Combination Therapy
in Type 2 Diabetes
Combination Therapy in Type 2 Diabetes

Dr. J. R. Conway, Diabetes Clinic, Smiths Falls, K7A 2H6

17 April 2003 Note: Numbers in parentheses refer to slide numbers of this presentation (click here to download the presentation).

In order to understand and rationally treat diabetes, we need to understand the Pathophysiology. Years or even decades before the development of diabetes, the susceptible individual develops progressive Insulin Resistance (3) initially the pancreas responds by producing increasing amounts of insulin (hyperinsulinemia) sufficient to compensate for the increasing insulin resistance and glucose levels remain normal. After a decade if increasing insulin resistance and insulin levels; the pancreas reaches maximum output and further increases in Insulin Resistance do not result in increases in insulin production so in times of stress such as after meals when insulin need is greatest, enough insulin cannot be produced and there is insulin deficiency which in turn leads to increased post prandial glucose levels and Impaired Glucose Tolerance (IGT). As time goes on, the ability of the pancreas to produce insulin further deteriorates as Beta Cell Dysfunction progresses. Thus we start with predominantly Insulin Resistance and about the time that diabetes is diagnosed we develop insulin deficiency which progresses until years after the diagnosis of diabetes it becomes the primary defect. In order to rationally treat the diabetes we need to know what stage the patient is in. From the early stages of insulin resistance, all the way through to the stages Beta Cell Dysfunction , lifestyle measures of exercise, weight loss and diet offer effective prevention of the development of Type 2 Diabetes. After development of insulin deficiency and Type 2 Diabetes the same lifestyle measures are the cornerstone of treatment (3a). In the early stages of Diabetes, when Insulin Resistance predominates, Metformin and/or the Thiazolidenediones are rational and effective treatment choices. (3b) Indeed Metformin in the Diabetes Prevention Study as well as the Thiazolidenedione Troglitazone were effective in prevention of Type 2 Diabetes. If these medications are not enough to achieve glycemic control then in the early stages when the pancreas can be stimulates to produce more insulin the insulin Secretagogues (3c) may be effective in controlling glucose levels by stimulating insulin production. As insulin deficiency progresses, the Secretagogues become less effective and insulin treatment is needed (3d). Generally complementary treatments are added to each other, thus we may start with Metformin, add an Insulin sensitizer, then an insulin secretagogue. As insulin treatment is needed, the insulin Secretagogues may become less effective and ultimately provide little benefit so they would be removed from the treatment plan.

Each class (4) of treatment agent has the potential to lower A1c about 1-1.5% (except Acarbose which only lowers A1c about .5%). If initial A1c is above 9% (5) it is therefore recommended to start 2 agents at the same time. (6) Further therapy is added rather than substituted until glycemic control goals are reached (7). Early aggressive treatment is needed to reach treatment goals within 6 months. The experience of the UKPDS (8) showed us that to achieve treatment goals most patients require multiple medications. It is frequently preferred (9) to treat with sub maximal doses of several medications than to increase to maximal dose of each medication before adding another because we generally get 75% of the maximal effect with 50% of the maximal dose and as we increase the dose, side effects may increase more rapidly than therapeutic effect this example illustrates the dose response with metformin, similar curves are seen with other classes of oral hypoglycemic agents, the point is that we get the most benefit from several medications at sub maximal doses and there is no point and indeed there is usually a disadvantage in giving more than the maximal recommended dose. There are different mechanisms of lowering glucose (10) and we take advantage of these to develop an individual plan of treatment that addresses the most significant defects.

The classes of medications that we have for the treatment of diabetes are (in order of preference), the Biguanides (Metformin), the major mechanism of action is to decrease glucose production by the liver (11), it has the advantage (12) of decreasing insulin resistance, is safe and does not cause weight gain, but (13) the drug has to be titrated up gradually because of GI side effects, should not be used in renal failure or dehydration because of risks of lactic acidosis.

Thiazolidenediones (Actos and Avandia) directly reduce Insulin Resistance (14) by increasing glucose uptake into muscle and fat, they have the advantage of directly affecting insulin resistance (15), are usually dosed once a day and have beneficial effects on lipids as well as fat distribution. Disadvantages are (16), delayed onset of action because of their unique mechanism of stimulating gene expression, some potential for fluid retention and weight gain which precludes their use in patients with or at risk for congestive cardiac failure. An earlier member of the class (Troglitazone) had problems with liver toxicity but the newer members of the class have not manifested this tendency although periodic liver function testing is still recommended for the first year of use. This class of drugs is fairly new so we do not have much long term data although early reports (Einhorn D et al, Clin Ther 2000, 22,12) have shown durability of effect for over 72 weeks suggesting that the inevitable decline in glycemic control over time (17) with conventional therapy used in the UKPDS may be overcome with this new class of drug and there may be some preservation of pancreatic function. This study shows (18) that in combination with sulphonylurea we see that it takes 16 weeks to realize the full effect of the TZD Pioglitazone on A1c but that the hypoglycemic effect is stable for at least 40 weeks with no rebound. We see similar stability in A1c (19) lasting 72 months with the combination of Pioglitazone with metformin

Insulin Secretagogues act by stimulating the pancreatic beta cell to increase insulin production. There are the long acting Secretagogues, the Sulphonylureas (20) which have the advantage (21) of correcting the fundamental defect of insulin deficiency, they are usually rapidly effective but may be associated with high rates of hypoglycemia (22) and weight gain. With Glyburide, the most commonly used sulphonylurea, rates of hypoglycemia are particularly high in the elderly and third generation products such as Gliclazide or Glimepiride may be preferred as they cause less hypoglycemia. In the elderly or those with irregular eating habits, the Meglitinides (Repaglinide or Nateglinide) have very short stimulatory action on the beta cell and may reduce (though not eliminate) the risk of hypoglycemia.

Insulin can be used to correct the Insulin Deficiency that is present in all diabetics. It is a logical treatment because it treats a fundamental defect (23) and it can be used to control glycemia in virtually all patients. It can overcome glucose toxicity and thus improve pancreatic function. There are many different insulins from the short acting insulin analogues such as Humalog which is almost immediately effective and has a 2 hour action to cover the post prandial insulin need to the long acting Ultralente which may provide for insulin needs for 24 hours. In type 2 diabetes, insulin is usually started as a bedtime dose of NPH insulin to signal the liver to switch off nighttime glucose formation, thus improving fasting glucose levels. The disadvantages of insulin (24) are the need for injections which both physicians and patients are often reluctant to start. Hypoglycemia may be a problem and weight gain is common. As diabetes progresses and endogenous insulin production declines, we come to the point where round the clock insulin support is needed. At this point we may reduce oral sulphonylureas or other secretagogues as there is very little beta cell function for these drugs to stimulate.

Alpha Glucosidase Inhibitors (Acarbose) inhibit the enzyme (25) that splits disaccharides and polysaccharides into monosaccharides that can be absorbed across the intestinal border into the blood stream, since they slow the absorption of carbohydrates, the compromised pancreas has longer to secrete the insulin needed to deal with the rise in glucose levels and post prandial hyperglycemia is decreased. The advantage of these drugs (26) is that they are safe and do not cause weight gain; but, on the other hand (27) they have a very modest (0.5%) effect on A1c and frequently cause GI side effects, particularly with a high carbohydrate diet.

In the past, the treatment paradigm (28) was to start with lifestyle measures, wait a few months and reassess . If we did not achieve treatment goals then we would start monotherapy, wait a few months, increase the dose of the monotherapy, wait a few more months and add another agent. It could take 18 months or more to achieve control. We have now realized that if A1c is greater than 9% we will not achieve targets on Monotherapy alone so we will start combination therapy together with lifestyle changes in order to achieve glycemic control more rapidly. Respecting the pathophysiology of the disease process we need to choose complementary therapies that address the dual defects (29) of Insulin Resistance and Insulin Deficiency. If we are to make an impact on the diabetes epidemic we need to treat early, aggressively and with logical combination therapy (30) . The prevalence of type 2 diabetes is increasing , the family physician is the first line of defense and if we wish to decrease the morbidity and mortality of this disease we must be aggressive and use early combination therapy to control hyperglycemia as it is the glucose level (31) that determines the incidence of microvascular and macrovascular complications. We now have a range of treatment options available to treat hyperglycemia while avoiding hypoglycemia. The Thiazolidenediones are new novel agents that treat insulin resistance and may preserve beta cell function.


Einhorn D et al, Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes. Clin Therapeutics 2000; 22,12:1395-1409

Hanefeld M et al. Exp Clin Endocrinol Diabetes 2000; 108 (suppl 2):S256-66

Harris S et al, Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2)

UKPDS group. Intensive blood glucose control with sulphonylurea or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853

Turner R et al. Glycemic control with diet, sulphonylurea, metformin or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-2013