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Dvd.sagepub.comThe British Journal of Diabetes & Vascular Disease Avandamet
Biju Kunhiraman, William Itoua-Nganongo and Vivian Fonseca British Journal of Diabetes & Vascular Disease 2004 4: 268 The online version of this article can be found at: can be found at:
The British Journal of Diabetes & Vascular Disease
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BIJU KUNHIRAMAN, WILLIAM ITOUA-NGANONGO, VIVIAN FONSECA Abstract
A typical patient with type 2 diabetes will be on an aspirin, Type 2 diabetes mellitus is characterised by multiple an insulin sensitiser, a lipid-lowering agent and most likely, an
defects including decreased insulin mediated
ACE inhibitor. Furthermore, most patients also have hyperten- glucose disposal, higher endogenous glucose
sion and the average patient will need another two to three production mainly from liver and inadequate pancreatic
medications to reach the goal for blood pressure. Thus, patients secretion of insulin. Metformin and thiazolidinediones
faced with taking multiple drugs with escalating costs find com- (TZDs) decrease insulin resistance by different
pliance with complex regimens challenging. In the face of such mechanisms of action, and since both have the
a conundrum, a combination of medications that can reduce advantage of decreasing hyperglycaemia without
the number of pills one patient has to take can only improve increasing insulin secretion, they make an attractive
option for combination. Metformin decreases hepatic
glucose production and enhances peripheral glucose
Rationale for combination
uptake while TZDs, by acting on peroxisome
Increased glucose in type 2 diabetes is caused by insulin resis- proliferator-activated receptor-gamma (PPARγ) receptors
tance, which causes decreased insulin mediated glucose dispos- increase glucose uptake.
al, higher endogenous glucose production mainly from liver, and The combination has also been shown to improve
by inadequate pancreatic secretion of insulin.6 glycaemic control, improve insulin sensitivity and
Combination therapy is logical for type 2 diabetes as patients improve beta-cell function. The availability of the two
quite often respond poorly to monotherapy and about 50% of drugs in one pill has the potential to improve patient
patients on monotherapy will need additional treatment to compliance and decrease costs.
achieve goals about three years after initial diagnosis.5,7 In the Br J Diabetes Vasc Dis 2004;4:268–71
UKPDS, metformin was shown to decrease cardiovascular eventsin type 2 diabetes, but failed to maintain a HbA1C < 7% in most Key words: combination therapy, type 2 diabetes,
patients. Fonseca et al. have shown that nearly 30% of the patients on the combination achieved an HbA1C < 7 comparedto metformin alone.8 Since metformin and TZDs have different Introduction
mechanisms of action, both with advantages of decreasing Type 2 diabetes mellitus is a chronic progressive disease caused by hyperglycaemia without increasing insulin secretion, they make a combination of insulin resistance in the skeletal muscle, adipose an attractive option for combination,6 by targeting the underly- tissue and liver. It is also characterised by impaired pancreatic ing causes rather than the traditional approach of increasing insulin secretion. It has a variety of complications, both micro- and insulin secretion.7 Metformin decreases hepatic glucose produc- macrovascular. Various studies have shown that intensive control tion and enhances peripheral glucose uptake while TZDs of glycaemia along with blood pressure and lipids can decrease the decrease insulin resistance, by acting on the PPARγ receptors. development of these complications.1-5 In the past decade, the It has been shown that both drugs in combination decrease therapeutic options available for the treatment of type 2 diabetes fasting and post-prandial glucose better than either alone.6 The has seen the introduction of agents with novel mechanisms of effects of TZDs on insulin sensitivity despite maximum dose met- action, targeting the underlying causes, including insulin resistance formin supports the complimentary action of the combination.7 in muscle and liver, rather than just increasing insulin production.
The combination has also been shown to improve HbA1C, Monotherapy often fails and multiple drug combination therapy is decrease insulin resistance and improve beta-cell function.8 Compliance issues in diabetes
Complex regimens, although not one of the main reasons, is
stated as a reason for non-compliance, especially among young
Correspondence to: Professor Vivian A FonsecaTulane University Health Sciences Center, 1430 Tulane Ave (SL 53), New Fear of hypoglycaemia is another major compliance factor and drugs that have low propensity to cause them may lead to improved adherence to prescribed regimens.
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE Abbreviations
Traditional and nontraditional risk factors for CVD in patients peroxisome proliferator-activated receptor-gamma - abnormal fibrinolysis (fibrinogen, PAI-1) - endothelial dysfunction- markers of inflammation (CRP, TNF-α, IL-6)- homocysteine- hypercoagulation Key: ARIC = Atherosclerosis Risk in Communities study; CRP = C-reactive
protein; IL-6 = interleukin-6; PAI-1 = plasminogen activator inhibitor type-1; TNF-α = tumour necrosis factor-α United Kingdom Prospective Diabetes Study The combination of the other TZD; pioglitazone appears to be another option. However, pioglitazone is a once-a-day med- Insulin resistance
ication whereas rosiglitazone is taken twice-a-day, as is met- Insulin resistance is a recognised risk factor for CVD, in type 2 formin. The combined tablet has the same bioavailability com- diabetes and can be identified clinically as part of the metabolic pared to when the two agents are given as separate pills. Other syndrome. Patients with the metabolic syndrome meet at least potential advantages include lower cost and a better side effect three of the following criteria: TGs > 150 mg/dL (> 1.7 mmol/L), profile. A few studies from Europe have shown the combination HDL < 40 mg/dL (< 1 mmol/L), blood pressure > 130/85 mmHg, of pioglitazone and metformin or a sulfonylurea to be effective fasting blood glucose > 110 mg/dL (6.1 mmol/L), and waist cir- with no significant increase in cost.14 Studies in Wistar rats have cumference > 40 inches in males or > 35 inches in females. shown that the weight gain caused by pioglitazone can be ame- Insulin resistance along with compensatory hyperinsuli- liorated by the addition of metformin.15 Patients who were start- naemia not only contributes to hyperglycaemia in type 2 dia- ed on pioglitazone or rosiglitazone showed better effects of betes, but also plays a pathophysiologic role in a variety of other pioglitazone on lipids despite similar effects on HbA1C and metabolic abnormalities, including high levels of plasma TGs, low weight, in patients who were also concurrently on a statin.
levels of HDL-c, hypertension, abnormal fibrinolysis, and coro-nary heart disease.10,11 The metabolic syndrome is a cluster of risk Clinical efficacy
factors for CVD. Studies now show that the PPAR class of recep- Metformin is the only oral hypoglycaemic agent shown to tors are expressed in several tissues and may have implications in decrease cardiovascular events independent of glycaemia. The mechanism of action of metformin was shown by Hundal et al.12They showed that the rates of hepatic glycogenolysis, gluconeo- Advantages of a combination
genesis and glycogen cycling were two to four times higher in Metformin acts by inhibiting hepatic gluconeogenesis and helps patients with type 2 diabetes compared to healthy controls, decrease FPG and post-prandial glucose, with minimal peripher- resulting in hyperglycaemia. Metformin was shown to decrease al action, while the TZDs act to increase glucose uptake, mainly gluconeogenesis by 36%, glycogenolysis by 33% and fasting plasma glucose by about 30% in patients with type 2 diabetes. In patients whose fundamental abnormality is insulin resis- The TZDs have been shown to have beneficial effects on tance, such a combination treats the cause rather than the tradi- lipids, microalbuminuria and FFA, besides decreasing insulin lev- tional approach of increasing insulin secretion. Fonseca et al. els.7 They have also been shown to improve metabolic pathways have shown that the combination of metformin and rosiglita- influenced by insulin activity and have beneficial effects on blood zone decreases HbA1C, fasting blood glucose, and insulin resis- pressure, coagulation defects, lipid profile and beta-cell func- tance thereby improving beta-cell function, in a dose-dependent tion.16 To a lesser extent, they decrease glucose production by the manner.7 As insulin resistance is targeted, the levels of C – pep- liver. They also have positive effects on some of the non-tradi- tide and insulin decrease and glucose control improves.7,13 tional risk factors for CVD in diabetes table 1.17 The combination may also have less weight gain associated with it, due to the opposing effects these agents have on Safety of rosiglitazone and metformin
Medications being chosen for combination should have an Figure 1. TZDs and CHF
History and physical examination to establish ● Metformin and TZDs have different mechanisms of ● Metformin and TZDs have synergistic effects Oedema occurs or increases compared to baseline ● A fixed pill combination increases compliance term studies have shown a good safety profile for the combina- tion with good efficacy on glucose control.19 TZDs have been shown to increase LDL-c levels, but the increase is in the buoyant, less atherogenic LDL particles.
hypoglycaemic drugs metformin is contraindicated in patients with CHF requiring drug therapy.
Metformin can cause lactic acidosis in patients with impaired renal, pulmonary or cardiac function. A recent study showed an increase in the use of metformin and TZDs despite warnings against the same.20 The paper showed an increase from 11.2% in 1999 to 24.4% in 2001, in either drug being prescribed to of LV function- ?Stress perfusion myocardial imaging patients hospitalised with a primary diagnosis of CHF. As no safe-ty data are available in this regard, the combination should defi-nitely not be used in patients with a diagnosis of NYHA class 3 Patient selection
The ideal patients would be those who have failed monotherapywith metformin. The combination is especially suitable for Copyright 2004 American Diabetes Association patients who are obese and prone to insulin resistance and have From Diabetes Care 2004;27:260.
Reprinted with permission from the American Diabetes Association Both rosiglitazone and metformin should be used with cau- Key: BNP = brain natriuretic peptide; CCBs = calcium channel blockers;
tion in patients with evidence of CHF,21 although guidelines for CHF = congestive heart failure; CXR = chest X-ray; ECG = electrocardiogram; their use in cardiac patients are now established (figure 1). Since ECHO = echo cardio gram; EF = ejection fraction; LV = left ventricular; metformin is contraindicated in patients with renal insufficiency, MI = myocardial infarction; NSAIDs = non-steroidal anti-inflammatory drug; TZD = thiazolidinediones Avandamet® is also contraindicated in such patients. The combi-nation should be avoided in patients with a previous history ofallergic reactions to either component.
additive or synergistic effect without a decrease in efficacy. The Dosing schedule and monitoring
side effect profiles need to be at least comparable to either one The combination is available in various strengths and is used as a being used alone, if not better; and the combination of rosiglita- twice-daily pill. Patients need to be monitored for oedema, zone and metformin has not been shown to have any significant weight gain, decreasing renal function and elevated liver func- changes in steady state of either drug. Co-administration did not tion tests. Anaemia may be seen in some patients on TZDs and alter steady state pharmacokinetics and no adverse events were is thought to be due to haemodilution. Contraindications to the combination would be the same as for the individual drugs with Hypoglycaemia is always a feared complication of the treat- patients being excluded if they have hepatic and or renal impair- ment of diabetes and since neither rosiglitazone nor metformin ment, or NYHA class 3 or 4 CHF, as discussed above. augment insulin secretion, they are not expected to cause hypo-glycaemia.18 Conclusions
Smaller doses in combination of rosiglitazone and metformin Type 2 diabetes is a multifaceted syndrome that requires multiple may achieve treatment goals. The combination has been shown drug treatment. The use of combination therapy is superior to to decrease lactate levels, potentially making it safer7 and short- monotherapy in decreasing blood glucose and combining two THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE drugs in one pill may help decrease cost and improve compli- betes. Diabetes 2001;50:810-16.
11. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free ance. Since insulin resistance is a fundamental abnormality and fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide contributes to CVD, the combination of two drugs that target production. Diabetes 2000;49:1231-8.
insulin resistance by different mechanisms of action is theoreti- 12. Hundal RS, Krssak M, Dufour S et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49:2063-
cally attractive. Avandamet is such a combination and is now in 13. Gomez-Perez FJ, Fanghanel-Salmon G, Antonio BJ et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes.
Diabetes Metab Res Rev 2002;18:127-34.
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Basic Information Contact Information Mail: Multidisciplinary Science Building 203 E-Mail: RJCharn2@aol.com Internet: http://www.richardcharnigo.net Employment Professor July University of Kentucky Department of Biostatistics (College of Public Health) Department of Statistics (College of Arts and Sciences) University of Kentucky Department of Biostatistics (College o