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.

Can metformin help Type 1 diabetics?

Effect of Adjunct Metformin Treatment in Patients with Type-1 Diabetes and Persistent Inadequate Glycaemic Control. A Randomized Study
Original source: PLoS ONE 3(10): e3363
Authors: Søren Søgaard Lund (corresponding author), Lise Tarnow, Anne Sofie Astrup, Peter Hovind, Peter Karl Jacobsen, Amra Ciric Alibegovic, Ida Parving, Lotte Pietraszek, Merete Frandsen, Peter Rossing, Hans-Henrik Parving, Allan Arthur Vaag
Publication date: October 9, 2008
DOI (digital document ID): 10.1371/journal.pone.0003363
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Despite intensive insulin use, many people who have had Type 1 (autoimmune) diabetes for a long period of time have trouble maintaining adequate glucose control and achieving an HbA1c of under 7%, which is considered a threshold beneath which the risk of developing complications of diabetes is reduced. There are a number of reasons -- physiological (medical), environmental, and psychological -- for poor control. One of the physiological reasons may be the development of insulin resistance over time. This study looks at the potential for adding the use of metformin -- an initial drug of choice in treating Type 2 (metabolic) diabetes (which often includes insulin resistance) -- to the use of insulin to improve blood glucose control in Type 1 diabetes.

The study included 100 Type 1 diabetes patients with poorly-controlled blood glucose levels (defined as HbA1c over 8%). A one-month period in which all of them received identical placebo pills was followed by a three-week period in which the pills of half of the patients was gradually changed to include 1000 mg metformin, twice daily. The other patients continued to receive placebo pills. The patients were followed at one- to three-month intervals, for a period of a year after maximum/target dose was achieved.

The study was conducted as a double-blind study, which means that neither the investigators nor the patients knew who was taking metformin and who was not.

At each clinic visit before and during the study, patients were tested for HbA1c, c-peptide levels (a protein used as an indicator of remaining beta-cell function), and blood glucose level. Their body mass index (BMI -- a comparison of weight to height) was also measured. They were asked to estimate the average of the blood glucose measurements they took themselves at home. They were also requested to report serious adverse effects (including life-threatening events requiring hospitalization, or which resulted in persistent or significant loss of physical abilities, or which caused an adverse reaction due to a birth defect, and hypoglycemic events which resulted in unconsciousness or which required the intervention of a third party) and minor adverse effects (including hypoglycemia mild enough for the patient to be able to treat himself). They were also asked to report any changes to their insulin prescriptions and treatments (change of type of insulin, number of injections per day, sites used, and dosage).

In addition to analyzing the HbA1c measurements of the entire groups (metformin and placebo), researchers counter-checked changes in HbA1c with changes in patient weight and insulin dosage. They also analyzed the measurements from overweight and obese patients separately from those of normal weight, and the results from those taking higher amounts of insulin daily from those taking smaller amounts, since insulin resistance is often treated with higher doses of insulin; it is also associated with overweight and obesity.

The results of the analysis showed no significant changes in HbA1c level for either group. However, the metformin users lost, on average, a little more than a kilogram of body weight and were able to reduce their daily insulin usage by, on average, 0.03 units per kilogram of body weight. By comparison, those patients on placebo did not lose weight and, on average, needed to increase their insulin usage by 0.03 units per kilogram of body weight. (This corresponds to average total daily insulin use of 3 units less per day for the metformin group, and about 2.5 units more per day for the placebo group.)

The results of this study were compared to the results of previous studies, and the strengths and limitations of both this study and those were examined.

Reliability:
The authors are professionals in the fields of endocrinology and diabetes care, associated with accredited institutions. The results were published in a peer-reviewed journal.

The study size was small, so there is some potential for skew.

The use of double-blinding and placebos removed the variables of being able to attribute all good effects to the use of the drug, as well as that of all positive effects being due to the suggestion of the pills being effective.

The duration of the study was long enough to determine whether metformin would have any effect on HbA1c; however, the reduction in insulin use among the metformin patients may have counteracted the drug's effects on lowering HbA1c. The authors note that had they specified that the patients not drop their insulin dosages, there may have been a greater risk of serious hypoglycemic events.

Practical Applications:
The authors suggest that the mild weight reduction and apparent improved insulin sensitivity among the patients treated with metformin may lower these patients' diabetes-related cardiovascular risks; however, metformin does not appear to be a useful tool for improving glycemic control in patients with long-duration Type 1 diabetes.


This synopsis was based on the entire article.

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.