Metformin can be used to Treat certain Type II Diabetes Patients with Mild to Moderate Impaired Kidney Function

Traditionally, use of metformin is contraindicated in patients with renal failure due to concern about lactic acidosis.

Metformin 500mg tablets (Photo credit: Wikipedia)

In December of 2014, a seminal paper critically looked at the evidence for the use of metformin in mild to moderate renal failure and concluded that, “Metformin levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2).”
The paper suggested that given the benefit of metformin to patients with diabetes, of whom up to one-quarter have some degree of renal failure, and the lack of evidence of harm, metformin should be able to be used in this group.
The paper recommended dose adjustments of metformin with maximum total daily dose in patients with mild renal insufficiency (GFR 45-60) of 2000 mg per day and in patients with moderate renal insufficiency (GFR 30-35) not to initiate therapy but that one may continue metformin with maximum daily dose of 1000 mg daily.

English: Physiology of Nephron (Photo credit: Wikipedia)

Now, the US Food and Drug Administration (FDA) is requiring labeling changes regarding the recommendations for metformin-containing medicines for diabetes to expand metformin’s use in certain patients with reduced kidney function. The current labeling strongly recommends against use of metformin in some patients whose kidneys do not work normally.

After reviewing a number of medical studies, the FDA concluded that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function and is requiring changes to the metformin labeling to reflect this new information while providing the following specific recommendations on the drug’s use in patients with mild to moderate kidney impairment:
• FDA recommends that healthcare professionals follow the latest recommendations when prescribing metformin-containing medicines to patients with impaired kidney function.
• Patients should talk to their health care professionals, if they have any questions or concerns about taking metformin.

The labeling recommendations on how and when kidney function is measured in patients receiving metformin will include the following information: 

• Before starting metformin, obtain the patient’s eGFR.
• Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m².
• Starting metformin in patients with an eGFR between 30-45 mL/minute/1.73 m² is not recommended.
• Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently.
• In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m², assess the benefits and risks of continuing treatment.  Discontinue metformin, if the patient’s eGFR later falls below 30 mL/minute/1.73 m².
• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin, if renal function is stable.
  

Generally, 90-120 ml/minute/1.73 m² of eGFR is taken as normal value. Levels below 60 mL/min/1.73 m² for 3 or more months are a sign of chronic kidney disease. A GFR lower than 15 mL/min/1.73 m² is a sign of kidney failure and requires immediate medical attention.
Hence, in addition to the level of serum creatinine, it is recommended to have the eGFR estimated in patients of T2DM before starting of Metformin or metformin in combination; also periodically measure, while on the medication.
The article was published in FDA Web site, April 8, 2016. US Food and Drug Administration. Metformin-containing drugs: Drug safety communication – revised warnings for certain patients with reduced kidney function.

Dosing Blood Pressure Control Medicines at Bed Time Reduces the risk of Stroke and T2 Diabetes Mellitus

We all prescribe medications for control of Hypertension. Most common among those are the ACE (Angiotensin Converting Enzyme) inhibitors, ARBs (Angiotensin Receptor Blocker) and Third generation β-Blocker like Nebivolol. But, seldom we advise the patients which is the preferred time to take these groups of medications. Most of the patients, conventionally, take these medicines after awakening, in the morning.

It has been observed that most susceptible people get heart attack towards dawn or early morning. One of the factors can possibly be due to the fact that blood pressure starts rising from 03 to 04 AM and gradually rises till 12 Noon.

Normally, there is a fall of systolic blood pressure more than 10% of mean day time BP reaching the zenith from 12 Mid-Night to 03-04 AM, regulated by circadian rhythm. This phenomenon is called as “Dipping.”

Alterations in these intrinsic circadian rhythms can result in the absence of the nocturnal BP decline (non-dipping). This altered pattern is commonly seen in patients with essential hypertension, several forms of secondary hypertension and disorders of the autonomic nervous system.

The clinical relevance of this phenomenon lies in the fact that non-dipping has been associated with increased frequency of hypertensive target organ damage (brain, heart and kidney), as well as cerebrovascular and cardiovascular events in hypertensive patients.

Circadian rhythms typically originate in “master oscillators” located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. How this hypothalamic rhythm is translated into changes in blood pressure is not entirely known, but the autonomic nervous system is suspected to play a role; sympathetic activity is also modulated by hypothalamic centers, and follows a circadian pattern similar to that of blood pressure.

Patients are categorized, usually based on systolic blood pressure, as extreme dippers (night–day blood pressure ratio ≤ 0.8), dippers (0.8 < ratio ≤ 0.9), non-dippers (0.9 < ratio ≤ 1.0) and reverse dippers or risers (ratio > 1.0). Reverse dipper are particularly in the risk of developing end organ damages.

A new research article published in The Diabetologia by Ramón C. Hermida, Diana E. Ayala, Artemio Mojón and José R. Fernández of University of Vigo, Campus Universitario, Vigo, Pontevedra 36310, Spain, titled as”Bedtime ingestion of hypertension medications reduces the risk of new-onset type 2 diabetes: a randomised controlled trial” has concluded that in hypertensive patients without diabetes, ingestion of ≥1 BP-lowering medications at bedtime, mainly those modulating or blocking the effects of angiotensin-II, compared with ingestion of all such medications upon awakening, results in improved ambulatory BP (ABP) control (significant further decrease of asleep BP) and reduced risk of new-onset diabetes.

Renin angiotensin pathway or RAAS. (Photo credit: Wikipedia)

Drugs that target angiotensin include angiotensin receptor blockers (ARBs), ACE inhibitors and beta blockers. These medications act through blockade of the RAAS (Rennin-Angiotensin-Aldosterone System) in kidney that causes blood vessels to constrict and blood pressure to rise. 

Angiotensin, Aldosterone and adrenaline also contribute to increased glucose (sugar) release from the liver and decreased insulin sensitivity. These factors can lead to Type 2 diabetes.

 The researchers conducted a prospective, randomised, open-label, blinded endpoint trial of 2,012 hypertensive patients without diabetes, 976 men and 1,036 women, 52.7±13.6 years of age. Patients were randomised, using a computer-generated allocation table, to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime.

During a median follow-up of 5.9 years, 171 participants developed type 2 diabetes. Patients in the bedtime, compared with the morning-treatment group, showed a significantly lower asleep mean BP and a greater sleep-time relative BP decline.
In the bedtime treated group, there was a lower-prevalence of a phenomenon known as 'non-dipping' -- in which patients' night time BP falls by less than 10% compared to daytime BP. Non-dipping occurred in 32% of bedtime-treated patients and 52% of those getting their treatment in the morning.
There was also a 57% decrease in the risk of developing new-onset type 2 diabetes in the bedtime-treated group after adjustment for the potential confounders of fasting glucose, waist circumference, mean asleep systolic BP, dipping classification and chronic kidney disease.
Specifically, the odds of type 2 diabetes dropped 61 percent for people taking angiotensin receptor blockers at bedtime compared to morning. For those on ACE inhibitors at night, the odds went down 69 percent. People on beta blockers reduced their odds of the blood sugar disease by 65 percent when they took their medicine at night, the researchers reported.
All three classes of medication were associated with a reduced risk of type 2 diabetes when taken at bedtime as the effect will be much more on liver/kidney in comparison to the waning effect at night when taken in the morning.
Let us remember to advise our hypertensive patients to take their anti-hypertensive medications at bed time, especially ARBs, ACE-Inhibitors and Nebovolol for better effect and delaying development of T2DM.