metformin and Headache studies

Metformin: A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)
metformin : A member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1.

Headache: The symptom of PAIN in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of HEADACHE DISORDERS.

Research Excerpts

Excerpt	Relevance	Reference
"In this PROBE design trial, people who had recent stroke (within 3 months) with pre-diabetes were randomized to either the active arm (n = 13) receiving usual care plus Metformin XR (500 mg daily increased to a total daily dose of 1500 mg) or the control group receiving only usual care (n = 13)."	9.41	Feasibility trial of metformin XR in people with pre-diabetes and stroke (MIPPS)-randomised open blinded endpoint controlled trial. ( Borschmann, K; Churilov, L; Donnan, G; Ekinci, EI; Hachem, M; Lau, LH; Price, SAL; Sumithran, P; Tabesh, M; Thijs, V; Zajac, J, 2021)
"The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS."	9.12	Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia. ( Aregawi, D; Glueck, CJ; Goldenberg, N; Golnik, KC; Sieve, L; Wang, P, 2006)
"In this PROBE design trial, people who had recent stroke (within 3 months) with pre-diabetes were randomized to either the active arm (n = 13) receiving usual care plus Metformin XR (500 mg daily increased to a total daily dose of 1500 mg) or the control group receiving only usual care (n = 13)."	5.41	Feasibility trial of metformin XR in people with pre-diabetes and stroke (MIPPS)-randomised open blinded endpoint controlled trial. ( Borschmann, K; Churilov, L; Donnan, G; Ekinci, EI; Hachem, M; Lau, LH; Price, SAL; Sumithran, P; Tabesh, M; Thijs, V; Zajac, J, 2021)
"Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain."	5.17	Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. ( Fleck, P; Rosenstock, J; Wilson, C, 2013)
"The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS."	5.12	Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia. ( Aregawi, D; Glueck, CJ; Goldenberg, N; Golnik, KC; Sieve, L; Wang, P, 2006)
" During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66."	2.78	Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. ( Barnett, AH; Charbonnel, B; Donovan, M; Fleming, D; Iqbal, N; Li, J, 2013)

Research

Studies (7)

Authors

Clinical Trials (1)

Trial Overview

Trial Outcomes

Adjusted Mean Change From Baseline in A1C Levels (Last Observation Carried Forward [LOCF])

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	2 (28.57)	29.6817
2010's	4 (57.14)	24.3611
2020's	1 (14.29)	2.80

Authors	Studies
Tabesh, M	1
Hachem, M	1
Lau, LH	1
Borschmann, K	1
Churilov, L	1
Price, SAL	1
Sumithran, P	1
Donnan, G	1
Zajac, J	1
Thijs, V	1
Ekinci, EI	1
Krüger, HJ	1
De Wet, R	1
Blumberg, LH	1
Weyer, J	1
Lemke, FG	1
Rosenstock, J	1
Wilson, C	1
Fleck, P	1
Barnett, AH	1
Charbonnel, B	1
Li, J	1
Donovan, M	1
Fleming, D	1
Iqbal, N	1
Matyjaszek-Matuszek, B	1
Lenart-Lipińska, M	1
Rogalska, D	1
Nowakowski, A	1
Glueck, CJ	1
Golnik, KC	1
Aregawi, D	1
Goldenberg, N	1
Sieve, L	1
Wang, P	1
Nagai, T	1
Tomizawa, T	1
Tonooka, N	1
Mita, Y	1
Misumi, S	1
Mori, M	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Multicenter, Randomized, Double-Blind, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin Added to Insulin Monotherapy or to Insulin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Ins[NCT00757588]	Phase 3	455 participants (Actual)	Interventional	2008-11-30	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Change from baseline: post-pre. Adjusted for baseline (value and metformin use). ANCOVA model: difference between week t and baseline values=baseline values + treatment + metformin use (NCT00757588)
Timeframe: Baseline to Week 24

Change From Baseline in 120-minute PPG Values During an MTT

Intervention	Percentage of change (Mean)
Saxagliptin, 5 mg + Insulin	-0.73
Placebo + Insulin	-0.32

An MTT is a 2-part test that measures glucose and insulin levels after an overnight fast and before ingesting a meal consisting of a nutritional drink and power bar and again at prespecified times (30, 60, 120, and 180 minutes) after the start of ingestion of the meal. (NCT00757588)
Timeframe: Baseline to Week 24

Change From Baseline in Fasting Plasma Glucose Values

Change From Baseline in Mean Total Daily Dose of Insulin (MTDDI) (LOCF)

Intervention	mg/dL (Mean)
Saxagliptin, 5 mg + Insulin	-27.2
Placebo + Insulin	-4.2

Intervention	mg/dL (Mean)
Saxagliptin, 5 mg + Insulin	-10.1
Placebo + Insulin	-6.1

Based on information recorded in the participant's daily diary. The MTDDI was calculated at every visit using the values patients recorded since the last regularly scheduled visit (minimum of 80% of days with a value). At every visit, the MTDDI was compared with the participant's baseline MTDDI (measured during a 4-week lead-in period) to identify any changes in insulin use at that visit compared with insulin use at baseline. (NCT00757588)
Timeframe: Baseline to Week 24

Change From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Meal Tolerance Test (MTT)

Intervention	Units (Mean)
Saxagliptin, 5 mg + Insulin	1.71
Placebo + Insulin	5.01

Number of Participants With Abnormal Changes From Baseline in Electrocardiogram (ECG) Results

Intervention	mg*min/dL (Mean)
Saxagliptin, 5 mg + Insulin	-4548.5
Placebo + Insulin	-718.8

"ECG abnormalities included those in nonspecific other categories (Other nonspecific ST/T, Other intraventricular conduction defect, Other, and Other rhythm abnormalities)and nonspecific findings, such as sinus bradycardia, sinus arrythmia, sinus tachycardia, poor R-wave progression, and ventricular premature contractions." (NCT00757588)
Timeframe: Baseline to Week 52

Percentage of Participants Achieving a Therapeutic Glycemic Response

Intervention	Participants (Number)
Saxagliptin, 5 mg + Insulin	15
Placebo + Insulin	11

Therapeutic glycemic response is defined as an A1C<7%. Significance was not interpreted with a p value. (NCT00757588)
Timeframe: Baseline to Week 24

Mean Changes From Baseline in Heart Rate

Intervention	Percentage of participants (Number)
Saxagliptin, 5 mg + Insulin	17.3
Placebo + Insulin	6.7

(NCT00757588)
Timeframe: Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52

Mean Changes From Baseline in Systolic and Diastolic Blood Pressure Readings

Intervention	Beats per minute (Number)
	Week 2 (n=294, 147)	Week 4 (n=293, 144)	Week 6 (n=280, 141)	Week 8 (n=290, 142)	Week 12 (n=286, 144)	Week 16 (n=278, 139)	Week 20 (n=276, 137)	Week 24 (n=273, 134)	Week 28 (n=264, 132)	Week 36 (n=261, 129)	Week 44 (n=250, 125)	Week 52 (n=246, 125)
Placebo + Insulin	-0.7	-1.0	-0.9	-0.7	0.2	-0.6	0.4	-1.0	-0.6	-0.0	-0.7	0.2
Saxagliptin, 5 mg + Insulin	-0.5	-0.5	-0.5	-0.0	0.3	-1.0	-0.5	0.0	-1.0	0.0	0.2	-0.3

(NCT00757588)
Timeframe: Baseline to Weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, and 52

Number of Participants With at Least 1 Adverse Event (AE), at Least 1 Treatment-related AE, Death as Outcome, at Least 1 Serious Adverse Event (SAE), at Least 1 Treatment-related SAE, Discontinuations Due to SAEs, and Discontinuations Due to AEs

Intervention	mm Hg (Number)
	Systolic blood pressure (Week 2) (n=294, 147)	Systolic blood pressure (Week 4) (n=293, 144)	Systolic blood pressure (Week 6) (n=280, 141)	Systolic blood pressure (Week 8) (n=290, 142)	Systolic blood pressure (Week 12) (n=286, 144)	Systolic blood pressure (Week 16) (n=278, 139)	Systolic blood pressure (Week 20) (n=276, 137)	Systolic blood pressure (Week 24) (n=273, 134)	Systolic blood pressure (Week 28) (n=264, 132)	Systolic blood pressure (Week 36) (n=261, 129)	Systolic blood pressure (Week 44) (n=250, 125)	Systolic blood pressure (Week 52) (n=246, 125)	Diastolic blood pressure (Week 2) (n=294, 147)	Diastolic blood pressure (Week 4) (n=293, 144)	Diastolic blood pressure (Week 6) (n=280, 141)	Diastolic blood pressure (Week 8) (n=290, 142)	Diastolic blood pressure (Week 12) (n=286, 144)	Diastolic blood pressure (Week 16) (n=278, 139)	Diastolic blood pressure (Week 20) (n=276, 137)	Diastolic blood pressure (Week 24) (n=273, 134)	Diastolic blood pressure (Week 28) (n=264, 132)	Diastolic blood pressure (Week 36) (n=261, 129)	Diastolic blood pressure (Week 44) (n=250, 125)	Diastolic blood pressure (Week 52) (n=246, 125)
Placebo + Insulin	2.3	0.0	1.0	2.4	2.2	1.1	1.3	-0.1	1.8	3.6	2.6	1.0	1.4	1.8	0.3	2.1	1.0	1.3	1.1	0.5	0.2	0.2	0.4	0.1
Saxagliptin, 5 mg + Insulin	-1.0	-1.2	-0.8	-0.8	-1.7	-1.2	-0.6	-1.5	-1.4	-0.7	-0.6	0.0	0.1	0.0	0.0	-0.5	-0.8	-1.1	-0.7	-1.7	-1.6	-1.2	-0.3	-0.5

An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; requires inpatient hospitalization; or prolongs existing hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment. (NCT00757588)
Timeframe: Baseline to Week 52, continuously

Number of Participants With Marked Laboratory Abnormalities During the 24-Week ST + 52-Week LT Treatment Period

Intervention	Participants (Number)
	At least 1 AE	At least 1 treatment-related AE	Deaths	At least 1 SAE	At least 1 treatment-related SAE	Discontinuations due to SAEs	Discontinuations due to AEs
Placebo + Insulin	108	34	0	13	0	0	3
Saxagliptin, 5 mg + Insulin	202	56	2	25	3	4	9

"Marked abnormality=a laboratory value lying outside the predefined criteria and more extreme (farther from the limit)on-treatment than at baseline. ULN=upper limit of normal; LLN=lower limit of normal; prx=pre-RX=pretreatment.~Criteria 1: if prx=0 use >=2, if prx=0.5 or 1 use >=3, if prx=2 use 4." (NCT00757588)
Timeframe: Baseline and during and up to 14 days after last dose of study drug (in Week 52)

Percentage of Participants With Reported and Confirmed Hypoglycemia

Intervention	Participants (Number)
	Hemoglobin <8 g/dL (n=300; 150)	Hematocrit <0.75*prx (n=300; 150)	Platelets <50*10^9 c/L (n=297; 145)	Platelets >1.5*ULN (n=297; 145)	Leukocytes <2*1000 c/uL (n=300; 150)	Neutrophils <1*1000 c/uL (n=296; 150)	Eosinophils >0.9*1000 c/uL (n=296; 150)	Lymphocytes <=0.75*1000 c/uL (n=296; 150)	Alkaline phosphatase >3*prx & >ULN (n=302; 150)	Alkaline phosphatase >1.5 ULN (n=302; 150)	Aspartate aminotransferase >3* ULN (n=298; 148)	Aspartate aminotransferase>5* ULN (n=298; 148)	Aspartate aminotransferase >10*ULN (n=298; 148)	Aspartate aminotransferase >20*ULN (n=298; 148)	Alanine transaminase >3*ULN (n=300; 148)	Alanine transaminase >5*ULN (n=300; 148)	Alanine transaminase >10*ULN (n=300; 148)	Alanine transaminase >20*ULN (n=300; 148)	Bilirubin, total >2 mg/dL (n=301; 150)	Bilirubin, total >1.5*ULN (n=301; 150)	Bilirubin, total >2*ULN (n=301; 150)	Blood urea nitrogen >2*prx & >ULN (n=302; 150)	Creatinine >2.5 mg/dL (n=303; 150)	Glucose, serum fasting <50 mg/dL (n=0; 0)	Glucose, serum fasting >500 mg/dL (n=0; 0)	Glucose, serum unspecified <50 mg/dL (n=0; 0)	Glucose, serum unspecified >500 mg/dL (n=0; 0)	Glucose, plasma fasting <50 mg/dL (n=301;150)	Glucose, plasma fasting >500 mg/dL (n=301;150)	Glucose, plasma unspecified <50 mg/dL (n=272; 133)	Glucose, plasma unspecified >500 mg/d (n=272; 133)	Sodium, serum <0.9*prx & <=130 mEq/L (n=302; 150)	Sodium, serum >1.1*prx & >=150 mEq/L (n=302; 150)	Potassium, serum <0.8 prx &<=3.2 mEq/L(n=300; 148)	Potassium, serum >1.2*prx&>= 6.0 mEq/L(n=300; 148)	Chloride, serum <90 mEq/L (n=302; 150)	Chloride, serum >120 mEq/L (n=302; 150)	Albumin <0.9*LLN; if prx	Creatine kinase >5*ULN (n=301, 148)	Uric acid >1.5*ULN; if prx >ULN, >2 (n=0,0)	Protein urine (see criteria 1) (n=297,146)	Blood urine (see criteria 1) (n=297; 146)	Red blood cells urine (see criteria 1) (n=53; 31)	White blood cells urine (see criteria 1)(n=115;53)
Placebo + Insulin	0	2	0	0	1	0	7	2	1	5	0	0	0	0	3	0	0	0	0	1	0	7	0	0	0	0	0	0	1	1	1	0	0	1	8	0	0	0	2	0	3	2	3	10
Saxagliptin, 5 mg + Insulin	2	2	0	0	0	1	9	3	2	10	2	1	0	0	5	1	0	0	0	0	0	5	0	0	0	0	0	5	0	5	1	1	0	3	8	1	0	1	6	0	8	14	8	35

Confirmed hypoglycemia=fingerstick glucose measurement of ≤50 mg/dL with associated symptoms/ (NCT00757588)
Timeframe: Baseline to Week 52

Shift in Absolute Lymphocyte Counts From Baseline to Selected Visits (LOCF)

Intervention	Percentage of Participants (Number)
	Reported	Confirmed
Placebo + Insulin	24.5	6.6
Saxagliptin, 5 mg + Insulin	19.4	7.6

Absolute lymphocyte count=value*10^3 c/uL (NCT00757588)
Timeframe: Baseline and Weeks 24 and 52

Shift in Platelet Counts From Baseline to Selected Visits (LOCF)

Intervention	Participants (Number)
	Baseline <= 0.75; Week 24 <= 0.75	Baseline <= 0.75; Week 24 >0.75- <= 5.00	Baseline <= 0.75; Week 24 >5.00	Baseline >0.75- <= 5.00; Week 24 <= 0.75	Baseline >0.75- <= 5.00; Week 24 >0.75- <= 5.00	Baseline >0.75- <= 5.00; Week 24 >5.00	Baseline >5.00; Week 24 <= 0.75	Baseline >5.00; Week 24 >0.75- <= 5.00	Baseline >5.00; Week 24 >5.00	Baseline <= 0.75; Week 52 <= 0.75	Baseline <= 0.75; Week 52 >0.75- <= 5.00	Baseline <= 0.75; Week 52 >5.00	Baseline >0.75- <= 5.00; Week 52 <= 0.75	Baseline >0.75- <= 5.00; Week 52 >0.75- <= 5.00	Baseline >0.75- <= 5.00; Week 52 >5.00	Baseline >5.00; Week 52 <= 0.75	Baseline >5.00; Week 52 >0.75- <= 5.00	Baseline >5.00; Week 52 >5.00
Placebo + Insulin	0	2	0	0	148	0	0	0	0	0	2	0	0	147	1	0	0	0
Saxagliptin, 5 mg + Insulin	0	0	0	1	293	1	0	0	1	0	0	0	0	295	0	0	0	1

Platelet count=value*10^9 c/L (NCT00757588)
Timeframe: Baseline and Weeks 24 and 52

Intervention	Participants (Number)
	Baseline <= 100; Week 24 <= 100	Baseline <= 100; Week 24 >100 - <= 600	Baseline <= 100; Week 24 >600	Baseline >100 - <= 600; Week 24 <= 100	Baseline >100 - <= 600; Week 24 >100 - <= 600	Baseline >100 - <= 600; Week 24 >600	Baseline >600; Week 24 <= 100	Baseline >600; Week 24 >100 - <= 600	Baseline >600; Week 24 >600	Baseline <= 100; Week 52 <= 100	Baseline <= 100; Week 52 >100 - <= 600	Baseline <= 100; Week 52 >600	Baseline >100 - <= 600; Week 52 <= 100	Baseline >100 - <= 600; Week 52 >100 - <= 600	Baseline >100 - <= 600; Week 52 >600	Baseline >600; Week 52 <= 100	Baseline >600; Week 52 >100 - <= 600	Baseline >600; Week 52 >600
Placebo + Insulin	0	0	0	1	143	0	0	0	0	0	1	0	0	144	0	0	0	0
Saxagliptin, 5 mg + Insulin	0	0	0	1	296	0	0	0	0	0	0	0	2	295	0	0	0	0

Article	Year
Feasibility trial of metformin XR in people with pre-diabetes and stroke (MIPPS)-randomised open blinded endpoint controlled trial. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2021, Volume: 86 Topics: Adult; Aged; Australia; Delayed-Action Preparations; Feasibility Studies; Female; Headache; Humans;	2021
Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes, obesity & metabolism, 2013, Volume: 15, Issue:10 Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitor	2013
Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clinical drug investigation, 2013, Volume: 33, Issue:10 Topics: Adamantane; Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV	2013
Exenatide twice daily versus insulin glargine for the treatment of type 2 diabetes in Poland - subgroup data from a randomised multinational trial GWAA. Endokrynologia Polska, 2013, Volume: 64, Issue:5 Topics: Administration, Oral; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Sch	2013
Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia. Translational research : the journal of laboratory and clinical medicine, 2006, Volume: 148, Issue:5 Topics: Adolescent; Adult; Body Mass Index; Body Weight; Combined Modality Therapy; Diet, Reducing; Female;	2006

Article	Year
Atypical presentation of Crimean-Congo haemorrhagic fever: Lessons learned. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 2019, Jan-31, Volume: 109, Issue:2 Topics: Acidosis; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Diagnosis, Differential; Dr	2019
Diabetes mellitus with left transverse sinus thrombosis and right transverse sinus aplasia. Diabetes research and clinical practice, 2001, Volume: 51, Issue:1 Topics: Aged; Aspirin; Cerebral Angiography; Cranial Sinuses; Diabetes Mellitus, Type 2; Diabetic Angiopathi	2001

metformin and Headache