Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, and 1,000 mg metformin XR with each treatment period separated by a 2-week course of placebo.

Patients will be assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of placebo, followed by 500 mg placebo, 750 mg, and 1,000 mg placebo with each treatment period separated by a 2-week course of metformin XR in the same increments of dosage.

Metformin hydrochloride extended release tablets in dosages of 250 mg, 500 mg, 750 mg, and 1,000 mg. Individual encapsulations of metformin will contain dosages of 250 mg or 500 mg.

The primary outcome of this portion of the study will be the global satisfaction subscale of the Treatment Satisfaction Questionnaire for Medication (TSMQ II). The TSQM II is a 12-question survey with four satisfaction domains: effectiveness, side effects, convenience and global satisfaction. Each domain is described by a single numeric score. For each of these domains the lowest possible score (less satisfaction, ie a worse outcome) is 0, the highest (more satisfaction, ie a better outcome) is 100. We report this score global satisfaction domain (ie, subscale). (Note that the global satisfaction score is not a synthesis of the various subscales associated with each domain. It is a subscale in its own right comprised of distinct questions.)

For aim 2 of this study, the primary objective is to test the hypothesis > 30% of the patients enrolled in this study are able to tolerate (continue taking) a higher-dose of metformin at 6 months than they were taking at baseline.

For aim 1, the secondary objectives are to test the hypotheses that scores on a gastrointestinal symptom questionnaire are the same between between placebo and intervention periods; that adherence is the same between periods; and that the answer to the question 'Were you taking placebo or metformin for the past two weeks' is correct no more often than would be predicted by chance. Each question in the Gastrointestinal Symptom Rating Scale (GSRS) is scored on scale from 1 to 7 with 1 being no discomfort at all and 7 being very severe discomfort. The GSRS has separate questions to separately assess each of a range of potential GI symptoms (abdominal pain, reflux, diarrhoea, indigestion and constipation). Each symptom area can be described with the mean score of its contributing questions (so that the range in each symptom area is also 1 to 7, with lower numbers being better)

Participants took their baseline medication plus escalating doses of metformin in 250 mg increments, alternating with placebo in a randomized, double-blinded fashion.

Patients were assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, and 1,000 mg metformin XR with each treatment period separated by a 2-week course of placebo.

Metformin Extended Release Oral Tablet: Metformin hydrochloride extended release tablets in dosages of 250 mg, 500 mg, 750 mg, and 1,000 mg. Individual encapsulations of metformin will contain dosages of 250 mg or 500 mg.

Patients were assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of placebo, followed by 500 mg placebo, 750 mg, and 1,000 mg placebo with each treatment period separated by a 2-week course of metformin XR in the same increments of dosage.

Placebo oral capsule: Placebo capsule

The primary outcome of this portion of the study will be the global satisfaction subscale of the Treatment Satisfaction Questionnaire for Medication (TSMQ II). The TSQM II is a 12-question survey with four satisfaction domains: effectiveness, side effects, convenience and global satisfaction. Each domain is described by a single numeric score. For each of these domains the lowest possible score (less satisfaction, ie a worse outcome) is 0, the highest (more satisfaction, ie a better outcome) is 100. We report this score global satisfaction domain (ie, subscale). (Note that the global satisfaction score is not a synthesis of the various subscales associated with each domain. It is a subscale in its own right comprised of distinct questions.)

The results from 3 participants were not analyzed as these participants were lost to follow-up or violated study protocol. Results are presented in two study arms, as reporting a separate arm for each sequence of drug and placebo exposure would have resulted in reporting individual level results, potentially compromising patient confidentiality. All patients contributed data to both arms except for 2 patients who had missing data during their placebo-exposed time.

Participants took their baseline medication plus escalating doses of metformin in 250 mg increments, alternating with placebo in a randomized, double-blinded fashion.

Patients were assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of metformin extended release, followed by 500 mg metformin XR, 750 mg, and 1,000 mg metformin XR with each treatment period separated by a 2-week course of placebo.

Metformin Extended Release Oral Tablet: Metformin hydrochloride extended release tablets in dosages of 250 mg, 500 mg, 750 mg, and 1,000 mg. Individual encapsulations of metformin will contain dosages of 250 mg or 500 mg.

Patients were assigned to take their baseline medication regimen plus 2 weeks of 250 mg per day of placebo, followed by 500 mg placebo, 750 mg, and 1,000 mg placebo with each treatment period separated by a 2-week course of metformin XR in the same increments of dosage.

Placebo oral capsule: Placebo capsule