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 Table of Contents  
EDITORIAL
Year : 2012  |  Volume : 24  |  Issue : 1  |  Page : 1-3

Advances in the management of type 2 diabetes mellitus


Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission01-Feb-2011
Date of Acceptance02-Feb-2011
Date of Web Publication16-Jul-2014

Correspondence Address:
Nariman Moustafa
21 Officer Buildings, Farouk Al-Sawy Street Al-Haram, Al-Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJIM.0000418015.54092.98

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Keywords: blood glucose, oral hypoglycaemic agents, type 2 diabetes mellitus,


How to cite this article:
Moustafa N. Advances in the management of type 2 diabetes mellitus. Egypt J Intern Med 2012;24:1-3

How to cite this URL:
Moustafa N. Advances in the management of type 2 diabetes mellitus. Egypt J Intern Med [serial online] 2012 [cited 2019 Jul 21];24:1-3. Available from: http://www.esim.eg.net/text.asp?2012/24/1/1/128279


  Introduction Top


Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and β-cell dysfunction 1.

It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. Established macrovascular pathology is common at the time of diagnosis of T2DM, suggesting either latency in diagnosis and/or an atherogenic prediabetes 2,3 state.

The first-line treatment for T2DM is diet, weight control and physical activity. If the blood glucose level remains high despite these lifestyle modifications, usually, tablets are prescribed to reduce the blood glucose level.

Because of the progressive nature of T2DM, many individuals require insulin to optimize glycaemic control over time as oral hypoglycaemic agents fail to achieve targets. Data from the UK Prospective Diabetes Study (UKPDS) suggest that 53% of patients will require insulin 6 years following the diagnosis and 75% of patients will need multiple treatments after 9 years 4.

Although insulin treatment is very effective in achieving glycaemic control, its use is invariably associated with weight gain because of increased body fat mass, in particular, abdominal obesity 5,6. Increased abdominal obesity in turn may lead to worsening of insulin resistance and therefore increasing insulin requirements, and a vicious circle may ensue. Along with weight gain, the use of insulin can also cause problems with episodes of hypoglycaemia if insulin treatment is not managed appropriately.


  Medicines for type 2 diabetes mellitus (glucose-lowering tablets) Top


Several different types of medicine, usually taken as tablets, are used to treat T2DM. Patients may need to take a combination of two or more medicines to control the blood glucose level.

Medications that primarily stimulate insulin secretion

Sulphonylureas

Sulphonylureas increase the amount of insulin that is produced by the pancreas. Examples of sulphonylureas include the following:

  1. glibenclamide
  2. gliclazide
  3. glimerpirizide
  4. glipizide
  5. gliquidone.


They appear to have an effect similar to metformin, and they lower glycated haemoglobin (A1C) by ∼1.5 percentage points 7. The major adverse side effect is hypoglycaemia, but severe episodes, characterized by the need for assistance, coma or seizure, are infrequent. However, such episodes are more frequent in the elderly. Episodes can be both prolonged and life threatening, although these are very rare. Several of the newer sulphonylureas have a relatively lower risk for hypoglycaemia 8. In addition, a weight gain of ∼2 kg is common with the initiation of sulphonylurea therapy. This may have an adverse impact on the risk of cardiovascular diseases (CVD), although it has not been established.

Nateglinide and repaglinide

Nateglinide and repaglinide stimulate the release of insulin by the pancreas. They are not commonly used but may be an option if meals are consumed at irregular times. This is because their effects do not last very long, but they are effective when taken just before a meal.

Nateglinide and repaglinide can cause side effects, such as weight gain and hypoglycaemia (low blood glucose).

Medications that primarily lower glucose levels by their actions on the liver, muscle and adipose tissue

Metformin

Metformin is the only biguanide available in most countries. Its major effect is to decrease hepatic glucose output and reduce fasting glycaemia. Typically, metformin monotherapy will lower A1C by ∼1.5 percentage points 9,10. It is generally well tolerated, with the most common adverse effects being gastrointestinal. Although always a cause for concern because of its potentially fatal outcome, lactic acidosis is quite rare (<1 case/100 000 treated patients) 11. Metformin monotherapy is usually not accompanied by hypoglycaemia and has been used safely, without causing hypoglycaemia, in patients with prediabetic hyperglycaemia. The major nonglycaemic effect of metformin is either weight stability or moderate weight loss, in contrast to many of the other blood glucose-lowering medications. The UKPDS showed a beneficial effect of metformin therapy on CVD outcomes that needs to be confirmed.

Glitazones (thiazolidinediones)

Thiazolidinediones (TZDs or glitazones) are peroxisome proliferator-activated receptor γ modulators; they increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin (insulin sensitizers) 12. The limited data on the blood glucose-lowering effect of TZDs when used as a monotherapy have shown a 0.5–1.4% decrease in A1C. The most common adverse effects with TZDs are weight gain and fluid retention. There is an increase in adiposity, largely subcutaneous, with the redistribution of fat from visceral deposits shown in some studies. The fluid retention usually manifests as peripheral oedema, although new or worsened heart failure can occur. TZDs either have a beneficial or a neutral effect on atherogenic lipid profiles, with pioglitazone having a more beneficial effect than rosiglitazone 13.

Rosiglitazone has been withdrawn from use because of the increased risk of cardiovascular disorders, including heart attack and heart failure.

Medications that affect absorption of glucose

α-Glucosidase inhibitors

α-Glucosidase inhibitors reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily reducing the postprandial glucose levels without causing hypoglycaemia. They are less effective in lowering glycaemia than metformin or sulphonylureas, reducing A1C by 0.5–0.8 percentage points 14. As carbohydrate is absorbed more distally, malabsorption and weight loss do not occur; however, increased delivery of carbohydrate to the colon commonly results in increased gas production and gastrointestinal symptoms. This side effect has led to the discontinuation of α-glucosidase inhibitors by 25–45% of participants in clinical trials 14,15. One clinical trial examining acarbose as a means of preventing the development of diabetes in high-risk individuals with impaired glucose tolerance showed an unexpected reduction in severe CVD outcomes 15.

Incretins 16

Gliptins (DPP-4 inhibitors)

Gliptins work by preventing the breakdown of a naturally occurring hormone called glucagon-like peptide 1 (GLP-1). GLP-1 helps the body produce insulin in response to high blood glucose levels, but is rapidly broken down. By preventing this breakdown, gliptins (sitagliptin and vildagliptin) act to prevent high blood glucose levels, but do not result in episodes of hypoglycaemia. Patients may be prescribed a gliptin if they unable to take sulphonylureas or glitazones. They are not associated with weight gain.

Glucagon-like peptide 1 agonists

GLP-1 7-37, a naturally occurring peptide produced by the L-cells of the small intestine, stimulates insulin secretion. It binds strongly to the GLP-1 receptor on the pancreatic β cell and potentiates glucose-mediated insulin secretion. Exenatide is a GLP-1 agonist, an injectable treatment that acts in a manner similar to the natural hormone GLP-1. It is injected twice a day and boosts insulin production when there are high blood glucose levels, reducing blood glucose without the risk of hypoglycaemic episodes. It also leads to moderate weight loss in many patients who take it. It is mainly used in patients on metformin plus sulphonylurea who are obese (with a BMI of 35 or above).

Another GLP-1 agonist called liraglutide has recently been launched in the UK. It is a once-daily injection. Similar to exenatide, it is mainly used in patients on metformin plus sulphonylurea who are obese, and in clinical trials, it has been shown to cause moderate weight loss.

Others

Amylin agonists (pramlintide)

Pramlintide is a synthetic analogue of the β-cell hormone amylin. Currently, pramlintide is approved for use in the USA only as adjunctive therapy with insulin.

Pramlintide is administered subcutaneously before meals and slows gastric emptying, inhibits glucagon production in a glucose-dependent manner and predominantly decreases postprandial glucose excursions 17. In clinical studies, A1C has been decreased by 0.5–0.7 percentage points 18. The major clinical side effects of this drug, which is injected before meals, are gastrointestinal in nature. Approximately 30% of treated participants in the clinical trials have developed nausea. Weight loss associated with this medication is ∼1–1.5 kg over 6 months; as with exenatide, some of the weight loss may be the result of gastrointestinal side effects.

Rimonabant

Rimonabant is the first agent of the class of drugs that act on the novel endocannabinoid system (ECS). The ECS is a novel physiological neuroendocrine system that plays a key role in appetite and energy metabolism, both in the brain and in adipose tissue 19,20. Animal studies have shown that blocking the ECS leads to weight loss and improved insulin sensitivity. Because of this effect, agents that block receptors (CB1 and CB2) in this system have been developed for the management of human obesity.

By blocking CB1 receptors, rimonabant has been shown to reduce weight by suppressing appetite and by modifying glucose and fat metabolism 21. It is usually given at a dose of 20 mg once a day before breakfast. In the brain, rimonabant reduces hunger and therefore results in weight loss, and in the adipose tissue, the drug increases the concentrations of adiponectin. This helps improve insulin sensitivity as reduced levels of adiponectin have been associated with increased insulin resistance. Because of this close link with various adipocytokines, agents within this group are hypothesized to play a role in atherogenesis and the pathophysiology of T2DM 22.

A1C of at least 7% should serve as a call to action to initiate or alter therapy with the goal of achieving an A1C level as close to the nondiabetic range as possible or, at a minimum, decreasing the A1C to less than 7%.[22]

 
  References Top

1.Turner R, Cull C, Holman R. United Kingdom prospective diabetes study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124(1 II):136–145  Back to cited text no. 1
    
2.Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: The Framingham Study. Diabetes Care. 1979;2:120–126  Back to cited text no. 2
    
3.. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res. 1990;13:1–11  Back to cited text no. 3
    
4.Wright A, Burden ACF, Paisey RB, Cull CA, Holman RR. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25:330–336  Back to cited text no. 4
    
5.Bagg W, Plank LD, Gamble G, Drury PL, Sharpe N, Braatvedt GD. The effects of intensive glycaemic control on body composition in patients with type 2 diabetes. Diabetes Obes Metab. 2001;3:410–416  Back to cited text no. 5
    
6.Mäkimattila S, Nikkilä K, Yki Järvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia. 1999;42:406–412  Back to cited text no. 6
    
7.Groop LC. Sulfonylureas in NIDDM. Diabetes Care. 1992;15:737–754  Back to cited text no. 7
    
8.Tessier D, Dawson K, Tetrault JP, Bravo G, Meneilly GS. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabetic Med. 1994;11:974–980  Back to cited text no. 8
    
9.Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579  Back to cited text no. 9
    
10.Defronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:541–549  Back to cited text no. 10
    
11.Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006:CD002967  Back to cited text no. 11
    
12.Yki Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106–1118  Back to cited text no. 12
    
13.Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547–1554  Back to cited text no. 13
    
14.Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005:CD003639  Back to cited text no. 14
    
15.Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA. 2003;290:486–494  Back to cited text no. 15
    
16.Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010;33:428–433  Back to cited text no. 16
    
17.Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes. 2004;53(Suppl 3):S233–S238  Back to cited text no. 17
    
18.Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 2003;26:784–790  Back to cited text no. 18
    
19.Gerich J, Raskin P, Jean Louis L, Purkayastha D, Baron MA. PRESERVE-β: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. Diabetes Care. 2005;28:2093–2099  Back to cited text no. 19
    
20.Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, et al. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care. 2004;27:1265–1270  Back to cited text no. 20
    
21.Kristen JS, Frandsen KB, Bayer T, Muller PG. Compared with repaglinide sulfonylurea treatment in type 2 diabetes is associated with a 2.5-fold increase in symptomatic hypoglycemia with blood glucose levels <45 mg/dl. Diabetes. 2000;49(Suppl 1):A131  Back to cited text no. 21
    
22.Khan MA, St. Peter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care. 2002;25:708–711  Back to cited text no. 22
    




 

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