Can combined oral therapy improve muscular fitness?

Combined thiazolidinedione–metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle
Original source: Diabetologia Volume 52, Number 1
Authors: N. Temofonte, M. P. Sajan, S. Nimal, T. Pastoor, C. Fumero, L. Casaubon, J. L. Powe, M. L. Standaert1, and R. V. Farese (corresponding author)
Publication date: January, 2009
DOI (digital document ID): DOI: 10.1007/s00125-008-1180-z
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
Impaired insulin responses in Type 2 diabetes can make it difficult for glucose to get to muscles, where they are needed. It is believed that this is because certain insulin-activated protein enzymes (atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt)) are not as thoroughly activated as they should be. Both metformin and thiazolidinediones (a class of oral diabetes-management drugs that includes rosiglitazone (Avandia) and pioglitazone (Actos)) improve this deficiency. The investigators wanted to know if adding both drugs together would create an even greater improvement.

Combined metformin-thiazolidinedione therapy was administered to Type 2 test ubjects for 5-6 weeks and the results measured. The investigators observed improved glucose movement and improved insulin-induced activity of four muscle signalling factors (insulin receptors plus two protein kinases). Despite this improved activity, the levels of aPKC in muscle tissues were not improved.

Because of the improvement in the four signalling factors, the investigators consider this test successful.

Reliability:
The number of patients tested was not available in the abstract, nor was any CONSORT statement, so it's difficult to tell whether the sample size was large enough to counteract small-sample skew. Several of the investigators are associated with a Veteran's Administration (VA) center. VA patients often get the worst possible levels of care, so it is hard to tell how far along the subjects' T2 had progressed, or how well it had been treated before the test. That we are looking at combined therapy and it is being called "therapeutically useful" even though depressed muscular aPKC levels were not affected by the treatment suggests that this is the sort of experiment that would be funded by a drug manufacturer, with an eye towards pushing more expensive drugs (such as Avandamet, a combination of Avandia and metformin) on the T2 public.

Practical Applications:
Improved muscular uptake of glucose could improve physical performance, and with it, positive incentives toward exercise. This could result in T2 patients being more interested in exercising, and thereby, improving both physical fitness and insulin sensitivity.

This synopsis was based on the abstract only.

Effects of adding a second drug to Metformin

Outcomes of adding second hypoglycemic drug after metformin monotherapy failure among type 2 diabetes in Hungary
Original source: Health and Quality of Life Outcomes 2008, 6:88
Authors: Gyorgy Jermendy, Diana Erdesz, Laszlo Nagy, Don Yin, Hemant Phatak, Sudeep Karve, Samuel Engel and Rajesh Balkrishnan (corresponding author)
Publication date: 31 October 2008
DOI (digital document ID): 10.1186/1477-7525-6-88
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors' goal is to determine how well patients' blood glucose levels are controlled, and how the patients felt about their quality of life with diabetes, when metformin was not sufficient to control their diabetes and a second drug was added. The medical records of patients who had been on two oral diabetes drugs for at least a year were followed back for at least one year when they were on the two drugs, and going back as far as six months before the second drug was added. Other medical conditions that might affect the choice of medications, or that might need different medications, were tagged.

The goal of diabetes care was to achieve an HbA1c of under 6.5%. HbA1c is a long-term measure of average blood glucose levels; it is believed that sustained high blood glucose levels are the cause of many of the complications of diabetes. One issue that complicates this goal is that the HbA1c level includes the effects of unusually or dangerously low blood glucose -- hypoglycemia.

414 patients, average age 60 years, participated in this survey, in which they were asked about hypoglycemic incidents, satisfaction with their treatment, and overall health-related quality of life (HRQoL).

Hypoglycemic episodes were ranked as mild (little disruption to activities), moderate (requiring the to interruption of normal activities), or severe (requiring immediate medical assistance). The patients were also asked to report any swelling, weight gain, and digestive discomfort that might have occurred since starting the second drug. They were also given a standardized questionnaire to determine whether or not they took one, or both, drugs as prescribed.

27 percent reported hypoglycemic incidents, one third of that group reporting at least one moderate or severe hypoglycemic incident. Three-quarters of the patients did not meet their HbA1c goal after a year of therapy; many blamed their weight for this, though the surveys suggest it is more likely that this failure was because they were not taking their medications correctly. Reasons for not taking medications included side effects and the belief that the medications would cause them to gain weight. Patients who did not get their HbA1c below 6.5% were as a whole heavier than those who reached the goal, and they were less likely to be satisfied with the change in treatment. The participants felt that hypoglycemic incidents reduced their health-related quality of life; also, the longer they had diabetes, the lower their self-reported HRQoL.

Reliability:
The group of patients examined was relatively small, and because the individuals reported their issues themselves, it is possible that some did not admit to not using their drugs correctly, or to other issues that might affect the results of their care.

The results were published in a peer-reviewed journal, and the effectiveness of oral diabetes drugs is a hot issue. This study shows some possible reasons for why dual-drug therapy is not always successful.

It is important to note that all but one of the authors works for Merck, either as a direct employee or a paid consultant. Merck is the manufacturer of sitagliptin (Januvia), which is in a different class of oral diabetes drug from those used in the study (DP-4 inhibitors). The failure rates of both sulfonylurea and thiazolidinedione drugs used in the study could be used to build a case for the preferential use of Merck drugs Januvia and Janumet (Januvia plus Metformin) for diabetes management, which would be very profitable for Merck. Merck paid for the study.

Practical Applications:
The care protocols recently issued by both the American Diabetes Association and the European Association for the Study of Diabetes suggest either adding a sulfonylurea (a class of drug which helps the pancreas make more insulin) or moving directly to insulin injections if metformin by itself does not provide effective results. While some second-tier drugs such as Actos and Byetta were mentioned, the use of these and other classes of oral diabetes drugs (including DP-4 inhibitors such as Januvia) were considered more expensive and not as well-tested.

Another issue to consider is that the time-frames for changing ineffective therapy are much shorter in the current recommendations than those followed by the doctors in this study. Since diabetes is a progressive disease, it is possible that by the time the second medication was added, the disease had progressed too far for that medication to be effective.

For further reading:
New Major Changes in Recommendations for the Treatment of Type 2 Diabetes by ADA and EASD -- a synopsis of the new treatment recommendations from Diabetes In Control
Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy -- the abstract of the new treatment protocols, as published in Diabetologia

This synopsis was based on the entire article.