The Third Cornerstone of Treatment: Medication

Introduction

Clinical studies of controlling hyperglycemia in DMT2 have consistently concluded that therapies must be more focused on achieving a near-normal A1c. Other clinical studies have shown that such blood glucose control typically requires two or three drugs to be successful in this goal (McCall & Riddle, 2003).

Metformin (along with lifestyle management – nutritional changes and exercise) is the drug of choice when an individual with DMT2 (or pre-diabetes) is first diagnosed (barring contraindications to the drug) unless the blood glucose is so high that the initial drug of choice is insulin. Insulin is used until the blood glucose is brought to more reasonable levels at which time oral medications (typically metformin) may be used in its place. Dosing of metformin is slowly increased until blood glucose control or maximum dosing is achieved. If maximum dosing still does not provide adequate control, another drug from a different class is added and again titrated upward in terms of dosing until blood glucose control or maximum dosing is achieved. A factor that must be considered in the process, however, is tolerance of side effects.

As indicated above, some providers will add a third drug from a different class of drugs if control remains elusive. Others will add a daily injection of insulin. Eventually, insulin may be the only drug that effectively controls blood glucose, and in some cases, only through multiple daily injections of insulin.

Compliance with the DMT2 medication regimen, however, is predictably more likely if the regimen does not require insulin injections. Unfortunately, when the patient is an older person with a relatively sedentary lifestyle and firmly established eating habits, adhering to advice about obtaining regular exercise and changing how, what, and/or when one eats is often difficult.

Agents Used to Treat Blood Glucose in DMT2

Oral agents are those in the families of the sulfonylureas (first- and second-generations), the biguanides, the meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, amylin mimetics, DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors. The second-generation sulfonylureas became available in the 1980s. The incretin mimetics are the new kids on the block when it comes to treating DMT2, but there will be more on them, later.

As indicated above, the drug of choice for the initial treatment of DMT2 (provided the A1c is < 10%), along with lifestyle management is the biguanide, metformin (American Diabetes Association, 2018). If metformin is contraindicated or is not well tolerated, a second-generation sulfonylurea may be an acceptable alternative.

If the presenting A1c is > 10%, insulin, with or without oral medications is recommended as the starting treatment of DMT2 (Texas Diabetes Council, 2010). The initial dose would be calculated using the following formula: 0.1-0.25 units/kg of current body weight/day of basal or NPH insulin. If, however, the patient is thin or is elderly, the recommendation is to start low and go slow which would translate as starting with 6-10 units of insulin/day. Once-daily insulin therapy might mean basal insulin will be given as a morning dose or a bedtime dose. Or the insulin selected could be NPH insulin given prior to the evening meal.

Other recommended options are to use NPH insulin + Regular or NPH + fast-acting insulin given at a 2:1 ratio or Premix insulin (70/30 or 75/25) might be the selected once-daily dose of insulin given before the evening meal (Texas Diabetes Council, 2016). Basal insulin is to be administered subcutaneously at 24 hour intervals, so it would be administered in the morning or in the evening – upon rising or upon going to bed. The time chosen is less important than is giving the doses of basal insulin 24 hours apart. The algorithm referenced above provides specific guidelines for increasing dosages based on fasting blood glucose values.

DMT2 is characterized as a progressive disorder that includes declining control of glycemia requiring incrementally higher doses of medications and the addition of medications over time. This is often referred to as drug failure, but is thought to be due more to progressive dysfunction of the beta cells than to increasing insulin resistance (Dorkhan et al., 2006). Others have added that this drug failure was due, in part to physiological tolerance to the drug, poor adherence to recommendations for nutritional intake and exercise, or to the combined effects of other comorbid conditions, and that the resultant chronic hyperglycemia (glucotoxicity) was believed to be a factor in the loss of glycemic control (Inzucchi & Sherwin, 2007).

Loss of blood glucose control continues to be a predictable event over time even in patients treated with metformin. Considering this, health care providers should avoid "clinical inertia" when it comes to getting the patient on the correct dose of medication (oral and/or injectable) to control the blood glucose. There is a tendency to procrastinate when it comes to making the appropriate changes, which is to be avoided (Khunti, Wolden, Thorsted, Andersen, & Davies, 2013).

Research into new ways to treat diabetes has uncovered a substance, GLP-1 (glucagon-like peptide-1) which is a hormone secreted by intestinal cells in response to the ingestion of food. Such chemicals are called incretins. GLP-1 stimulates the islet cells in the pancreas to produce insulin (possible in DMT2; not possible in DMT1). It also slows gastric emptying, reduces appetite, increases one's sense of satiety, and suppresses glucagon secretion. Unfortunately, it has a very short activity period because it is degraded by the intestinal enzyme, dipeptidyl peptidase 4 (DPP-4) which works to reduce insulin synthesis and release and allows increased glucagon secretion. Clearly, this enzyme works against the goal in DMT2 of reducing blood glucose.

The first synthetic incretin, exenatide, was developed to capitalize on GLP-1 activity in the treatment of DMT2. This drug is in the category of incretin mimetics; it is a GLP-1 agonist which means that it enhances the glucose-dependent secretion of insulin by the beta cells of the pancreas. Exenatide was approved for use in the US in 2005 and is administered by subcutaneous injection. (FYI: Exenatide is a synthetic version of a hormone discovered in the saliva of the Gila monster!)

Other drugs have been developed to counteract the actions of DPP-4. These are the DPP-4 inhibitors. One might think of them as GLP-1 enhancers because the end result of the effect of DPP-4 inhibitors is an increase in GLP-1. The first oral DPP-4 inhibitor, sitagliptin which is administered orally, was approved by the FDA in October of 2006. Another in this class is saxagliptin which is also administered orally. Drug combinations are also available. One such combination is saxagliptin plus extended release metformin.

Another drug (pramlintide acetate) has been developed as a synthetic analogue of a hormone produced in the pancreas, amylin. As in the case of the natural-occurring hormone, amylin, pramlintide (administered by injection) slows gastric emptying, blocks glucagon production from the liver, and promotes a sense of gastric fullness. In these ways the drug reduces postprandial glucose elevations. This drug was approved by the FDA in 2005 to treat DMT2 and, in conjunction with insulin, may be used to treat DMT1.

Canagliflozin was approved by the Food and Drug Administration (FDA) of the United States on 03/29/13 to treat DMT2. It is not to be used to treat DMT1. Canagliflozin is representative of the group, SGLT2 inhibitors (sodium-glucose co-transporter 2 inhibitor) and is being marketed by the pharmaceutical company Janssen as Invokana®. A useful website that provides a great deal of information about this medication is https://www.invokana.com/about-invokana/what-is-invokana.

This drug works in the renal tubules by inhibiting the reabsorption of glucose from the urine. In this way, the amount of glucose excreted in the urine is increased, thereby reducing the amount of glucose in the blood. Creatinine clearance must be monitored closely in patients who take this drug. A serious adverse effect of this drug that has been documented is an increased risk for lower extremity amputations. The risk is increased in those who “have a history of amputation, heart disease or are at risk for heart disease, have had blocked or narrowed blood vessels (usually in leg), have damage to the nerves (neuropathy) in the leg, or have had diabetic foot ulcers or sores” (Invokana Safety Information, March, 2018).

A similar drug, empagliflozin (marketed by Boehringer Ingelheim Pharmaceuticals, Inc. as Jardiance®) was approved by the FDA as an effective treatment, in conjunction with diet and exercise, for type 2 diabetes. Later, on December 2, 2016, the FDA approved empagliflozin as an effective agent to reduce the risk of cardiovascular death in adults with both cardiovascular disease and type 2 diabetes mellitus.

Please see Appendix B – Summary of Drugs (Other Than Insulin) Used to Treat DMT2. The content in this appendix provides a comprehensive guide to the addition of various categories of medications to metformin when the A1c goal has not been met. The chart addresses critical factors for each category that would need to be considered by the prescriber. The categories identified on the chart include efficacy (the extent to which the medication category is predicted to reduce the A1c), risk of hypoglycemia, the effect on body weight – gain, loss, or neutral –, side effects/ adverse effects, and cost.

Of course, insulin is a very effective drug in the treatment of DMT2, though it is typically not the initial drug of choice. Insulin is the most effective drug in terms of lowering blood glucose. There is no maximum dose of insulin beyond which a therapeutic effect cannot be appreciated.

When used to treat DMT2, initial therapy is usually with intermediate- or basal insulins. But, patients on such regimens may also require before-meal treatment with short- or rapid-acting insulins. In any case, when treating DMT2, relatively large doses are required (> 1 unit/kg/day) in comparison with doses needed to treat DMT1 (initial dose is typically calculated as 0.5-0.6 units/ kg/day) due to the fact that the underlying problem in DMT2 is insulin resistance, and, in DMT1, the underlying problem is absence of endogenous insulin. Treatment with insulin leads to weight gain and is strongly associated with hypoglycemia.

The 2018 Standards of Medical Care in Diabetes of the American Diabetes Association provide an excellent resource for the diagnosis and comprehensive treatment of diabetes:

https://professional.diabetes.org/content-page/standards-medical-care-diabetes

The standard of care is to initiate treatment of persons with DMT2 with life style management (LSM) plus metformin, if at the time of diagnosis the A1c is < 10%. The dosage is gradually increased until blood glucose control has been achieved or the maximum dosage of the drug has been reached. At that time, combination therapy – adding oral agents to metformin -- is initiated as needed to obtain the desired effect: blood glucose control. What has been observed is that combination therapy allows corresponding pharmaceutical mechanisms to occur that provide a greater benefit along with the beneficial effects of reducing dosages of each oral agent, and thereby reducing side effects. As indicated above, new options are now available in the form of the incretin medications and the amylinomimetic, pramlintide, any of which can also be added to the regimen. When combination therapy begins to wane in effectiveness, intermediate or basal insulin is added. Greater and greater amounts of insulin are typically required to maintain control. Eventually, therapy moves to multiple daily insulin injections (Bloomgarden, 2007).