included 10,251 adults with Type 2 diabetes who were considered to be at especially high risk of heart attacks and strokes. One of the treatments in the study involved using combinations of FDA-approved diabetes drugs to aggressively lower participants' blood sugar to levels as close to normal as possible."Of these, 257 in the intensive treatment group have died, compared with 203 within the standard treatment group," the NIH announced. At the time of the experiment's cancellation, patients had been undergoing treatment for an average of four years.The NIH said that it does not know what caused the increased risk of death among patients undergoing intensive treatment, but it does not believe that the risk came from any individual drug or combination of drugs. Rather, there appears to be some negative effect on the body from so aggressively lowering blood sugar levels."This presents a real dilemma to patients and their physicians," said Richard Kahn, chief scientific and medical officer for the American Diabetes Association. "How intensive should treatment be? We just don't know."Previously, health experts have believed that the closer to normal a diabetic's blood sugar can be lowered, the better. The NIH findings have offered a major challenge to that conventional wisdom.Approximately 21 million people in the United States suffer from Type 2 diabetes, and the numbers increase every year. The elevated blood sugar that is characteristic of the disease is well-established to lead to a host of other health problems, including an elevated risk of cardiovascular disease, heart attack and stroke

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Newer drugs in Treatment of Type 2 Diabetes

Incretins

Incretins are gastrointestinally secreted insulinotropic hormones that play an important role in glucose homeostasis as they are involved in augmentation of -cell secretion of insulin and in suppression of glucagon secretion by the cell. The incretin effect refers to the augmented release of insulin that is observed from oral ingestion of glucose when compared with intravenous glucose challenge, even though the glucose concentration achieved in plasma may be equivalent. There are two different gut hormones that are mainly responsible for the incretin effect, which may include glucose-dependent insulinotropic peptide and GLP-1. In contrast to glucose-dependent insulinotropic peptide, GLP-1 maintains a glucoregulatory function in individuals both with and without diabetes. For this reason, GLP-1 was identified as a potential therapeutic agent for diabetes treatment.

One of the major concerns for GLP-1 that limited clinical applicability is the rapid enzymatic degradation by DPP-4 and as such, requires continuous intravenous or subcutaneous infusion. To address the problem, two research approaches have been attempted. One is to modify the molecule to resist or delay degradation. Agents such as exenatide and liraglutide are GLP-1 receptor agonists that are resistant to DPP-4 inhibition. A second approach has been to inhibit endogenous DPP-4 activity, thus prolonging the circulating half-life of native GLP-1. Agents in the DPP-4 inhibitor class are represented by vildagliptin and sitagliptin

Treatment of Type 2 Diabetes

Type 2 diabetes, the most common form of diabetes, is characterized by abnormalities in hepatic glucose production, insulin resistance, and a progressive decline in -cell function over time. To treat effectively the individual with type 2 diabetes, the provider must have a thorough understanding of the underlying pathophysiology to provide treatment that precisely addresses the metabolic abnormalities. Currently, the provider who cares for subjects with type 2 diabetes can choose an antidiabetic agent from no less than eight pharmacologic classes. These classes include agents that increase insulin secretion, improve insulin action, and delay absorption of carbohydrates. The newer treatments available, specifically incretin therapy, address a previously unmet need in diabetes by modulating glucose supply. The currently available agents can be combined and combination therapy markedly improves glycemic control. This allows the provider to design regimens to specifically address underlying abnormalities.
Goals
A1c goal recommended by the American Diabetes Association (ADA) is a A1c value <7%. This is not a value considered in the normal range, as an A1c level of 4.0–6.0% is considered as the non-diabetic range. However, this level was selected on the basis of practicality and the projected reduction in complications over time. The ADA guidelines also suggest that for "the individual patient," the A1c should be "as close to normal (<6%) as possible without significant hypoglycemia". The most recent glycemic goal set by both the American Association of Clinical Endocrinologists and the European Union–International Diabetes Federation is an A1c level <6.5%.